Several studies have confirmed the comorbidity of various substances of abuse. The Epidemiológica! Catchment Area (ECA) study found that 16% of the general population experienced alcoholism at some point during their lifetime. Thirty percent of these alcoholics also suffered from other drug dependence. Similarly, the rates of alcohol dependence among other drug addicts were high: 36% of cannabis addicts, 32% of amphetamine addicts, 67% of opiate addicts, and 84% of cocaine addicts were also alcoholics.1 These studies, combined with clinical observations regarding the concurrent use of multiple substances, suggest common biological determinants.2
Responding to the need for both stimulant and opiate investigation and for a greater comprehension of addiction, several researchers have attempted to discern commonalities in the reinforcement, addiction, and withdrawal processes for a variety of drugs. A thorough understanding of these processes requires a discussion of how drug use results both from seeking drugs (reinforcement) and avoiding withdrawal (pharmacological dependence). The clinical implications of reinforcement and withdrawal will be discussed in detail.
In the 1950s researchers suggested that addiction-prone drugs activated brain reinforcement circuits. Since that time, studies have confirmed that all drugs of abuse/ addiction:
* either enhance brain stimulation reinforcement or lower brain reinforcement thresholds;
* affect brain reinforcement circuits either through basal neuronal firing and /or basal neurotransmitter discharge;
* will cause animals to work for injections into the brain reinforcement area but not for injections into other areas of the brain;
* will have their reinforcement properties significantly mediated by blockades of the brain reinforcement system either through lesions or pharmacological methods.3
The medial forebrain bundle (MFB) region of the brain, together with the nuclei and projection fields of the MFB, have been found to be primarily responsible for the positive reinforcement associated with drugs of addiction. Histofluorescence mapping techniques have revealed a close association between the brain stimulation reinforcement region and the mesotelencephalic dopamine (DA) system. Additional studies have confirmed the importance of DA neurotransmission to brain reinforcement.4 While the initial hypothesis suggested that electrical brain stimulation reinforcement directly triggered DA rveuratransmission, it is now believed that the activation of the DA neurons occurs as a convergence following activation of a myelinated caudaily running fiber system whose neurons lack the properties associated with DA neurons^ (Figure). Drugs of abuse/addiction enhance brain reinforcement through their actions upon this DA convergence.
Species-specific survival drives, such as eating, drinking, copulation, and seeking shelter, are positive reiiiforcers. Drugs of abuse/ addiction are also positive reinforcers. The fundamental element in animal response to these survival drives appears to be forward locomotion. In fact, forward locomotion response apparently results from a number of drugs, including cocaine, amphetamine, opiates, barbiturates, benzodiazepines, alcohol, nicotine, caffeine, cannabis, and phencyclidine.11 Specifically, these positive reinforcement drugs of abuse/addiction appear to share a common effect on DA systems (Table).
Figure. Schematic diagram of the brain-reward circuitry of the mammalian (laboratory rat) brain, with siles at which various abusable substances appear to act to enhance brain-reward arid thus to induce drug-using behavior and possibly drug craving (CSS indicates [fie descending, myelirtated. moderately fast-conducltrig component o! the brain-reward circuitry that is preierentiaily activated by electrical intracranial selfstimulation DA indicates the subcomponent of the ascending mesolimb/c dopaminergic system !hat appears to be preierentiaily activated by abusable substances. LC indicates the locus coeruleus. VTA indicates the ventral tegmental area, and Ace indicates the nucleus accumbens. NE indicates the noradrenergic fibers, which originate in the locus coeruleus and synapse into the general vicinity of the ventral mesencephalic DA cell fields GABA indicates the GABAergic inhibitory fiber systems synapsing upon both the locus coeruleus noradrenergic libers and the ventral mesencephalic DA cell fields. (From Gardner E Brain reward mechanism. Chapter 7 in Substance Abuse: A Comprehensive Textbook. 2nd ed. Lowinson JH. Fiuiz P. Millman RB, eds. Baltimore, Md: Williams & Wilkins. 1992, with permission.)
Amphetamine and cocaine achieve positive reinforcement by blocking the rcuptake of DA into the presynaptic neuron.7 By preventing DA reuptake, greater concentrations of DA remain in the synaptic cleft with more DA available at the postsynaptic site for stimulation of specific receptors. The abnormally high levels of DA in the synapse inhibits the firing rate of dopaminergic cells and mediates the process by which synaptic DA is inactivated. Numerous studies have supported the positive reinforcement effects associated with increased synaptic levels of DA.0 Nicotine has also been found to enhance DA levels and to be a positive reinforcement, although not to the same extent as cocaine. DA release in the nucleus accumbens has occurred in vitro in response to small concentrations of nicotine. s This DA effect of nicotine may explain the addictive power of tobacco.
Unlike other drugs of abuse/ addiction, marijuana had previously been thought to lack any pharmacological interaction with the brain's reinforcement system. However, it now appears that marijuana's principal psychoactive ingredient, deltal'-tetrahydrocannabinol (delta"-THC), acts as a DA agonist in a manner similar to other noncannabinoid drugs of abuse/ addiction.9 In addition, delta9-THC has been shown to bind with the distinct opioid receptor subtype called the mu receptor. Chen and colleagues have demonstrated that deItal>-THC administration enhances presynaptic DA levels at brain reinforcement loci and that this increase can be attenuated by the opiate antagonist naloxone.4 Naloxone's alteration of deltayTHC effects suggests that marijuana engages endogenous brain opioid circuitry and formulates an essential association between these endogenous opioid s and DA neurons in the MFB. Furthermore, this association appears fundamental to marijuana's positive effects upon the brain's reinforcement system and, ultimately, marijuana's abuse potential.
Possible Neurochemical Basis for Reinforcement/ Withdrawal
Although the primary opiate effect is sedation, opiates have been shown to provoke the dopaminergic cells of the ventral tegmental area and the substantia nigra, sometimes to the point of exhaustion.6 As with marijuana, opiate ability to engage endogenous opiate receptors may be associated with the increased DA activity. Opiates produce their analgesia, respiratory depression, hypotension, and axiolytic effects by binding with the delta and mu receptors and inhibiting adenylate cyclase. This inhibition results in diminished conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) and decreased phosphoprotein levels. It has been suggested that opiate withdrawal may result in increased c A M P levels.10
Studies show that direct injection of opiates into the ventral tegmental area activates feeding, which provides additional support for the role of opiate interaction with the DA system in the reinforcement of drive states." In addition, pharmacological inhibition of the DA system in hungry and thirsty animals reduces the reinforcing effects of food and water.12
Similar to the stimulants and opiates, ethanol has been shown to induce the release of DA in the nucleus accumbens. Furthermore, low-dose ethanol apparently will stimulate neurons in the ventral tegmental area, suggesting that ethanol activates DA projection from the ventral tegmental area to the nucleus accumbens. In addition, alcohol-preferring rats will self-administer alcohol directly into the stomach, apparently for its reinforcement properties and not because of its taste, smell, or caloric content.13
Although this section has concentrated on the pharmacological effects of addictive drugs in the reinforcement process, other factors may lead to positive reinforcement. For example, drug use may enhance a user's social standing, encourage approval by drug-using friends, and convey a special status to the user.
REINFORCEMENT LEADS TO LEARNING
As demonstrated above, cocaine and opiates, on a primitive level, produce rapid reinforcement described as seeking a sense of wellbeing. This reinforcement is clearly neurobiological in that drug use stimulates repetition of the behavior and produces a sense of accomplishment similar to speciesspecific survival behaviors. Drug users feel as if they have acted to preserve the species, when in reality they have simply bypassed the normal behavior reinforcement system.
The changes in mood associated with drug reinforcement serve as an unconditioned stimulus. Given frequent association with these changes, a variety of other factors, including the psychological (mood states, cognitive expectations of euphoria, stress, etc.) and environmental (drug paraphernalia, drugusing locations or friends, etc.), can become conditioned stimuli. Exposure to these conditioned stimuli can precipitate withdrawal-like physiological responses that the user interprets as drug cravings and that often lead to relapse.
While significant evidence supports the role of dopamine in the reinforcement process, the neuroanatomy of withdrawal is not as clearly defined. However, a wide variety of dependence-producing drugs, with apparently little in common pharmacologically, share common withdrawal effects associated with the locus coeruleus (LC). Support for a shared withdrawal pathway also stems from similarities in withdrawal treatment-opiates, benzodiazepines, nicotine, and alcohol have all had their withdrawal symptoms treated effectively by clonidine, a medication that suppresses LC hyperactivity.14
Normally, the LC is activated by pain, blood loss, and cardiovascular collapse, but not by nonthreatening stimuli. ' ^ However, in the opiate-dependent animal, withdrawal precipitation clears opiates from the mu receptor and places neurons in the LC into a state of hyperexcitability (also referred to as rebound from chronic inhibition or LC hyperactivUy)."1 The resultant noradrenergic hyperactivity and release appears to be an essential factor in the precipitation of withdrawal symptoms and signs.
In 1988, Grant and colleagues demonstrated that behavioral patterns associated with electrical activation of the LC also occur during opiate withdrawal in nonhuman primates, thereby establishing that the LC hyperactivity seen during opioid withdrawal is responsible for important aspects of the opioid withdrawal syndrome.17 Furthermore, other studies have confirmed that the LC cells are hyperactive during withdrawal and that the actual chronology of opiate withdrawal effects correlated to the in vivo activity of LC and increases in G-protcins, adenylate cyclase, and cAMP-dependent protein kinase in the rat LC.18
Studies show that withdrawal activation of the LC is not observed in isolated slice preparations or by lesions of the paragigantocellularis (the major excitatory input to LC), which suggests the importance of this input to the LC hyperactivity in withdrawal.14 Lesions of the glutaminergic nucleus paragigantocellularis, in addition to excitatory amino acid antagonists, can suppress opiate withdrawal.2'1 A recent study using antagonists of the Nmethyl-d-aspartate N MDA) subtype of excitatory amino acid receptors lessened morphine withdrawal behaviors while not apparently reversing LC hyperactivity.21
Numerous studies have chronicled ethanol's ability to suppress LC activity,- with significant evidence supporting the role of Q2 adrenoreceptors in the pathogenesis of alcohol addiction. An a.2 agonist, clonidine, has been shown to be effective in treating alcohol withdrawal.23 Recently, administration of the O2 antagonist yohimbine has been found to reverse the LC inhibition of ethanol.24 This finding suggests that the a, receptors are involved in LC inhibition and in the development of ethanol tolerance and even withdrawal. Furthermore, this finding presents the possibility that a morphine/ yohimbine combination may provide effective analgesia with a decreased risk of addiction.
Unlike opiate and alcohol withdrawal, symptoms of cocaine withdrawal can be relatively mild and transient.2^ The relative dearth of withdrawal symptoms may explain the episodic patterns of use reported by many cocaine addicts where periods of intense cocaine use alternate with intervals of abstinence.2'1 Chronic cocaine administration has been shown to decrease brain levels of DA and norepinephrine (NE) while inhibiting LC activity.2' One might expect that abstinence in cocaine abuse would trigger LC activity and subsequent withdrawal symptoms in a manner similar to opiate withdrawal; however, it appears that NE depletion limits the withdrawal response. The intense craving and high recidivism rate associated with cocaine use appears to derive from a drive state rather than the avoidance of withdrawal discomfort.
In fact, for all drugs, reinforcement may be more important than withdrawal in the persistence of addiction and relapse since successful treatment of withdrawal has not generally improved treatment reten tion and recovery. All addiction-prone drugs are used, at least initially, for their positive effects and because the user believes the short-term benefits of this experience surpass the long-term costs. Once initiated, drug use permits access to the reinforcement system, which is believed to be anatomically distinct from the negative/ withdrawal system in the LC and elsewhere.28 This reinforcement system, accessed now by exogenous self-administration of the drug, provides the user with an experience that the brain equates with profoundly important events like eating, drinking, and sex.
Tolerance may occur when the brain environment redefines "normal" and resets neurochemical homeostasis. If a brain affected by 30 mg of methadone or a gram of cocaine per day becomes the new neural "normal," then it should not be surprising that relapse and drug use are the rule rather than the exception. If drugs are taken because of drive states, they develop a life of their own as the brain redefines normal to require their presence in expected quantities.29
Drug use becomes an acquired drive state that permeates all aspects of human life. Withdrawal from drug use activates separate neural pathways that cause withdrawal events to be perceived as life- threatening, and the subsequent physiological and psychological reactions often lead to renewed drug consumption. The treatment research consensus that time in treatment and /or abstinence is the greatest predictor of treatment success may reflect the amount of time required to reinstate predrug neural homeostasis, fading of drug reinforcement behavior patterns and conditioned cues, and the reemergence of endogenous reinforcement for work, friends, shelter, food, water, and copulation.29
With the exception of methademe, the current pharmacological treatments for drug abuse/addiction, including desipramine, bromocriptine, fluoxetine, and clonidine, rely primarily on the alleviation of withdrawal symptoms. While these medications have helped some patients facilitate the transformation from addiction to a drug-free state, the frequency of relapse experienced by most addicts suggests the importance of reinforcement in encouraging future drug use.
Drug reinforcement is so powerful that even when it is eliminated by pharmacological blockade (e.g., naltrexone), humans quickly identify themselves as "opiate unavailable" and non receptive. While under pharmacological blockade, humans will change their behavior (i.e., stop taking opiates). Without additional treatment, their attachment to the drug and its effects remains unchanged. Once an antagonist is discontinued, the untreated addict continues selfad ministration. The data are in agreement with Griffiths et al on the difficulties of lasting suppression of drug self-administration behavior.30
Aversi ve conditioning and systematic deconditioning have been similarly disappointing since the effects of drug stimuli arc wellknown and well-remembered by the addict. For example, contingency incarceration programs where probationers with drug offenses face a return to prison upon relapse have not proved to be an effective deterrent to drug use.31 However, reduced probation time was shown to be a reinforcer.32 Even medical practitioners who faced the loss of their professional license did not totally avoid relapse to cocaine and opiate abuse.33
The failure of aversive conditioning in the treatment of drug addiction is logical given the assumption that the brain emphasizes the positive reinforcement of survival behaviors such as eating, drinking, and sex while decmphasizing the hostility of the environment. Reinstatement of drive status appears more persistent than memory for pain or dysphoria. Memory is highly state-dependent and access to memories while intoxicated may be severely limited to similar intoxication states. Reinforcement of drive states is naturally more important than a real risk of some future consequences from drug use.
Extinction treatment was thought to be of potential benefit if addicts would be forced to use heroin in the presence of a naltrexone blockade or to perform nonreinforced drug self-administration. However, studies where the addict was encouraged to perform his drug-use ritual in the laboratory and use heroin during active blockade demonstrated a state-dependent extinction.34 However, since extinguished response could be readily reinstated upon discontinuation of naltrexone, usefulness in treatment was limited.
Clearly, relapse prevention and successful treatment for addiction require much more than the alleviation of withdrawal symptoms. It is well known that patients with higher pretreatment levels of social supports, employment, and productivity have a better prognosis for successful response to initial treatment and long-term abstinence.35 Treatment outcome for these patients may improve because these patients perceive the long-term cost of drug use (loss of family or job) as outweighing the short-term "benefit" of drug use. Educational efforts that mobilize the family, employer, and friends while stressing the risks associated with drugs help individuals to stop or avoid drug use.
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Possible Neurochemical Basis for Reinforcement/ Withdrawal