Causes of Substance Abuse

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CAUSES OF SUBSTANCE ABUSE

This section contains articles on some of the many factors thought to contribute to substance use, abuse, and dependence. It includes discussions of Drug Effects and Biological Responses, Genetics Learning, and an article on the Psychological (Psychoanalytic) Perspective. Sociocultural causes and Vulnerability, are discussed in several articles throughout the Encyclopedia, for example, Ethnicity and Drugs, Families and Drug Use, Poverty and Drugs. See also the article Disease Concept of Alcoholism and Drug Addiction and the section on Vulnerability.

Drug Effects and Biological Responses

Although many indirect factors lead to an individual abusing drugs, a person's response to the effects of the drugs themselves contribute both to their use and abuse. These drug effects should be considered in relation to four phases of drug use: (1) initiation-consolidation, (2) maintenance, (3) repeated withdrawal and relapse, and (4) postwithdrawal. During the initiation-consolidation phase, behaviors that lead to the taking of a drug are gradually strengthened through operant and classical conditioning processes and by biochemical changes in the brain. The drug effects include a cascade of discriminative or internally appreciated drug cues (i.e., subjective effects). The presence of these cues often leads to associated autonomic responses and reports of urges in humans. These responses and urges may result in an unfolding of a sequence of behavioral and physiological events leading to continued drug consumption.

After a pattern of chronic drug use is established, individuals may become tolerant to certain effects of a drug. In addition, they may experience withdrawal effects when they stop taking a drug. Withdrawal effects are often opposite to the drug-induced state and usually involve some form of dysphoriaa state of illness and distress. Over time, withdrawal effects become associated with stimuli in the environment, as was the case for the euphoric and other direct effects of the drug. Because of operant and classical conditioning processes, these associated stimuli can then produce conditioned effects that are often characterized as urges or cravings, and that may trigger relapse.

The underlying Neurotransmitter systems within the brain, subserving these behavioral features of drug effects, are just beginning to be understood. Early Research on the neural substrates of reward in general used electrical brain stimulation as the reward. For example, Olds (1977) found that rats would press a lever to receive a brief electrical pulse to the hypothalamus; rats would press this lever to such an extent that they did not engage in consummatory reward activities such as eating and drinking. Subsequent research indicated that activation of certain systems in the brain, namely the mesolimbic and nigrostriatal dopaminergic systems, were most sensitive to brain stimulation reinforcement. Several theories have been suggested to explain the importance of the brain reward system for the survival of species (Conrad, 1950; Glickman & Schiff, 1967; O'Donahue & Hagmen, 1967; Roberts & Carey, 1965).

Further research demonstrated that most drugs of abuse lower the threshold for this brain stimulation reward, thus suggesting that such drugs may activate the same, or similar, reward pathways (see Koob & Bloom, 1988). As will be seen, furthermore, the reinforcing effects of the drugs themselvesthat is, effects that lead individuals to take the drugsare directly mediated by these Reward systems. The fact that many drugs induce activation of these systems may indicate a mechanism underlying the addiction-related effects of drugs of abuse.

COCAINE AND OTHER STIMULANTS

Cocaine is an indirect catecholamine agonist that acts by blocking the reuptake of monoamines, including Dopamine (DA), Norepinephrine (NE), and serotonin (5-HT). During the process of reuptake, the previously released neurotransmitter is actively transported back from the synaptic cleft into the presynaptic terminal of the neuron where the neurotransmitter was produced and released (Pitts & Marwah, 1987). In contrast to cocaine, Amphetamine acts not only by inhibiting uptake, but also by releasing catecholamines from newly synthesized storage pools from the presynaptic terminal of the neuron (e.g., Carlsson & Waldeck, 1966).

Amphetamine and cocaine are both potent Psy-Chomotor stimulants. They produce increased alertness and energy and lower Anxiety and social inhibitions. The acute reinforcing actions of the stimulants are primarily determined by their augmentation of DA systems. With prolonged consumption: (1) acute Tolerance becomes substantial, and (2) the individual starts to regularly consume higher and many more doses if the resources are available. Over time, in high-dose regimens, the behavioral pattern of use becomes stereotyped and restricted. In settings of low availability, the individual focuses on the acquisition and consumption of the drug. These effects of stimulants occur within weeks or months of continued use. The individual may also start "bingeing" during this period. A binge is characterized by the read-ministration of the drug approximately every ten to twenty minutes, resulting in frequent mood swings (i.e., alternations of highs and lows). Cocaine binges typically last twelve hours, but may last as long as seven days.

It has been proposed that cocaine abstinence consists of a three-phase pattern: crash, With-Drawal, and extinction (Gawin & Kleber, 1986; Gawin & Ellinwood, 1988). The crash phase immediately follows the cessation of a binge and is characterized by initial depression, agitation, and anxiety. Over the first few hours, drug craving is replaced by an intense desire for sleep. During this time, the individual may use Alcohol, Benzodiazepines, or Opiates to induce sleep. Following the crash, hypersomnolence (excessive sleep) and hyperphagia (excessive appetite) develop. Following the first few days of hypersomnolence and hyperhagia, other symptoms emerge that are the opposite of the effects of cocainewithdrawal symptoms. During this withdrawal period, which lasts three to ten days, individuals experience decreased energy, limited interest in their environment, and anhedonia. They are also strongly susceptible to Relapse and starting another binge cycle (Gawin & Ellinwood, 1988; Gawin & Kleber, 1986; Jaffe, 1985). This phase is followed in time by the extinction phase, in which relapse to cocaine use is prevented. During the extinction phase, brief periods of drug Craving also occur. These episodes of craving are thought to be triggered by conditioned stimuli that were previously associated with the drug. If the individual experiences these cues without the associated drug effectsthat is, resists relapsethen the ability of these cues to elicit drug cravings should diminish over time, which in turn should lessen the probability of relapse (Gawin & Ellinwood, 1988).

As already noted, acute administration of cocaine produces profound inhibition of dopaminergic uptake (Fuxe, Hamberger, & Malmfors, 1967). The relation between cocaine dose and DA levels is linear; therefore, larger amounts of cocaine result in higher extracellular DA levels. These levels of DA are thought to underlie the reinforcing effects of cocaine (Gawin & Ellinwood, 1988). Because both cocaine and amphetamine result in enhanced dopaminergic neurotransmission, thereby producing elevated extracellular levels of catecholamines, these elevated neurotransmitter levels would presumably have local time-dependent inhibitory effects on the enzyme tyrosine hydroxylase, which is responsible for controlling their rate of synthesis. Therefore, this substrate-inhibitory mechanism might compensate for the increased catecholamine levels and activity by decreasing their synthesis. Galloway (1990) found that cocaine, in a way that was consistent with this proposition, decreased DA synthesis in a dose-dependent manner in various brain regions.

Chronic, intermittent stimulant use (e.g., 1-2 injections per 24 hrs) produces other behavioral effects besides euphoria and increased energy: (1) stimulant psychosis, which is characterized by paranoia, anxiety, stereotyped compulsive behaviors, and Hallucinations, and (2) sensitization or "reverse tolerance." Sensitization refers to the fact that the effects of cocaine are progressively enhanced. Although sensitization has been demonstrated in animal studies, it is not clear whether it occurs in humans. There are nevertheless several possible explanations for sensitization. First, because cocaine blocks dopaminergic, uptake, chronic cocaine use could somehow harm the functioning of the dopamine uptake mechanism; the evidence regarding this possibility is equivocal (Zahniser et al., 1988b). Second, sensitization could also be the result of enhanced dopaminergic release, similar to that found to be chronic after amphetamine administration (Castaneda. Becker, & Robinson, 1988). Akimoto, Hammamura, & Otsuki (1989) found enhanced DA release in the striatum one week following chronic cocaine administration. Similar data has been obtained by others (Kalivas et al., 1988; King et al., 1993; Pettit el al., 1990). Cocaine levels in blood and cerebrospinal fluid have also been reported to be elevated in chronically treated subjects (Reith, Benuck, & Lajtha, 1987); however, these increases cannot account for most of the change in DA release (Pettit et al., 1990). Furthermore, some researchers report no consistent effects in this regard. Third, there could be changes in autoreceptor sensitivity following chronic cocaine administration. Autoreceptors for particular neurotransmitters are those receptors that reside on the same Neuron that releases the Neurotransmitter. The autoreceptors on the somatodendritic area of neurons regulate impulse flow along the neuron, whereas autoreceptors on the terminal regions of the neuron regulate the amount of neurotransmitter released per impulse and neurotransmitter synthesis (Cooper, Bloom, & Roth, 1986). Sensitization could, therefore, be the result of decreased autoreceptor sensitivity. Such subsensitivity would result in either increased impulse flow, if somatodendritic autoreceptors were altered, or increased neurotransmission/synthesis, if terminal autoreceptors were altered. The net effect, in either case, would be an increase in dopaminergic neurotransmission. There is some evidence of decreased somatodendritic autoreceptor sensitivity twenty-four hours after the cessation of chronic cocaine administration (Henry, Greene, & White, 1989). However, seven days after termination of daily cocaine injections, when cocaine-induced sensitization is still fully present, somatodendritic autoreceptors are no longer reduced in sensitivity (Zhang, Lee, & Ellinwood, 1992). Evidence regarding changes in terminal autoreceptor sensitivity is mixed. Dwoskin et al. (1988) found that terminal autoreceptors were supersensitive, not subsensitive, to a DA agonist twenty-four hours following chronic cocaine use. Henry et al. (1989) also found that terminal autoreceptors were super-sensitive to DA following chronic daily cocaine injections. Although autoreceptor supersensitivity cannot explain sensitization, it is a possible mechanism underlying the previously described anhedonia and anergy experienced by cocaine abusers during the withdrawal phase. Fourth and last, there could be an increase in the number or sensitivity of postsynaptic DA receptors. The evidence regarding this hypothesis is also mixed (Zahniser et al., 1988a). For example, Peris et al. (1990) found an increased number of postsynaptic D2 receptors in the Nucleus Accumbens one day following cessation of chronic cocaine administration; however, after one week the number of receptors had returned to normal levels. In contrast, there is some evidence that postsynaptic DA receptors are decreased following chronic cocaine use. Volkow et al. (1990) found lower uptake values for [18 F]n-methylspiroperidol in human cocaine users who had been abstinent for one week, as compared with normal subjects. Uptake values were similar, however, for normal subjects and cocaine users who had been abstinent for one month.

In contrast with these results, Yi and Johnson (1990) have reported that chronic intermittent cocaine use impairs the regulation of synaptosomal 3[H]-DA release by DA autoreceptors, thus suggesting a subsensitivity or down-regulation of release-modulating DA autoreceptors seven days after chronic cocaine administration. The differences in the results of the Yi and Johnson (1990) and the Dwoskin et al. (1988) studies may be due to differences in the administration schedules or in the procedures used to measure autoreceptor sensitivity.

In contrast with the changes induced by intermittent but chronic drug administration, a regimen that involves the chronic administration of steady-state levels of drug results in decreased DA overflow when striatal brain slices are perfused with cocaine. This result may be due to the development of supersensitive autoreceptors. Autoreceptor supersensitivity would result in decreased dopaminergic activity. There is some support for this hypothesis from research involving the chronic administration of amphetamine. Lee and colleagues (Lee, Ellinwood, & Nishita, 1988; Lee & Ellinwood, 1989) found that twenty-four hours after withdrawal from a week of continuous administration of amphetamine, all indicators of autoreceptor activity demonstrated a pronounced subsensitivity. Similar results have been found following the continuous infusion of cocaine (Zhang et al., 1992). However, by the seventh day of withdrawal (a period associated with anergia, irritability, and "urges" in human stimulant abusers), nigrostriatal somatodendritic autoreceptors progress from an initial subsensitivity to a supersensitive state, whereas terminal autoreceptors are normosensitive. The changes in sensitivity of receptors clearly depend on the way the drug is administered and which receptors are evaluated. The evidence, moreover, is not always consistent.

There is also evidence that chronic cocaine administration produces neurotoxicityi.e., actual destruction of neural tissuealthough there are conflicting results and the relationship of this neurotoxicity to the addiction process is unclear. For example, Trulson and colleagues (1986) demonstrated decreased tyrosine hydroxylase activity sixty days after chronic cocaine treatment (see also Trulson & Ulissey, 1987), thereby indicating decreased DA synthesis. (Tyrosine hydroxylase is the rate-limiting step in the biosynthesis of DA; Cooper el al., 1986.) Similarly, Taylor and Ho (1978) found that chronic administration of cocaine decreased tyrosine hydroxylase activity in the caudate, but Seiden and Kleven (1988) were unable to replicate the findings of Trulson. As contrasted with the inconclusive results on cocaine, research involving amphetamine is much clearer. First, chronic Methamphetamine administration reduces the number of DA uptake sites (Ricaurte, Schuster, & Seiden, 1980; Ricaurte, Seiden, & Schuster, 1984). Second, DA and tyrosine-betahydroxylase levels are reduced for extended periods following chronic amphetamine administration (Ricaurte et al., 1980, 1984). Third, there is evidence of neuronal degeneration, chromatolysis, and decreased catecholamine histofluorescence (Duarte-Escalante & Ellinwood, 1970).

As with cocaine's effects on DA reuptake, cocaine also blocks 5-HT reuptake. Since activation of 5-HT postsynaptic receptors affects neurotransmission in neurons that release DA, this blockade prolongs the inhibitory effects of 5-HT on dopaminergic neurotransmission (Taylor & Ho, 1978). However, cocaine also inhibits the firing rates of dorsal raphe 5-HT neurons (Cunningham & Lakoski, 1988, 1990). Thus, acutely the net effect of cocaine on 5-HT neurotransmission in the nucleus accumbens will depend on the relative contributions of uptake inhibition, which would increase synaptic 5-HT, and inhibition of neuronal firing, which would decrease synaptic 5-HT. Broderick (1991) reported that acute, subcutaneous injections of cocaine resulted in a dose-dependent increase in DA levels, as measured by dialysis of the nucleus accumbens. This suggests a decrease in 5-HT levels that may result from activation of somatodendritic 5-HT autoreceptors located in the dorsal raphe nucleus. Acute cocaine administration has indeed been reported to almost completely inhibit the basal firing rate of dorsal raphe serotonergic neurons.

As with the effects of chronic amphetamine administration on the functioning of DA systems, chronic methamphetamine administration has been shown to induce pronounced long-term changes in tryptophan hydroxylase activity, as well as in 5-HT content and number of uptake sites (Ricaurte et al., 1980). The effects of chronic cocaine on serotonergic functioning are less well established. For example, Ho et al. (1977) found decreased levels of 5-HT following chronic cocaine administration. Seiden and Kleven (1988). however, failed to find any effects of chronic cocaine on the biosynthesis of serotonin.

Some of these discrepancies can be reconciled by the fact that different chronic dosing regimens produce different changes in 5-HT systems. For example, Cunningham and colleagues found that daily injections of cocaine resulted in an increased sensitivity of dorsal raphe somadendritic 5-HT autoreceptors to cocaine's inhibitory effects as measured by electrophysiological techniques (Cunningham & Lakoski, 1988, 1990). These results are consistent with the behavioral data of King and colleagues (1993a), who found that daily cocaine injections produced an enhanced inhibitory effect of NAN-190 on cocaine-induced locomotion and an enhanced excitatory effect of 8-OH-DPAT on locomotion. In contrast with these results, the continuous infusion of cocaine via an osmotic minipump results in a decreased sensitivity of dorsal raphe somadendritic 5HT autoreceptors and a decreased excitatory effect of 8-OH-DPAT on locomotion (King, Joyner, & Ellinwood, 1993b; King et al., 1993b).

Interestingly, the depletion of 5-HT or reduction of 5-HT neurotransmission is associated with impulsive behavior. For example, Linnoila et al. (1983) found that violent offenders with a diagnosis of Personality Disorder associated with impulsivity had lower levels of 5-hydroxyindoleacetic acid (5-HIAA, the metabolite of 5-HT) than other offenders. Bouilliouc et al. (1978, 1980) reported suppressed 5-HIAA levels in the cerebrospinal fluid (CSF) of XXY-chromosome (aggressive) institutionalized criminals. Lithium has been successfully used to treat violent offenders (Sheard, 1971, 1975; Sheard et al., 1976; Tupin et al., 1973). Lithium treatment produces increases in CSF 5-HIAA in humans (Fyro et al., 1975; Sheard & Aghajanian, 1970), and central nervous system (CNS) 5-HT in nonhumans (Sheard & Aghajanian, 1970; Mandell & Knapp, 1977); this indicates that increases in 5-HT are associated with decreases in violent and aggressive behavior. After extensively reviewing the literature, Brown and Linnoila (1990) concluded that low levels of CSF 5-HIAA are related to disinhibition of aggressive/impulsive behavior and not to antisocial acts in and of themselves. The transition to high-dose cocaine use might be considered impulsive behavior because the individual is focusing on the immediate, short-term advantages of drug consumption while ignoring the long-term advantages of drug abstinence. Hence, the 5-HT receptor supersensitivity, and resulting inhibition of 5-HT neurotransmission, may be a contributing factor to the development of the high-dose, bingelike pattern of cocaine abuse.

OPIATES

The Opiates are derived from the Poppy plant and have been used for centuries. A number of types of endogenous opiate Receptors have been identified and their locations mapped. There are high concentrations of opiate receptors in the caudate nucleus, nucleus accumbens, periventricular gray region, and the nucleus arcuatus of medobasal hypothalamus (Pert, Kuhar, & Snyder, 1975, 1976). These areas may be differently involved in the reinforcing, aversive, and dependence-producing effects of the opiates. Furthermore, different receptor subtypes may mediate the different effects of the opiates.

The opiates produce Analgesia, changes in mood (e.g., euphoria and tranquility), drowsiness, respiratory depression, and nausea (Jaffe & Martin, 1990). These drugs also reduce motivated behavior; there is a decrease in appetite, sexual drive, and aggression. Intravenous administration of opioids results in initial effects of flushing of the skin and sensations in the abdominal regions that have been likened to a sexual orgasm (Jaffe, 1990).

With continuous use of opioids, marked tolerance develops to some, but not all, of the effects of these drugs. Tolerance to opioids is generally characterized by a shorter duration of effect and attenuated analgesia, euphoria, and other CNS-depressant effects; however, there is less tolerance to the lethal effects of opiates. Therefore, if an individual administers ever larger doses to obtain the same effect (e.g., the rush or high), this may increase the probability of a lethal overdose (Jaffe, 1990).

Although the course and severity of withdrawal symptoms following opiate abstinence depend on which opiate was used, the dose and pattern of consumption, the duration of use, and the interdose interval, the opiate withdrawal syndrome follows the same general progression. Approximately eight to twelve hours after the last dose, individuals experience yawning, lacrimation, and rhinorrhea; twelve to fourteen hours after the final dose, they may fall into a fitful, restless sleep and awaken feeling worse than when they went to sleep. With the continuation of opiate withdrawal, they experience increasing dysphoria, anorexia, gooseflesh, irritability, agitation, and tremors. At the peak intensity of the withdrawal symptoms, they may experience exacerbated irritability, insomnia, intense anorexia, weakness, and profound depression. Common symptoms include alternating coldness and intense skin flushing and sweating, vomiting and diarrhea (Jaffe, 1990). This pattern of symptoms indicates that during the initial withdrawal phase there is a generalized CNS hyper-excitability. Thus, the addicted opiate abuser continues to recycle opiate use to both avoid or terminate the wtihdrawal symptoms, and to reexperience the euphoric effects. This powerful combination of euphoria, tolerance, and withdrawal can lead to profound levels of addiction.

Studies have found that rats and monkeys will self-administer opioids, thus indicating that these drugs serve as reinforcers (Koob & Bloom, 1988). Chronic opioid administration results in physical dependence, as demonstrated by the presence of a withdrawal syndrome following drug cessation. Most clinicians hold the classic position that Physi-Cal Dependence (i.e., avoidance of withdrawal symptoms) is a major motivating factor in opiate self-administration, but evidence indicates that reinforcement and withdrawal are separate processes. Bozarth and Wise (1984) demonstrated that rats will self-administer morphine into the ventral tegmental area without the presence or development of any apparent withdrawal symptoms. Chronic administration of morphine into the periaqueductal gray area, however, produces signs of a strong withdrawal syndrome.

Several lines of evidence indicate that dopaminergic neurotransmission may partially mediate the reinforcing effects of opiate administration. First, injection of met-enkephalin into the ventral tegmental area results in increases in DA release in the nucleus accumbens (Di Chiara & Imperato, 1988). Second, although opiates generally produce sedation, low doses of systemic morphine increase locomotor activity (Domino, Vasko, & Wilson, 1976). Third, injections of morphine into the ventral tegmental area produce circling behavior (Holmes, Bozarth, & Wise, 1983); injections of opiates into the ventral tegmental area produce increased locomotion, as with systemic injections of opiates, thereby suggesting increased dopaminergic transmission (Blaesig & Herz, 1980). Fourth, selective lesions of the dopaminergic system decrease opiate self-administration, although not to the extent of affecting cocaine self-administration (Bozarth & Wise, 1985). Fifth, rats learn to self-administer opiates directly into the ventral tegmental area (Bozarth & Wise, 1981), rats also inject opiates into the nucleus accumbens and the lateral hypothalamus (Goeders, Lane, & Smith, 1984). Sixth, administration of the D1 antagonist SCH 23390, but not the D2 antagonists sulpiride and spiperone, block the reinforcing effects of morphine.

Ettenberg et al. (1982) found no effect of alpha flupenthixol, primarily a D2 antagonist, on heroin self-administration, although the same doses decreased cocaine self-administration. Similar results have been reported by others using other dopaminergic antagonists (De Wit & Wise, 1977). Thus, both place preference and self-administration procedures indicate that opiates are not reinforcing through D2 receptors, which are vital to stimulant reinforcement. These results indicate that opiate reinforcement is at least partially independent of the D2 stimulant type of reinforcement, yet they do act through a dopaminergic mechanism to induce a significant part of their effects.

Chronic administration of opiates produces several behavioral and neurochemical effects that may be related to their reinforcing effects. First, chronic administration of Morphine results in the augmentation of the behavioral effects of low doses of morphine. In other words, subjects undergoing chronic opiate administration become sensitized to the behavioral effects of morphine (Ahtee, 1973, 1974). Second, chronic morphine administration results in decreased DA turnover in the striatum and limbic system during withdrawal (Ahtee & Attila, 1980, 1987). Third, in mice withdrawn from morphine, the synthesis and release of DA are attenuated (Ahtee et al., 1987); similar results have been obtained with human heroin addicts in which CSF homovanillic acid concentrations were decreased (Bowers, Kleber, & Davis, 1971).

These results indicate that during chronic morphine administration there is a down-regulation of the dopaminergic system and a neuroadaptation to this depletion. During withdrawal from opiate administration there is an augmentation of dopaminergic mechanisms. Indeed, during withdrawal rats are sensitized to the behavioral effects of apomorphine (Ahtee & Atilla, 1987), and small doses of morphine increase striatal homovanillic acid levels more in withdrawn than in control rats, thereby indicating that the dopaminergic system is sensitized at this point (Ahtee, 1973, 1974). Thus, some of the withdrawal symptoms (e.g., irritability and dysphoria) may be mediated by changes in dopaminergic functioning.

Acute administration of opiates increases the synthesis of 5-HT and the formation of 5-HIAA, and these effects are eliminated by the administration of opiate antagonists (Ahtee & Carlsson, 1979), thus suggesting that opiate administration results in increased serotonergic functioning. Indeed, acute administration of dynorphin-(1-13), while it decreases striatal dopamine, actually increases striatal serotonin (Broderick, 1987). This increased serotonergic functioning may contribute to the "post-consummatory calm" produced by opiate drugs: Increasing serotonergic functioning would tend to inhibit incentive-motivated behaviors and produce a calm, tranquil state. Indeed, the atypical anxiolytic drug buspirone exerts its anxiety-reducing effects via serotonergic activation.

During withdrawal from chronic opioid administration, 5-HIAA levels are decreased (Ahtee, 1980; Ahtee et al., 1987). This pattern of serotonin results could well cause increased impulsivity and a higher probability of relapse, similar to that described earlier in relation to the psychomotor stimulants.

In summary, like cocaine, the opiates are consumed because of their reinforcing properties. These reinforcing properties are the result of activation of endogenous opiate receptors; furthermore, activation of the dopaminergic system modulates the reinforcing effects of opiates. During chronic opiate administration, subjects become physically dependent. There is an increase in dynorphin levels that may mediate some of the aversive aspects of the withdrawal syndrome (e.g., decreased dopaminergic functioning). Furthermore, during chronic administration, there is functional down-regulation of both the dopaminergic and serotonergic systems. Upon withdrawal from opiates, there is a subsequent supersensitivity of the dopaminergic system. This dopaminergic supersensitivity may be involved in opiate craving and general irritability during withdrawal.

(See also: Addiction: Concepts and Definitions ; Brain Structures and Drugs ; Opioids: Complications and Withdrawal ; Research: Animal Model ; Tolerance and Physical Dependence ; Wikler's Pharmacologic Theory of Drug Addiction )

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Linnoila, M., et al. (1983). Low cerebrospinal fluid 5-hydroxyindolacetic acid concentrations differentiates impulsive from nonimpulsive violent behavior. Life Sciences, 2609-2614.

O' Donahue, N. F., & Hagmen, W. D. (1967). A map of the cat brain for regions producing self-stimulation and unilateral attention. Brain Research, 5, 289.

Pert, C., Kuhar, M. J., & Snyder, S. H. (1975). Autoradiographic localization of the opiate receptor in the rat brain. Life Sciences, 16, 1849-1854.

Pert, C., Kuhar, M. J., & Snyder, S. H. (1976). The opiate receptor: Autoradiographic localization in the rat brain. Proceedings of the National Academy of Sciences of the United States of America, 73, 3729-3733.

Pettit, H. O., et al. (1990). Extracellular concentrations of cocaine and dopamine are enhanced during chronic cocaine administration. Journal of Neurochemistry, 55, 798-804.

Pitts, D. K., & Marwah J. (1987). Neuropharmacology of Cocaine: Role of monoaminergic systems. Monographs in Neural Science, 13, 34-54.

Reith, M. E. A., Benuck, M., & Lajtha, A. (1987). Cocaine disposition in the brain after continuous or intermittent treatment and locomotor stimulation in mice. Journal of Pharmacology and Experimental Therapeutics, 243, 281-287.

Ricaurte, G. A., Schuster, C. R., & Seiden, L. S. (1980). Long-term effects of repeated methylamphetamine administration on dopamine and serotonin neurons in the rat brain: A regional study. Brain Research, 193, 153-163.

Ricaurte, G. A., Seiden, L. S., & Schuster, C. R. (1984). Further evidence that amphetamines produce long-lasting dopamine neurochemical deficits by destroying dopamine nerve fibers. Brain Research, 303, 359-364.

Roberts, W. W., & Carey, R. J. (1965). Rewarding affects performance of gnawing aroused by hypothalamic stimulation in the rat. J Comp Physio Psychol, 59, 317.

Seiden, L. S., & Kleven, M. S. (1988). Lack of toxic effects of cocaine on dopamine or serotonin neurons in the rat brain. In D. Clouet, K. Asghar, & R. Brown (Eds.), Mechanisms of cocaine abuse and toxicity (National Institute on Drug Abuse Research Monograph No. 88). Washington DC: U.S. Government Printing Office.

Taylor, D., & Ho, B. T. (1978). Comparison of inhibition of monoamine uptake by cocaine and methylphenidate and amphetamine, Res Comm Clin Path Pharmacol, 21, 67-75.

Trulson, M. E., & Ulissey, J. J. (1987). Chronic cocaine administration decreases dopamine synthesis rate and increases [3H]-spiroperidol binding in rat brain. Brain Research Bulletin, 19, 35-38.

Trulson, M. E., et al. (1986). Chronic cocaine administration depletes tyrosine hydroxylase immunoreactivity in the rat brain nigral striatal system: Quantitative light microscopic studies. Exp Neurology, 94, 744-756.

Volkow, N. D., et al. (1990). Effects of chronic cocaine abuse on postsynaptic dopamine receptors. American Journal of Psychiatry, 147, 719-724.

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Everett H. Ellinwood

G. R. King

Genetic Factors

Why do some people become alcoholics or drug addicts, while others who try the same substances, even to excess, avoid the snare of dependence? Could there be a genetic basis for such behavior? Given the strong familial patterns of substance abuse that often occur, the answer may be yesin some cases. Evidence points toward at least one inheritable form of Alcoholism; a genetic vulnerability to drug abuse has not been confirmed by research, although it may exist.

Researchers know that many environmental and psychological factors are implicated in addictions, including a dysfunctional family, poor academic performance, delinquent behavior, and perhaps most importantly, easy access to drugs. The abuser's personality is also a factor, and alcoholics, in particular, often exhibit similar traits: an inability to handle frustration, extreme sensitivity, poor self-image, and isolation. While some of these qualities may be inherited, they do not prove a direct genetic link to alcohol or drug abusethey simply act as a petri dish in which self-destructive behavior can develop.

Physiology, on the other hand, is determined directly by genetic inheritance, and it is in this arena that scientists have begun to discover what may be an inborn predispostion to some forms of substance abuse-particularly alcoholism. Heredity may also influence an individual's response to drug ingestion by either heightening pleasant sensations or suppressing unpleasant ones, such as the "flushing" reaction to alcohol (which can include elevated skin temperature, increased pulse rate, headache, and nausea) and the queasiness caused by opioids. An individual's response to drugs may also be determined by genetically influenced differences in the receptor proteins on which the drugs act, differences in the enzymes that metabolize these drugs, or differences in the proteins that remove these drugs from their sites of action.

GENETIC PREDISPOSITION

Researchers suspect that a tendency to alcoholism can be inherited, and studies of twins, adopted children of alcoholics, and half siblings of alcoholic parents have confirmed these suspicions, although a direct genetic link has yet to be found. Studies have shown that the first-degree relatives of alcoholics are fourteen times more likely to be addicts themselves. Even when the children of alcoholic parents are adopted into new families, their risk of becoming alcoholics is still far higher if one of their biological parents was an alcoholic. All of these statistics are especially significant for males, who seem more than twice as likely as females to inherit drug and alcohol dependence.

Animal studies indicate that an inherited difference in nerve cell membranes may be a factor in alcoholism. Alcohol lowers the viscosity of the nerve-cell membrane, which may interrupt neural excitation or interfere with the membrane proteins involved with neurotransmission. Studies performed on two genetically different strains of mice showed that alcohol-sensitive mice had nerve-cell membranes that were more susceptible to the viscosity-lowering effects of alcohol than mice that were less susceptible to alcohol (Goldstein, 1982).

Another genetic factor may be the alteration of membrane-bound neuronal enzymes, such as sodium-potassium ATPase, an ion pump that is responsible for the movement of sodium-potassium ions through the cell membrane. Alcohol inhibits the sodium-potassium ATPase, leading to speculation that there may be a genetic predisposition to alcoholism in people who show an atypical resistance to the alcohol-induced inhibition of this enzyme.

Alcohol also affects the proteins that make up Receptors, including the NMDA receptor, which mediates neuronal excitation following release of the Neurotransmitter glutamate and is the major excitatory pathway in the brain, and the GABA receptor, the major inhibitory pathway in the central nervous system. Changes in either of these receptor proteins could predispose an individual to alcoholism by altering their response to the drug.

The A1 allele.

Alcohol interferes with the release of the neurotransmitters Norepinephrine and Dopamine. One promising area of research indicates that some severe forms of alcoholism (and possibly drug abuse) may occur in subjects who have up to 30 percent fewer Dopamine receptors in their brains than usual; this deficiency is caused by a variant gene for the dopamine D2 receptor, called the A1 allele.

People with this trait may be far less able than most to find enjoyment in everyday activities and have much greater difficulty coping with the stresses of life. One researcher, in fact, has tied the presence of the A1 allele to a condition he calls the "reward-deficit syndrome" (Blum et al.). Possession of the A1 allele is identified with a range of impulsive behaviors, possibly caused by a brain chemistry that spurs people to substance abuse and other self-destructive behaviors in the search for neurochemical satisfaction.

Because alcohol and many other drugs release a flood of dopamine into the brain, addicts may turn to alcohol and drugs to get the feelings they crave. A smaller-than-usual number of dopamine receptors may also diminish or suppress the unpleasant sensations many people feel when they become intoxicated and heighten the inebriation, which increases the likelihood that the substance will be used again and in greater quantities.

Predisposition against substance abuse.

Genetic predisposition may also inhibit the development of alcoholism because heredity may determine the way people metabolize alcohol. The major chemical pathway for the metabolism of alcohol requires two enzymes: alcohol dehydrogenase, which converts alcohol to acetaldehyde; and acetaldehyde dehydrogenase, which converts acetaldehyde to acetic acid. Acetic acid is then converted by a series of enzymes to carbon dioxide and water.

Recent studies indicate that there is a genetic difference in the enzymes involved in the alcohol metabolism of Asians. In a significant proportion of Asians, alcohol dehydrogenase is more active than in Caucasians; it rapidly converts alcohol to acetaldehyde. In these same Asian populations, there is a genetic deficiency in acetaldehyde dehydrogenase, so that acetaldehyde accumulates and produces the unpleasant flushing reaction described above. This same rapid and unpleasant accumulation of acetaldehyde is what alcoholic patients risk when they take the drug Disulfiram (Antabuse) to deter them from drinking. The acetaldehyde dehydrogenase deficiency may actually deter many Asians from abusing alcohol. Asians that do become alcoholics do not exhibit the acetaldehyde dehydrogenase deficiency common in the general Asian population.

PSYCHIATRIC DISORDERS

In addition to a physiology that changes their metabolization of and reaction to drugs and alcohol, certain psychiatric diagnoses are regularly overrepresented among alcoholics and drug dependents. These include depression, anxiety disorders, and Antisocial personality, all of which may be inherited. When these complications are factored in, it becomes difficult to distinguish genetically based substance abuse from risky, self-destructive behavior caused by mental illness.

SAMPLE AND CONTROL VARIABLES

Many factors affect a person's susceptibility to drug abuse, which makes studying the genetic bases for addiction difficult, particularly where drug addiction is concerned. Studies must match control and drug-abusing populations adequately, and the sample size must be large enough to detect small genotype changes from background influences. Individual variables (such as severity of dependence) need to be consistent between research groups. It's also difficult to determine whether an individual currently in the control group will express addictive behavior in the future. For these and other reasons, scientists have been unable to prove a definitive link between an individual's genetic makeup and a tendency to substance abuse, although they strongly suspect its existence, especially in the more severe forms of alcoholism and drug dependence.

(See also: Conduct Disorder ; Complications: Mental Disorders ; Epidemiology of Drug Abuse ; Women and Substance Abuse ;Vulnerability As Cause of Substance Abuse )

BIBLIOGRAPHY

Blum, K., Cull, J. G., Braverman, E. R., & Comings, D. E. Reward Deficiency Syndrome. American Scientist. http://www.sigmaxi.org/amsci/Articles/96Articles/Blum-full.html.

Goldstein, D., Chin, J., & Lyon, R. (1982). Ethanol disordering of spin-labeled mouse brain membranes: Correlation with genetically determined ethanol sensitivity in mice. Proceedings of the National Academy of Sciences, U.S.A., 79, 4231-4233.

Hesselbrock, M. M., & Keener, J. (1985). Psychopathology in hospitalized alcoholics. Archives of General Psychiatry, 42, 1050-1055.

Rounsaville, B., Weissman, M., Kleber, H., & Wilber, C. (1982). Heterogeniety of psychiatric diagnosis in treated opiate addicts. Archives of General Psychiatry, 39, 161-166.

Uhl, G. R., Persico, A. M., & Smith, S. S. (1992). Current excitement with D2 receptor gene alleles in substance abuse. Archives of General Psychiatry.

George R. Uhl

Revised by Amy Loerch Strumolo

Learning

The role played by learning factors in drug and alcohol abuse has recently received much attention. Two basic learning mechanisms are thought to be activated when an organism repeatedly self-administers a psychoactive substance. First, classical conditioning processes are engaged when environmental stimuli signal the upcoming effects of the drug. Second, operant conditioning occurs as an organism learns that particular behaviors lead either to a drug reward or to punishment. The effects of these two processes presumably interact, and they are thought to influence repeated drug use and/or relapse to drug use following a period of abstinence.

Classical conditioning occurs when an organism learns about a contingency between two events in the external environment. The most common situation involves learning that a biologically neutral event (the conditioned stimulus, CS, such as a light or a tone) signals the upcoming occurrence of a biologically relevant event (the unconditioned stimulus, US, such as the effects of a drug or the Withdrawal syndrome from absence of a drug). As a result of this signaling relationship, the CS produces conditioned responses (CRs), related to the US in use. In the area of drug use, a number of investigators have suggested that environmental events that signal upcoming withdrawal or drug use in humans elicit CRswhich motivate further drug taking (Baker, Morse, & Sherman, 1987).

Operant conditioning involves learning about contingencies between behaviors and their outcomes. A typical operant conditioning situation sets up contingencies between three different eventsa response; the outcome of that response (the reward or reinforcer); and the stimulus situation in which that responseoutcome relationship is established (the discriminative stimulus). Drugs of abuse function as potent reinforcers for human addicts, since a variety of behaviors are directed solely toward their attainment and use. Consequently, understanding the rules governing the acquisition of operant behaviors directed toward drug reinforcers may be critical to understanding addiction.

Classical and operant conditioning processes may be activated simultaneously during drug seeking and self-administration. Events that have consistently signaled drug use may eventually come to evoke CRs in the form of cravingurges to use the drug. In this way, signals of drug use may act as discriminative stimuli motivating the drug user to begin drug-seeking behavior. For example, walking past a known dealer might act as a CS for a heroin addict, evoking the CR of craving for Her-Oin. This craving response might then increase the likelihood of behaviors that are rewarded by the desired drug effectsbuying and preparing heroin.

OPERANT CONDITIONING WITH DRUG REINFORCERS

A large body of data shows that virtually all drugs of dependence in human beings act as reinforcers for animals in operant-conditioning situations. Typical studies on the reinforcing properties of drugs involve rats or monkeys fitted with venous catheters, through which a drug can be administered directly. Responses directed toward an object, such as a lever, result in infusions of the drug.

The basic finding of such studies has been that a wide variety of abused drugsincluding Cocaine, Morphine, heroin, d -Amphetamine, pentobarbital, and Alcoholall serve to establish and maintain operant behaviors in animals. Other drugs with a lesser abuse potential in humanssuch as aspirin, tricyclic antidepressants, hallucinogens, and opioid mixed agonist/antagonistsfail to support responding.

The degree to which a given drug of abuse reinforces behavior appears to depend more on the schedule of reinforcement of the drug than on its intrinsic properties. A schedule of Reinforcement refers to the pattern of access provided to the reinforcing event. For example, ratio schedules require an animal to make some predetermined number of responses before a reinforcer is given. Yet interval schedules are set up so that responses are effective at producing a reinforcer only after a delay following the previous one. Reinforcers in ratio schedules depend solely on the number of responses made; therefore, these schedules typically result in higher response rates than interval schedules in which responses made too early are ineffective. Because reinforcement schedules largely determine the rate of responding in a given situation, the abuse potential of the various drugs cannot be reliably assessed by comparing how quickly animals respond for each substance.

Other techniques for making such comparisons are available, however, and one technique for comparing the reinforcing properties of various substances involves calculating for each a so-called breaking point under a fixed ratio schedule of reinforcement. A fixed ratio schedule requires that an animal make a fixed number of responses (the ratio) for each reinforcement received. For a given drug dose, the breaking point is reached when a ratio too high to support responding is required. The breaking point achieved with the highest tolerable dose of a drug is often taken to be an index of that drug's reinforcing properties. Drugs with the highest breaking point are considered to be the most reinforcing and hence to have the highest abuse potential. Of drugs studied with such a procedure, cocaine appears to have the highest breaking point. For example, in some experiments, animals have been willing to press a lever up to 12,000 times for a single dose of cocaine.

Choice experiments provide a second means for comparing the reinforcing properties of two different drugs. Animals in such designs are typically given a choice between two responses, each of which leads to infusions of a different drug. A preference for one response is taken to indicate a preference for the drug associated with that response. A finding of particular interest from such studies has been that cocaine appears to be preferred not only to a number of other drugs but also to nondrug rewards such as food and social contact (Johanson, 1984)but it is important to vary the other reinforcers as well. Animals will choose less cocaine when the amount of food provided is greater or tastier.

Far fewer systematic data on the reinforcing properties of drugs have been collected with human subjects. A number of experiments have shown that human subjects will work for tokens exchangeable for Opioids, alcohol, pentobarbital, Diazepam (Valium), and d -amphetamine. In addition, drug-abusing individuals will reliably produce arbitrary responses in a laboratory for immediate access to their drugs of choice. For example, heroin addicts will repeatedly push a button to receive heroin injections and cocaine users will choose to perform responses leading to cocaine injections over responses that yield injections of saline (Henning-field, Lukas, & Bigelow, 1986).

In sum, a body of both animal and human data now exists that documents the way drugs of abuse can act as potent reinforcing events. The pattern of drug use exhibited by an individual user, however, appears to depend as much on the schedule of drug availability as on the particular properties of the chosen drug. Therefore, predicting patterns of drug taking by humans will require a better understanding of the parameters of drug availability that exist in the real world.

CLASSICAL CONDITIONING OF DRUG-RELATED CUES

Conditioned Withdrawal Model.

A number of investigators have advanced the idea that stimuli that reliably signal drug use elicit CRs that motivate further drug use. For example, Wikler (1980) noted that drug-free heroin addicts participating in discussions of drug use appeared to go through episodes of withdrawal as a result. Withdrawal refers to the unpleasant symptoms experienced by drug abusers following the abrupt cessation of drug use. Since the individuals discussed by Wikler had not used heroin for a long time, their withdrawal symptoms could not have been the result of recent termination of the drug. Wikler proposed instead that events that reliably signal the onset of naturally occurring drug withdrawal become CSs capable of evoking withdrawal symptoms on their own. On future occasions, the mere presence of drug-related stimuli evoke conditioned withdrawal states that compel the person to counter these unpleasant feelings with drug use.

A second model that also invokes conditioning was put forth by Siegel (1979), who proposed that stimuli paired with drug use come to evoke conditioned compensatory responses, which oppose the direct effects of the drug. As these drug-opposite responses grow in size, over repeated conditioning experiences, they increasingly oppose the effects of the drug. Therefore, addicts should find that, over time, higher doses of the drug should be necessary to achieve a given effect. This pattern is indeed observed, and it is known as drug tolerance. According to Siegel's model, drug-related cues encountered in the absence of drug taking produce drug-opposite responses, which are not canceled by the direct effects of the drug. These drug-opposite responses are then thought to represent what the user experiences as withdrawal symptoms.

According to Siegel's model, conditioning can motivate drug use in two ways. First, the withdrawal symptoms generated by drug-related stimuli following a period of abstinence can lead to drug use aimed at relieving these unpleasant effects. Second, tolerance to the effects of a drug may motivate a user to increase his or her level of use in an attempt to maintain a fixed level of drug effect.

Siegel's model has not gone unchallenged. The primary problem appears to be that signals for drug use do not always produce drug-opposite responses. Instead, such signals sometimes produce responses that resemble the direct effects of the drug. The conditions determining whether CRs produced by drug-related stimuli are drug-like or drug-opposite have not been fully worked out. Yet drug-like responses (e.g., drug-induced euphoria) to environmental stimuli may act to motivate drug use as well. Some researchers have asserted that it is the memory of drug-induced euphoria that is the major factor contributing to continual drug use and relapse.

Conditioned Incentive Model.

Stewart, deWit, and Eikelboom (1984) have proposed that conditioned drug stimuli provide the impetus for further drug use by producing mild drug-like effects, which whet the appetite of the user (the priming effect). Thus drug-related events cause drug use by prompting the user to anticipate the pleasurable consequences. Like the models of Siegel and Wikler, this theory proposes that events signaling drug use become conditioned stimuli that encourage the drug user to initiate drug-seeking behaviors. The models differ only in their characterization of the CR elicited by the drug-related events.

Some evidence for this model lies in the observation that many animals show drug-like responses to stimuli paired with drug use, particularly when stimulant drugs such as cocaine or d -amphetamine are used. Furthermore, many researchers have found that animals that have stopped responding for a drug reinforcer may resume responding following a small unearned dose of the drug (a priming dose). Environmental signals for drug use may act in the same way as these priming doses. Some research suggests that the stimuli associated with rewards can elicit release of the neurotransmitter dopamine in the reward center of the brain, an event that is produced by the effects of most rewarding drugs.

Human Data.

Since the 1970s, investigators have collected data from a number of sources to document that stimuli associated with drug use in humans acquire conditioned properties. Evidence for this statement has come from three primary sources:

  • self-reports by addicts about the conditions under which they experience craving and withdrawal
  • attempts to establish drug conditioning in the laboratory
  • assessments of responding to cues thought to have become drug CSs in the natural environment

Self-reports of Conditioned Effects. Many drug-abuse patients report drug craving and withdrawal when faced with drug-related stimuli in their home environment. Wikler (1980) reported that drug-free heroin addicts who returned to their home (addiction) environment following a period of treatment experienced symptoms of heroin withdrawal. O'Brien (1976) took a more systematic approach, interviewing heroin addicts and constructing a hierarchy of real-world events that result in withdrawal feelings and craving for drug use. Such reports encouraged the idea that events that signal drug self-administration in the home environment come to evoke conditioned responses, which motivate further drug use. Consequently, investigations have attempted to study this phenomenon under controlled laboratory conditions.

Laboratory Conditioning Studies. O'Brien and his colleagues (1986) found that neutral stimuli paired either with opiate administration or with opiate withdrawal appeared to elicit conditioned withdrawal reactions. A number of later studies using alcohol as the unconditioned stimulus have also tended to find drug-opposite responses elicited by the experimental CS, although drug-like effects have been observed as well.

Studies of conditioning in the laboratory permit the conclusion that such conditioning can occur as a consequence of drug-taking behavior by addicts. However, the contingency between potential CSs and drug effects in the natural environment is undoubtedly less precise than that programmed in the laboratory. Therefore, affirming the role of drug-related stimuli in drug use requires a direct assessment of the effects of such events.

Cue-Assessment Studies. To determine whether events associated with drug use in the natural environment acquire conditioned properties, many studies have recreated typical drug-related stimuli in the laboratory. In such studies, subjects are exposed to audiotapes, videotapes, slides, and paraphernalia with drug-related content, while physiological and self-report responses are obtained. Responses to such drug-related stimuli are then usually compared with the responses subjects make when they are exposed to comparable stimuli lacking a drug-specific content. So far, the majority of cue-assessment studies have been carried out with either opiate-abusing subjects or alcoholics, although there have also been some studies of cocaine abusers.

For opiate users, exposure to visual stimuli and paraphernalia typically associated with opioid use have been found to produce subjective reports of craving for opiates and withdrawal, as well as other physiological changes associated with withdrawal, including drops in skin temperature and skin resistance and increases in heart rate. Other studies have shown that opiate users given a medication that blocks the effects of the opiates (an opiate An-Tagonist) initially report pleasurable sensations after only injectioneven of placebo (saline solution). After several repetitions of the placebo, the injections begin to become aversive, including elements of withdrawal. Opiate-related stimuli, then, appear to evoke both subjective and physiological responses related to drug use; it appears likely that such responses have a basis in prior conditioning.

Studies with alcoholics have yielded similar results. In a typical experiment, the reactions of alcoholics to the sight and smell of an alcoholic beverage are compared with responses evoked by a nonalcohol (placebo) drink. The results show greater craving/urges to drink induced by the alcohol cue than by the control stimulus. Such data suggest that alcohol-related cues acquire the ability to evoke conditioned responses.

Classical/Operant Conditioning Interaction.

As mentioned earlier, much of the work on drug conditioning contains the implicit notion that classical and operant learning effects combine to motivate drug use (or craving, even if no drug use actually occurs). The most common idea is that drug CSs evoke craving and withdrawal states, which motivate the performance of drug-seeking behaviors. These behaviors are reinforced, in turn, by the effects of the drug. Although much evidence suggests that psychoactive drugs of abuse have powerful reinforcing propertiesand that signals of those drugs elicit conditioned responsesthe question remains as to whether these classically conditioned responses actually motivate drug-seeking behaviors.

One technique used in a study to examine this issue involved asking opiate abusers to describe the conditions under which they had relapsed to drug use. After some probing, many patients were able to describe specific events or stimuli that triggered craving and withdrawal leading to use. Such reports, however, suffer from the difficulty that retrospective self-reports from individuals reluctant to analyze their own behavior may be inaccurate.

Because of the ethical limitations imposed on providing drugs to drug abusers, little laboratory work has been done to examine whether drug-related cues increase drug self-administration. Some data have been collected by Ludwig, Wikler, and Stark (1974), however, who found that alcoholics in a barlike environment worked harder at an alcohol-rewarded task than did subjects in a laboratory setting. This result supports the idea that alcohol-related stimuli impact directly on the motivation to drink alcohol. Yet, no nonalcoholic subjects were studied, preventing the conclusion that alcoholics are uniquely susceptible to alcohol-related events. Because the assumption that responses to drug-related stimuli motivate actual drug use is central to learning models, more studies using drug taking as a dependent measure are clearly needed.

Treatment Implications of Learning and Conditioning Theories.

If classical and operant conditioning motivate drug use, then substance-abuse treatments should aim at reducing the impact of these learning effects. The most commonly discussed interventions include aversion training, extinction, and behavioral alternatives.

Aversion Therapy or training involves teaching subjects that stimuli and responses that once terminated in drug effects will lead to unpleasant outcomes. The most common technique has been to pair self-administrations of a drug with electric shock or with chemically induced sickness (e.g., Antabuse). Although there are some anecdotal reports of successful treatment using such therapy, systematic data are not abundant. In addition, such aversion training suffers from the disadvantage that patients are unlikely to continue to administer punishments to themselves once outside treatment. Since the treatment setting is clearly different from the home environment, subjects may simply learn that drug-taking behavior is reinforced at home but punished in the clinic.

Extinction training consists of exposing subjects repeatedly to drug-related stimuli and responses, to break the association between these events and the effects of drug use. Operant extinction procedures require subjects to perform repeatedly drug-use behaviors in the absence of a drug reinforcer. This can be accomplished by having subjects administer their drug of abuse in the usual waywhile they are maintained on medication blocking the drug's effects. In this way, drug responses go unreinforced, because the drug effects are missing. Extinction of classically conditioned stimuli typically requires subjects to view repeatedly drug-related scenes and handle paraphernalia without using the abused substance. Such training has the advantage of not requiring subjects to accept punishment. Nevertheless, subjects might show extinction in the context of the clinic but continue to experience conditioned effects that lead to drug use in the unaffected home environment.

Behavioral alternatives training represents a third approach to reducing the impact of conditioning on drug abuse. This technique involves teaching subjects to avoid drug-related situations or to make alternative responses in the presence of drug-related stimuli. These new responses are designed to compete with the drug-seeking behaviors usually elicited by drug-related cues. Rather than try to eliminate craving produced by drug cues, this treatment attempts to give the patient ways to avoid cues plus alternatives to drug use. Behavioral alternatives to drug use range from simple time-out periods, to forming images inconsistent with drug use, to acting in ways that reduce the chances of use or cue exposure (e.g., going out to eat). These approaches are now commonly designated as Cogni-Tive Therapies or Relapse-Prevention approaches. The advantage of these procedures over aversion therapy and extinction lies in the greater potential for patients to use their training in the clinic to deal with high-risk situations in the real world.

Whether these particular conditioning interventions provide lasting help to substance abusers remains to be seenbut data exist to suggest that in alcoholics, opiate addicts, and cocaine users, these cognitive therapies and relapse-prevention techniques do have value. They reduce the probability of relapse.

(See also: Addiction: Concepts and Definitions ; Conditioned Tolerance ; Naltrexone in Treatment of Drug Dependence ; Wikler's Pharmacologic Theory of Drug Addiction )

BIBLIOGRAPHY

Baker, T. B., Morse, E., & Sherman, J. E. (1987). The motivation to use drugs: A psychobiological analysis of urges. In C. Rivers (Ed.), The Nebraska symposium on motivation: Alcohol use and abuse. Lincoln: University of Nebraska Press.

Childress, A. R., Mc Lellan, A. T., & O' Brien, C. P. (1985). Behavioral therapies for substance abuse. International Journal of Addiction, 20, 947-969.

Drummond, D. C., Cooper, T., & Glautier, S. P. (1990). Conditioned learning in alcohol dependence: Implications for cue exposure treatment. British Journal of Addiction, 85, 725-743.

Goudie, A. J., & Demellweek, C. (1986). Conditioning factors in drug tolerance. In S. R. Goldberg & I. P. Stolerman (Eds.), Behavioral analysis of drug dependence. Orlando, FL: Academic Press.

Henningfield, J. E., Lukas, S. E., & Bigelow, G. E. (1986). Human studies of drugs as reinforcers. In S. R. Goldberg & I. P. Stolerman (Eds.), Behavioral analysis of drug dependence. Orlando, FL: Academic Press.

Johanson, C. E. (1984). Assessment of the dependence potential of cocaine in animals. National Institute on Drug Abuse Research Monograph, No. 50, 54-71. Rockville, MD.

Johanson, C. E., & Fischman, M. W. (1989). The pharmacology of cocaine related to its abuse. Pharmacological Review, 41, 3-52.

Ludwig, A. M., Wikler, A., & Stark, L. H. (1974). The first drink: Psychobiological aspects of craving. Archives of General Psychiatry, 30, 539-547.

O' Brien, C. P. (1976). Experimental analysis of conditioning factors in human narcotic addiction. Pharmocological Review, 27, 533-543.

O' Brien, C. P., Ehrman, R. N., & Ternes, J. W. (1986). Classical conditioning in human opioid dependence. In S. R. Goldberg & I. P. Stolerman (Eds.), Behavioral analysis of drug dependence. Orlando, FL: Academic Press.

Sherman, J. E., Jorenby, M. S., & Baker, T. B. (1988). Classical conditioning with alcohol: Acquired preferences and aversions, tolerance and urges/craving. In D. A. Wilkinson & D. Chaudron (Eds.). Theories of alcoholism. Toronto: Addiction Research Foundation.

Siegel, S. (1979). The role of conditioning in drug tolerance and addiction. In J. D. Keehn (Ed.), Psychopathology in animals: Research and treatment implications. New York: Academic Press.

Stewart, J., De Wit, H., & Eikelboom, R. (1984). The role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants. Psychological Review, 91, 251-268.

Young, A. M., & Herling, S. (1986). Drugs as reinforcers: Studies in laboratory animals. In S. R. Goldberg & I. P. Stolerman (Eds.), Behavioral analysis of drug dependence. Orlando, FL: Academic Press.

Wikler, A. (1980). Opioid dependence: Mechanisms and treatment. New York: Plenum.

Steven J. Robbins

Psychological (Psychoanalytic) Perspective

The psychological study and understanding of substance abusers has tended to be difficult, controversial, and complicated. Part of this derives from the nature of addictive illness; the acute (short-term) and the chronic (long-term) use of drugs and Alcohol cause individuals to seem pleasure oriented, self-centered, and/or destructive to self and others, thus making them difficult to approach, understand, or treat. In other respects, the controversy or lack of understanding derives from competing ideas or schools of thought that debate (if not hotly contend) whether substance abuse is a disease or a symptom, whether biological and genetic factors are more important than environmental or psychological ones, and/or whether substance abuse causes or is the result of human psychological suffering. Furthermore, in recent years psychological factors were minimized, because we entered the era of biological psychiatry/psychology, in which empirical interest in brain structure and function (down to the microscopic and molecular level) has predominated over interest in the person, the person's mind, and subjective aspects of human psychological life that govern our emotions and behavior. Although one cannot ignore that substances of abuse are Psychoactivepowerful chemicals that act on the brainthere is a tendency to lose sight of the total person whose ways of thinking, feeling, and behaving (including subjective feelings about self and others) are equally and profoundly affected both by that chemistry and by the subjective effects produced by those psychoactive substances.

Clearly, biological, genetic (i.e., hereditary), and sociological factors are important in the development of drug abuse and dependence. Such factors are best studied by empirical methods, and modern technologyincluding the computerhas yielded new and valuable data since the late 1960s to explain aspects of addictive behavior. It is also noteworthy that during this period (a time when substance abuse has been most prevalent, studied, and treated), clinical work with substance abusers has yielded data and findings of equal importance and validity, and this work has focused on some of the important subjective psychological factors that also explain aspects of addictive behaviorsome which empirical methods alone do not adequately fathom or explain.

I will present here a psychological understanding of drug abuse and dependence based on the perspective gained from clinical work with alcoholic and drug-dependent individuals. In psychology and clinical psychiatry, it is referred to as the case method of study of human psychological problems. Guided by psychodynamic principles (the assumptions of which will be explained), this article will review what three decades of clinical work and case study with substance abusers has yielded on some of the main psychological influences that make likely or compelling the dependence on, and continued use and relapse to, drugs and alcohol.

ASSUMPTIONS

A psychodynamic perspective of human psychological life problems rests on the principle that we are all more or less susceptible to various forms of human psychological vulnerabilitiesat the same time, we are also more or less endowed with human psychological strengths or capacities to protect against these vulnerabilities. Without ignoring hereditary factors, especially those that affect temperament, a psychological, and in this case psychodynamic perspective attempts to understand psychological forces at work (for example, drives and feelings) that operate within the individual at the same time that there is a corresponding interest in the psychological structures and functions that observably (and just as often, less obviously) operate to regulate or control our drives, feelings, and behavior.

A psychodynamic approach to human psychology greatly depends on a developmental perspective or an appreciation of the psychological forces, structures, and functions as they develop and change over one's lifetime. Psychodynamic clinicians are especially interested in the way individuals are influenced in the earliest phases of development by parents (and other caregivers), and then in the development of relationships with other children and peers, and later in the life cycle in relationships with adults and small and large groupsall of which shape our life views and experiences, as well as our attitudes, values, and characteristic ways of reacting and behaving.

Based on these assumptions, clinicians have the opportunity, most usually in the context of treating patients, to study and understand how the degree of developmental impairments (or strengths) has predisposed toward (or protected against) psychological and psychiatric dysfunction, including addictive vulnerability. In my experience, and that of my associates, we believe that modern psychodynamic-clinical approaches are as relevant and useful for studying and treating substance-dependent individuals as they are for the many other patients who benefit from this perspective.

The psychological study and understanding of addictive illness necessarily requires the condition of abstinence (being free of drug/alcohol use). Again, there is considerable debate about the duration of abstinence required before meaningful or valid psychological inferences can be made about individuals with addictive disorders. In my experience, however, the confounding effects of acute and chronic drug/alcohol use are variable, and it is often surprising that within days or weeksbut certainly within several months of abstinencehow much can be learned about a person's makeup and psychology that predisposed him or her to use and become dependent on substances. This point about the requirement for a period of abstinence from drugs and alcohol is important to emphasize, otherwise it can be and is rightfully argued that what appear to be the psychological causes of dependence on psychoactive substances are actually the result of such a dependence. Fortunately, in recent years, the combination of modern detoxification approaches, psychoeducational/rehabilitation/Relapse Prevention programs, Twelve-Step groups, and individual and group psychotherapeutic approaches, have been increasingly successful in establishing and maintaining abstinence. This, in turn, has made psychological treatments and understanding increasingly possible.

PSYCHOLOGICAL SUFFERING AND SELF-CONTROL

A clinical-psychodynamic perspective suggests that human psychological suffering and problems with self-control are at the heart of addictive disorders. In fact, it is probably safe to say that to understand the psychology of addictive behavior is to understand a great deal about human psychological problems of suffering and control in general. The suffering that influences addictive behavior occurs at many levels, but it principally evolves out of susceptibilities involving people's self-esteem, relationships, emotions, and capacities to take care of themselves. Individuals who find various or particular drugs appealing (including alcohol) or who become dependent on them, discover that, short-term, the drug action or effect relieves or controls their distressthat is, such drugs are used to self-medicate distress. Although problems with self-esteem and relationships are important parts in the equation of addictive behavior, it is mainly the problems with how substance-dependent individuals experience, tolerate, and express their feelings and their problems with self-care that makes addictive behavior so malignantly likely and compelling.

Problems with emotions and self-care painfully and repetitiously become involved with attempts to control suffering and behavior. This process includes such self-defeating coping patterns as action, activity, psychological defensiveness (e.g., denial, boastful or arrogant postures, attitudes of invulnerability and toughness), and, ultimately, the use of drugs and alcohol. What originally was a "solution" for suffering and self-regulationwhere substances were used for relief or controlturns into a problem where there is a progressive loss of control of one's self, the drugs or alcohol employed to combat one's difficulties, and possibly life itself.

THE SELF-MEDICATION HYPOTHESIS

The self-medication hypothesis specifically refers to some individuals who, by dint of temperament or developmental factors, experience and find that certain painful feelings (or affects) are intense and unbearable and that the specific action or effect of one of the various classes of abused drugs (e.g., analgesics, depressants, or stimulants) relieves their psychological pain and suffering. The self-medication hypothesis also implies that the particular drug or class of drugs preferred is not random. Rather, it is determined by how that class of drugs with its specific actions interact with emotional states or particular painful feelings unique to the individuals who use or select their "drug-of-choice."

This is only one aspect of addictive sufferingnamely that emotions are experienced in the extreme and that addictive-prone individuals feel too much pain, so resort to particular drugs to relieve their suffering. Another aspect of addictive suffering, to be covered subsequently, is that emotions are just as often absent, nameless, and confusing and that such individuals experience pain of a different type; they consciously feel too little of their distress and do not know when or why they are bothered (e.g., feeling empty, void, or cut off from emotions), and drugs or alcohol in these instances are used to change or control their emotions or suffering. In the first instance the operative motive is the relief of suffering; in the second, it is the control of suffering.

The self-medication hypothesis rests on the observation that patients, if asked, will indicate that they prefer or discover that one class of drugs has more appeal than another. Still, the drugs preferred by an individual are not the ones that are always used. Drugs that are actually used are just as often the result of other factors, such as cost and availability.

The three main classes of drugs that have been studied are the Opioid analgesics (pain relievers), depressants or Sedative-Hypnotics (soothing, relaxing, or sleep-inducing drugs), and Stimulants (activating or energizing drugs). The main appeal of opioids (e.g., Heroin, Morphine, oxycodone) is that they are powerful subduing or calming agents. Besides calming or subduing physical pain for which they were originally intended, opioids are also very effective in reducing or alleviating distressing or disruptive emotions. Beyond its calming influence on physical and emotional pain in general, however, I have found that the main and specific action of opioids, namely as an anti-rage or anti-aggression drug, makes them especially appealing and compelling for those who struggle within, and with others, with feelings of intense anger, Aggression, and hostility. Such a state of affairs is not uncommon for people who, in their early life development or in later life experiences, have suffered major trauma, neglect, or abuse. Such individuals, when they first use opioids, discover the extraordinary calming and soothing effects of these drugs on their intense anger and rageand thus they become powerfully drawn or attached to them.

Whereas opioid-dependent people have much difficulty controlling their feelings, especially anger and rage, those who prefer or who are dependent on depressants generally have the opposite problemnamely they are too controlled or too "tightly wrapped" around their feelings. As is the case with other substance abusers, developmental life experiences, in this case often involving distrust and traumatic disappointment, have had a special influence on their experience of emotions. In the case of those who prefer depressants, they are the ones who have special difficulties experiencing emotions involving loving or caring feelings, interpersonal dependency, and closeness; in psychological terms, they are defensive and repressed around these emotions and have difficulty in experiencing or expressing them. Depressants (e.g., alcohol, Seconal, Xanax) have appeal for these people, because such drugs help them to relax their defenses and release them from their repressions. Mainly, such drugs briefly (the short- or quick-acting depressants) produce a sense of safety and an inner sense of warmth, affection, or closeness that otherwise these people cannot experience or allow.

Finally, stimulants (i.e., Amphetamines and Cocaine are the most popular and widely used) have appeal for those who suffer with overt and/or subtle states of depression, mania, and hyperactivityin which problems with activation, activity, and energy are common. For example, ambitious driven typesfor whom performance, prowess, and achievement are essentialfind such drugs especially appealing on two counts: (1) stimulants are uplifting when they become depressed if their goals and ambitions, often unrealistic, fail them; (2) stimulants are facilitating and make action and activity easier when such people are on the up-swing, making it easier for them to be the way they like to be when they are performing at their best. Stimulants cast a wide net of appeal because, in addition, they counter feelings of low energy, low activity, and low self-esteem in those suffering with overt or less overt (unrecognized or atypical) depression. Finally, those individuals suffering with attention deficit-hyperactivity disorder (ADHD), often subclinical or not recognized, are also drawn to and become dependent on stimulants, because of the paradoxically opposite calming effect that stimulants have for people with this disordermuch like hyperactive children who respond well to the prescribed stimulant Ritalin.

SELF-REGULATION VULNERABILITIES

To explain why people became addicted, early psychodynamic theory placed great emphasis on subconscious and unconscious factors, pleasure and aggressive instincts or drives, and the symbolic meaning of drugs. To some extent, the stereotype of substance abusers as pleasure-seeking destructive characters (to self and others), in part, still persists and derives from these early formulations. Albeit useful and innovative at the time, much of this early perspective is now outdated, counterempathic, and does disservice to understanding the motives of addicted and alcoholic individuals.

In contrast, the self-medication hypothesis has evolved from contemporary psychodynamic theory, which has placed the centrality of feelings (or affects) ahead of drives or instincts and has emphasized the importance of self-regulation, involving self-development or self-esteem (i.e., self-psychology), relationship with others (i.e., object-relations theory), and self-care (i.e., ego or structural psychology/theory). These contemporary psychodynamic findings have evolved since the 1950s, based on the works of investigators such as Weider and Kaplan, Milkman and Frosch, Wurmser, Krystal, Woody and associates, Blatt and associates, Wilson, Dodes, and Khantzian.

Although the self-medication hypothesis has gained wide acceptance as an explanation for drug/alcohol dependency, it is not without its critics and it fails to deal with at least two fundamental problems or observations that it does not explain or address. First, many individuals suffer with the painful feelings and emotions that substance abusers experience, but they do not become addicted or alcoholic. Secondly, the self-medication hypothesis fails to take into account that addicted and alcoholic individuals suffer as much if not more as a result of their drug/alcohol use, and this might appear to contradict the hypothesis that substances are used to relieve suffering.

Many of these criticisms, inconsistencies, and apparent contradictions are better understood or resolved when addictive problems are considered more broadlyin terms of self-regulation vulnerabilities or as a self-regulation disorder. For humans, life is the constant challenge of self-regulation, as opposed to the release, relief, or control of instincts and drives as early theory suggested. What is in need of regulation involves feelings, the sense of self (or self-esteem), relationships with others, and behavior. Those prone to addictive problems are predisposed to be so, because they suffer with a range of self-regulation vulnerabilities. Their sense of self, including self-regard, is often shaky or defective from the outset of their lives. A basic sense of well-being and a capacity for self-comfort and self-soothing is very often lacking or underdeveloped from the earliest phases of development. Subsequent development of self-esteem and self-love, if it develops at all, remains shaky and inconsistent, given the compromised sense of self from which self-regard evolves. Needless to say, a poor sense of self or low self-esteem (which usually originates in a compromised or deficient self-other parenting relationship), ultimately affects subsequent self-other relationships and profoundly affects one's capacity to trust or to be dependent upon or to become involved with others.

It should not be surprising, then, that for some the energizing and activating properties of stimulants help self-doubting reticent individuals to overcome their depressive slumps and withdrawal; or that the soothing, relaxing effects of depressants help individuals who are restricted and cut off from others to break through their inhibitions and briefly experience the warmth and comfort of human contact that they otherwise do not allow or trust; or yet still, that those whose lives are racked by anger and related agitation would find a drug like heroin (an opioid analgesic) to be a powerful containing calming antidote to their intense and threatening emotions, which disrupt them from within and threaten most of their relationships with others. These examples, and those previously covered in relation to self-medication motives that govern drug use and dependency, help demonstrate the how and why of specific drug effectswhich often become so compelling that they may consume the lives of some users.

In my experience, the regulation of feelings (or affects) and self-care become the two most compelling self-regulatory problems; they combine to make dependence on substances more likely than any other self-regulation factors. Focus on these two factors explains clearly why most people who suffer subjective painful emotions do not necessarily become addicted as well as why so many substance abusers persist in using debilitating substances despite the great suffering that ensues from their abuse.

It should be noted that in this article I have stressed psychological factors and have not pursued how the regular use of addictive drugs causes Tolerance and Physical Dependence; the drugs, then, are used to remain "normal." It is not insignificant however, that the emotional pain involved in physical Withdrawal just as often is an exaggerated form of the pain that the drug-of-choice originally relieved. This aspect of drug use and relapse are covered elsewhere in this encyclopedia.

As I have indicated, substance abusers suffer in the extreme with their emotionsthey feel too much or they feel too little. When there is too much, we have described how drugs can relieve the intense unbearable feelings that addicts and others experience. Where there is too little and people are (or seem to be) devoid of, cut off from, or confused by their feelings (e.g., alexithymia, disaffected, or affect deficits), addicts prefer to counter the helplessness and loss of control caused by their lack of feelings. Instead, they choose to use drugs to change and control their feelings, even if it causes them more distress. They exchange feelings that are vague, confusing, and out-of-control, for drug-induced feelings that they recognize, understand, and control, even if such are painful and uncomfortable. Therefore, the factors of relief and control dominate people's motives for depending on drugseven if these people have to endure the pain that their dependence on drugs also entails.

Finally, deficits in self-care (again deriving from early-life developmental problems) make it likely that certain individuals will become involved with hazardous activities and relationships that lead to drug experimentation, use, and dependence. Self-care deficits refer to a major self-regulation problem, wherein individuals feel and think differently around potential or actually dangerous situations and activities, including those that involve drug/alcohol experimentation and use. Where most of us would be apprehensive or frightened or would anticipate some guilt and shame, addictive and alcoholic-prone individuals show little or no such worry. Studying these patients' pre- and postaddictive behavior patterns very often reveals similar unfeeling, unthinking, fearless behavior in conducting other aspects of their livesfor example, preventable accidents, health-care problems, and financial difficulties seem evident and common. Being out of touch with, or not feeling, their feelings (that is, their "affect deficits" or "dis-affected state") contributes to their self-care problems and thus makes it more likely that they would engage in the dangerous pursuit of drug/alcohol abuse, where others with better self-care functions would not (even in those instances where the unbearable psychological suffering and states of distress are like those experienced by addicts). In this respect, painful or unbearable feelings, alone, are not sufficient to cause substance abuse or dependence. Rather, it is when individuals lack adequate self-care capacitiesand experience intense suffering that conditions exist for addictive behavior to develop or be likely.

(See also: Addiction: Concepts and Definitions ; Causes of Substance Abuse: Learning ; Complications: Mental Disorders ; Conduct Disorder and Drug Use ; Coping and Drug Use ; Disease Concept of Alcohol and Drug Abuse ; Vulnerability: Psychoanalytic )

BIBLIOGRAPHY

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Khantzian, E. J. (1990). Self-regulation and self-medication factors in alcoholism and the addictions. In M. Galanter (Ed.), Recent developments in alcoholism, vol. 8. New York: Plenum.

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Khantzian, E. J., & Mack, J. E. (1983). Self-preservation and the care of the self-ego instincts reconsidered. Psychoanalytical Study of Childhood, 38, 209-232.

Khantzian, E. J., Halliday, K. S., & Mc Auliffe, W. E. (1990). Addiction and the vulnerable self. New York: Guilford Press.

Krystal, H. (1982). Alexithymia and the effectiveness of psychoanalytic treatment. International Journal of Psychoanalysis and Psychotherapy, 9, 353-378.

Milkman, H., & Frosch, W. A. (1973). On the preferential abuse of heroin and amphetamine. Journal of Nervous and Mental Disease, 56, 242-248.

Weider, H., & Kaplan, E. (1969). Drug use in adolescents. Psychoanalytical Study of Childhood, 24, 399-431.

Wilson, A., et al. (1989). A hierarchical model of opiate addiction: Failures of self-regulation as a central aspect of substance abuse. Journal of Nervous and Mental Disease, 177, 390-399.

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Wurmser, L. (1974). Psychoanalytic considerations of the etiology of compulsive drug use. Journal of the American Psychoanalytical Association, 22, 820-843.

E. J. Khantzian

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