CLINICAL IMPLICATIONS OF THE NEUROBIOLOGY OF ADDICTION

Mark S. Gold, M.D.

Reinforcement and the Mesolimbic Dopamine System Behavioral Manifestations of Reinforcement Postreceptor Sites of Drug Addiction

Host Factors Associated with Reinforcement Clinical Implications

Responding to the need for a greater comprehension of addiction, researchers have attempted to discover commonalities in the addiction, reinforcement, and withdrawal processes of a variety of drugs. This research has been complicated by the fact that each drug of abuse has multiple actions, including many that appear to be contradictory. Moreover, the reports of laboratory scientists are viewed with some skepticism by clinicians who know too well that addictive drugs often are taken in combination with other drugs and/or alcohol, and in environments that are difficult to duplicate in the laboratory. Nevertheless, a common neuroanatomy for drug reward and drug abstinence symptoms for all drugs of abuse has been proposed (Wise & Rompre, 1989; Kuhar, Ritz & Boja, 1991; Gold & Miller, 1992; Miller & Gold, 1992). A thorough understanding of the neuroanatomical substrates for addiction requires a discussion of how drug use results from both seeking drugs (reinforcement) and avoiding withdrawal (pharmacological dependence). This area is the subject of many ongoing studies that attempt to understand the relationship between withdrawal and reinforcement. Are they independent, as suggested by the dissociation of opiate self-administration and opiate withdrawal symptoms? Will withdrawal discomfort ultimately be found to be dissociated from additional drug-taking, or are they related?

Reinforcement and the Mesolimbic Dopamine System All drugs that are addictive in humans are considered reinforcing, in that drug use stimulates further use. Indeed, it is their reinforcing properties that is the key element in their addictive nature. While this may seem

obvious, in the past it was a drug's withdrawal effects that primarily determined its addictive classification. As a result, drugs with overtly physical withdrawal symptoms (such as opiates) were labeled addictive, while drugs with more subtle physical withdrawal symptoms (such as cocaine) were considered non-addicting.

More recently, however, researchers have acknowledged the role of reinforcement in the addiction process. Several studies have confirmed that most drugs of abuse: Can either enhance brain stimulation reinforcement or lower brain reinforcement thresholds;

May affect brain reinforcement circuits either through basal neurotransmitter discharge;

Can cause animals to work for injections into the brain reinforcement area but not for injections into other areas of the brain;

Appear to have their reinforcement properties significantly mediated by blockades of the brain reinforcement system either through lesions or pharmacological methods.

Enhance the firing rate of reward relevant mesotelencephalic DA neurons originating in the ventral tegmental area and projecting to the nucleus accumbens. Opiates appear to stimulate DA firing by inhibiting other neurons but have the same net effect on these DA systems as nicotine, amphetamine and other drugs of abuse.

Produce a marked enhancement of extracellular DA in reward-relevant DA terminal projection areas as measured by in vivo microdialysis.

Further, cocaine, opiates, alcohol and other drugs have been found to be cross-sensitive to each other and environmental manipulations such as food deprivation or

starvation. For example, heroin addicts unable to find heroin typically smoke more cigarettes, stick themselves with syringes, drink more alcohol, and so forth. Animal studies of this cross-sensitivity (Cunningham & Kelly, 1992) may ultimately explain, at least partially, drug substitution patterns and polydrug abuse in humans. On a clinical level, polydrug abuse poses numerous diagnostic and treatment challenges. In addition, recent studies have reported that the combined use of ethanol and cocaine is a common drug use combination producing an active cocaine-metabolite (cocaetbylene), which also greatly increases the risk of cocaine-related mortality (Kreek, 1987). Cocaethylene combined with ethanol's inhibition of cocaine hydrolysis may account for this increased mortality (Dean et al, 1992).

OPIATE REINFORCEMENT.

Although the primary effect of opiates is sedation, they have been shown to provoke the dopaminergic cells of the VTA and the substantia nigra, sometimes to the point of exhaustion. As with marijuana, opiates' ability to engage endogenous opiate receptors may be associated with an increase in dopamine activity. Opiates produce their analgesic, respiratory depressant, hypotensive and anxiolytic effects by binding with the delta and u 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 cAMP levels (Kosten, 1990). Terwilliger et al (1991). found that chronic morphine decreased the inhibitory G-protein G* while increasing levels of adenylate cyclase and cAMP-dependent protein kinases activity in the NAc, suggesting that changes in cAMP pathway may lead to drug reward in the NAc.

In addition, studies showing that direct injections of opiates into the VTA activates feeding and provides additional support for the role of opiate interaction with the DA system in the reinforcement of drive states (Jenck, Graton & Wise, 1986). In addition, pharmacological inhibition of the dopamine system in hungry and thirsty animals reduces the reinforcing effects of food and water (Geary & Smith, 1985).

Gardiner and others have found that the brain reward enhancement produced by drugs of abuse like opiates, cocaine, amphetamine, ethanol, and benzodiazepines is attenuated by opiate antagonist such as naloxone and naltrexone (Gardner, 1992). Naloxone-induced attenuation of many drugs' effects on brain stimulation reward supports the importance of endogenous opioid systems in all drugs of abuse, not just opioids. The opioid-dopamine connections currently are the focus of scientific study to explain the abuse of all drugs and alcohol.

Neuroanatomical studies support the interrelationship between dopamine and opioid systems, since cell bodies, axons and synaptic terminals of enkephalin-containing and endorphinergic neurons are found throughout the extent of the mesotelencephalic dopamine reward pathway of the brain. Endogenous opioid peptide neurons synapse directly onto mesotelencephalic dopamine axon terminals, forming an axo-axonic synapse that could modulate the flow of dopamine and the reward signals through the existing and well-described dopamine circuitry. Some dopamine reward neurons may synapse directly on opioid peptide neurons, possibly explaining the reported success of anti-opioid treatments in modifying drug reward and relapse (Gold, 1994; O'Brien, 1992).

STIMULANT REINFOR CEMENT.

While amphetamine has a number of direct dopamine-releasing and dopaminestorage vesicle effects, both amphetamine and cocaine produce positive reinforcement by blocking the reuptake of dopamine into the presynaptic neuron and causing an acute increase in synaptic dopamine availability (Bradberry & Roth, 1989; Kalivas & Duffy, 1990; Kuhar et al, 1991; Baptista et al, 1993). By preventing dopamine reuptake, greater concentrations of dopamine remain in the synaptic cleft, with more available at the postsynaptic site for stimulation of receptors. The abnormally high levels of dopamine in the synapse inhibits the firing rate of dopaminergic cells. Numerous studies have supported the positive reinforcement effects associated with increased synaptic levels of dopamine (Caine & Koob, 1994).

Nicotine also has been found to enhance dopamine levels and to be a positive reinforcer, although not to the same extent as other stimulants. Dopamine release in the nucleus accumbens has occurred in vitro in response to small concentrations of nicotine (Stolerman & Shoaib, 1991).

Evidence suggests that cocaine (and possibly other abused psychoactive compounds) produces its rewarding effect by increasing synaptic dopamine concentrations and consequently producing a critical increase in the stimulation of NAc dopamine receptors (Berger et al, 1988; Chang et al, 1994). In operant-conditioning experiments where animals have been shown to self-administer large quantities of cocaine and many other compounds abused by humans, Ritz and colleagues (1987) have shown that the potency of various cocaine-related compounds in maintaining self-administration behavior can be predicted by each compound's affinity for the dopamine transporter. In contrast, self- administration behavior is not predictable from drug affinities for norepinephrine or serotonin transporters (Ritz et al, 1987). Further compelling support for this so-called dopamine hypothesis comes from in vivo microdialysis and other studies (Izenwasser,

Werling & Cox, 1990; Church, Justice & Byrd, 1987). Behavioral experiments of Pettit and Justice (1989) are consistent with our observations of cocaine abuse patterns in man. They describe cocaine self- administration with a burst of drug-taking, followed by periods of chronic or episodic use. Comparing the observed behavior to extracellular dopamine levels in the nucleus accumbens, they found that the initial binge produced a high or loading dose that quickly increased dopamine levels, and that animals self-administered additional cocaine in relation to dopamine levels. Animals appeared to titrate the dose of cocaine to maintain extracellular dopamine levels in the range established by the initial cocaine binge.

Naturally, with significant advances in receptor isolation and cloning, researchers have tried to determine which of the many dopamine receptor subtypes is most responsible for cocaine reward. Researchers have identified seven different proteins that can act as dopamine receptors (Dla, DIb, D2short, D21ong, D3, D4, D5), all of which are distinct from the dopamine transporter(s) (Table 1). The assumption that cocaine's affinity for the dopamine transporter is directly related to self-administration and underlies the dopamine hypothesis of cocaine reward. According to this theory, the dopamine transporter (which serves as the primary means of removing dopamine from the synaptic cleft after its release) and inhibition of this uptake results in an acute excess of dopamine in the synaptic cleft (Dackis & Gold, 1985). It has been hypothesized the dopamine transporter is the cocaine receptor, i.e., the initial site of action that ultimately leads to the reinforcement associated with the drug (Wise & Rompre, 1989). The recent cloning of the dopamine transporter and study of D3 agonists and antagonists may someday lead to a greater understanding of the mechanisms mediating cocaine and other drug and natural reward and treatments for addiction (Gold, 1994).

Further, the rewarding effects of cocaine self-administration are reduced by D1, D2, D3 receptor antagonists but not by noradrenergic receptor antagonist (Koob, Thai & Crees, 1987). Finally, self-administration of cocaine is reduced or eliminated following lesions of the dopaminergic innervation of the NAc or lesions of NAc cell bodies (Pettit et al, 1984; Zito, Vickers & Roberts, 1985). In contrast, lesions of noradrenergic or dopaminergic terminals in the striatum of prefontral cortex are without effect (Roberts & Zito, 1987).

Finally, evidence suggest that the dopamine receptors of the NAc may function as part of a neuronal mechanism responsible for endogenous reward, which reinforces behaviors leading to natural stimuli such as food and water. Thus, operant conditioning experiments with animals indicate that the rewarding properties of food, water, or intracranial brain stimulation may depend on the NAc dopamine receptor activation (Stellar & Corbett,

1989). Therefore, the rewarding properties of drugs that lead to excessive self-administration may result from the ability of one or a combination of compounds to activate this neural substrate for endogenous reward.

ETHANOL REINFORCEMENT.

Similar to the stimulants and opiates, other abusable substances like ethanol, marijuana and other drugs are both self-administered by

animals and cause increases in dopamine and brain reward mechanisms. The dopamine hypothesis has been constructed to explain these effects and has clinical relevance on the basis of Wise's (1980) description of dopamine as the brain messenger that signals "the rewarding impact of a variety of normally powerful rewarding events . . . sensory inputs are translated into the hedonic messages we experience as pleasure . . . . 5HT and endorphins appear to play a critical role as well (O'Brien, 1992; Sellers, Higgins & Sobell, 1992).

While we have focused on 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.

CANNABIS REINFORCEMENT.

Unlike other drugs of abuse, marijuana previously had been thought to lack any pharmacological interaction with the brain's reinforcement system. However, it now appears that marijuana's principal psychoactive ingredient, delta-9-tetrahydrocannabinol (delta-9-THC) has its own endogenous receptor and ligand(s) and also acts as a dopamine agonist in a manner similar to other noncannabinoid drugs of abuse. In addition, delta-9-THC has been shown to bind with the distinct opioid receptor subtype stimulated by morphine and called the u receptor. Chronic a-decreased LC activity could cause LC hyperactivity during withdrawal. Chen and colleagues have demonstrated that delta-9-THC administration enhances presynaptic dopamine levels at brain reinforcement loci and that this increase can be attenuated by the opiate antagonist naloxone (Chen et al, 1989). Naloxone's alteration of delta-9-THC effects suggest that marijuana engages endogenous brain opioid circuitry and forms an essential association between THC "receptors," endogenous opioids and dopamine neurons in the MFB. Moreover, this association appears fundamental to marijuana's positive effects on the brain's reinforcement system and, ultimately, marijuana's abuse potential.

Behavioral Manifestations of Reinforcement

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, drug-using 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 craving and which often leads to relapse. Animal studies using microdialysis show that a conditioned response can provoke an increase in dopamine levels in the nucleus accumbens; becoming, in effect, a "priming dose" that may enhance desire for the drug. O'Brien (1992) has studied the responses of cocaine addicts to videos of people using cocaine. These videos have been found to provoke craving and arousal (measured by increases in blood pressure and heart rate, and by decreases in skin temperature and skin resistance), that are very similar to the response from using cocaine or another stimulant (O'Brien, 1992). Recently detoxified and abstinent cocaine addicts claim that numerous environmental and internal cues provoke the "taste" of cocaine, a cocaine "rush," an olfactory aura or smell of cocaine, and intense cravings and drive for the drug. Provoked craving and dysphoria on acute drug discontinuation and relapse are common features of human addiction.

Postreceptor Sites of Drug Addiction

Recent research that has attempted to find commonalities in seemingly diverse drugs of abuse has centered on the role of postreceptor systems in mediating neurotransmission and receptor function. These postreceptor systems include intracellular messengers such as G-proteins, and intracellular effector systems consisting of second messengers (i.e., cAMP), protein kinases and protein phosphatases, and phosphoproteins (Nestler, 1992).

These postreceptor research efforts stem primarily from the attention devoted to understanding neural plasticity and the molecular process by which gene expression is altered, and from the specific molecular probes designed to study such phenomena. Concepts developed in oncogene research have been applied to the study of the nervous system, leading researchers to suggest that the transcription factors capable of oncogenic transformation and implicated in cell growth regulation also act as inducible transcription factors in the stimulus-response coupling in the nervous system (Curran et al, 1990). Regulation of neuronal gene expression may explain the need for continued drug exposure in the development of addiction as well as the continuance of addiction long after drug withdrawal.

ladarola and colleagues have suggested that the short-term stimuli of a single dose of cocaine may cause physiological effects in the brain long after the cocaine has cleared (Goodwin, 1991). Researchers have found that a single dose of cocaine in the rat causes an eightfold increase in c-fos proteins in the brain up to 24 hours after the cocaine dose. Other studies have found significant c-fos increases after cocaine-related seizure in rats.

The proliferation of c-fos proteins may help to explain how cocaine can trigger changes in the neurons' genetic expression, the redefinition of the chemical environment as normal, the number of receptors, and the powerful and long-lasting cravings and memory-like effects reported by cocaine users. Further, the changes in gene expression caused by cocaine may explain the phenomenon of "kindling" as well as the high incidence of panic attacks among cocaine addicts (Post, 1992). (Kindling refers to the process whereby repeated administration of cocaine may induce seizures at levels previously tolerated by the brain. Eventually the seizures may occur even in the absence of cocaine.) Even though there is no cocaine, the "memory" of cocaine produced through altered gene expression may be sufficient to induce seizures. Similarly, altered gene expression may trigger a physiological reaction, classified by the user as a panic attack, even in the absence of cocaine administration.

Studies of specific phosphoprotein substrates of cAMP-dependent protein kinase found that cocaine or morphine administration elicited similar effects on the same phosphoproteins in the mesolimbic dopamine systems; these phosphoproteins have been labeled MCRPPs (morphine- and cocaine-regulated phosphoproteins) (Beitner-Johnson, Guitart & Nestler, 1992; Beitner-Johnson & Nestler, 1991). Five MCRPPs have been identified: Tyrosine hydroxylase (THE), NF-H, NF-M, NF-L (the major components of neurofilaments), and NF-like protein called NF-66. Morphine and cocaine administration reduce the levels of most of these NFs, while increasing phosphylation in the VTA. Compared to many other brain regions, NFs are quite common within the VTA. This fact indicates that these proteins may play an important role in the dopaminergic neurons of the VTA and that NF function is altered by morphine and cocaine administration.

Chronic cocaine and morphine administration increased levels of THE immunoreactivity in the VTA by approximately 30-40%, but had no effect on the enzyme in the NAc, substantia nigra, or caudate/putamen (Beitner-Johnson & Nestler, 1991). This increase in THE activity may reflect greater VTA neuronal activity. Conversely, chronic morphine and cocaine administration decreased THE phosphorylation in the NAc without changing the level of the enzyme (Beitner-Johnson & Nestler, 1991). Because THE present in the NAc results from VTA projections, it appears that chronic morphine and cocaine affect the enzyme differently in the VTA cells than in its nerve terminals.

Host Factors Associated with Reinforcement

Clearly, genetic factors affect the tendency toward drug addiction (see Chapter 6). These genetic factors improve the likelihood of addiction occurring either by affecting

the neurochemical response in the brain to the abused drug or the long-term adaptations in the brain following prolonged drug exposure.

In animals, many inbred strains exhibit varying degrees of predilection to addiction, drug choice, self administration, and anticipatory increase in dopamine release. For example, Fisher and Lewis rats have been bred for their higher (Lewis) or lower (Fisher) preference for morphine, cocaine, and alcohol. Marijuana facilitates electrical brain self-stimulation in Lewis rats but not in Fisher, Sprague-Dawley, or Long-Evans inbred rat strains (Gardner & Lowinson, 1991; Guitart et al, 1993).

Genetically determined biochemical factors may account for these differences. Even in rats not exposed to drugs, the NAc of Lewis rats contains lower levels of G*, higher levels of adenylate cyclase and cAMP-dependent protein kinase, and lower THE levels than Fisher rats. Also, the differences in G-proteins, cAMP system, THE and NF proteins between Lewis and Fisher strains are primarily localized to the VTA-NAc pathway; other similar areas not normally associated with reward (such as the nigrostriatal dopamine system) do not reflect such differences. These differences in G-proteins and the cAMP pathway in the NAc may ultimately change NAc neuronal response to dopamine and reflect a major neurochemical alteration associated with drug addiction.

WITHDRAWAL.

While significant evidence supports the role of dopamine (particularly in the NAc) in the reinforcement process, the neuroanatomy of withdrawal is not as clearly related to one transmitter system. However, a wide variety of dependence-producing drugs, with apparently little in common pharmacologically, share common withdrawal effects associated with the locus ceruleus (LC). Support for a shared withdrawal pathway also stems from similarities in withdrawal treatment: withdrawal symptoms associated with opiates, benzodiazepines, nicotine, and alcohol all have been treated effectively by clonidine, a medication that suppresses LC hyperactivity (Gold, Redmond & Kleber, 1978).

Unlike opiate and alcohol withdrawal, symptoms of cocaine withdrawal can be relatively mild and transient (Satel et al, 1991). The relative dearth of withdrawal symptoms may explain the episodic patterns of use reported by many cocaine addicts where periods of intense cocaine binges alternate with intervals of abstinence (Gold & Dackis, 1985). Chronic cocaine administration has been shown to decrease brain levels of DA norepinephrine (NE) while inhibiting LC activity (Dackis & Gold, 1988). One might expect that abstinence in cocaine abusers would trigger LC activity and subsequent withdrawal symptoms in a manner similar to opiate withdrawal. Certainly addicts note a sense of unease and impending problems.

Jaffe (1980) has proposed that a drug's withdrawal effects are the opposite of its rewarding effects (Jaffe, 1980). With this model, opiate withdrawal is a flu-like syndrome with dysphoria, a withdrawal that reflects LC hyperactivity and dopamine deficiency at the nucleus accumbens. Cocaine withdrawal, although quite mild, can include anhedonia, boredom, and dysphoria, which suggests symptoms that are more nucleus accumbensrelated than LC-related.

It may be that drugs whose primary reinforcing effects involve endogenous opioid systems and the locus ceruleus are associated with withdrawal states dominated by autonomic responses (i.e., opiate withdrawal), while drugs whose primary reinforcing effects involve the dopaminergic system and the nucleus accumbens are associated with withdrawal states that are primarily affective (i.e., the dysphoria and boredom associated with cocaine withdrawal). We have previously suggested that while acute cocaine administration produces a temporary dopamine increase, repeated administration produces a functional decrease that can be corrected by another cocaine administration (Gold & Dackis, 1984). If abstinence from chronic cocaine administration is associated with long-lasting dopamine system abnormalities (Kalivas & Duffy, 1990; Farfel et al, 1992; Mayfield, Larson & Zahniser, 1992; Kleven et al, 1990; Mendelson et at, 1989; Krantzler & Wallington, 1992), then medications that bind to the dopamine receptor or that increase the functional levels of dopamine should be of some therapeutic benefit.

Clinical Implications

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 retention and recovery. All addiction-prone drugs are used, at least initially, for their positive effects and because the user believes the shortterm benefits of the experience surpass the long-term costs. Once initiated, drug use permits access to a reinforcement system that is believed to be anatomically distinct from the negative/withdrawal system in the LC and elsewhere (Bozarth & Wise, 1984). This reinforcement system, accessed now by exogenous self-administration of drugs of addiction, provides the user with an experience that the brain equates with profoundly important events such as eating, drinking and sex.

Tolerance may occur when the brain environment redefines "normal" and re-sets 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 re-defines normal to require their presence in expected quantities (Gold, 1991).

Treating withdrawal symptoms with clonidine or other agents, and post-abstinence craving with desipramine, carbamazepine, bromocriptine and the like, have had mixed success in eliminating drug use, improving outcomes and reducing relapse. To assess the role of craving and withdrawal in continued drug use, we analyzed data from 1,626 patients voluntarily admitted to a primary rehabilitation center in Minnesota (Gold & Miller, 1993). Comparing the alcohol-only versus the cocaine patients who relapsed, craving was not a major self reported cause of relapse. These data agree with other reports in the literature suggesting that relapse is not commonly related to craving. Thus, successful pharmacological treatment of craving may not have an effect on relapse. Drug seeking and use are such highly ritualized, automatic behaviors that the addict may not require the intervention of conscious thoughts or distinct craving states to return to use.

Developing an understanding of the biological and other factors involved in drug-taking ultimately may lead to new theories and treatments that reduce or eliminate drug-taking and allow physicians m treat patients with relapse prevention and other cognitive approaches aimed at re-prioritizing the addict's reward and drive status.

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