Neurobiology of marijuana abuse

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Neurobiology of marijuana abuse Mary E. Abood and Billy FL Martin Marijuana has a long histo y of abuse yet, as described here by Mary Abood and Billy Martin, there is little evidence that animals will self-administer the primary psychoactive constituent, tetrahydrocannabinol, or that marijuana stimulates brain reward pathways. While marked tolerance develops to marijuana, it has been difficult to demonstrate physical dependence, and unfil recently the mechanisms by which cannabinoids produced their behavioral effects were poorly defined. The development of new synthetic analogs played a critical role in the characterization and cloning of the cannabinoid receptor. Insight into cannabinoid receptors may lead to a better understanding of marijuana abuse in humans and provide new therapeutic strategies for several disorders. Marijuana is the common name for the plant Cannabis sativa. It has been used for centuries, primarily for its euphoric effects, and is one of the leading drugs of abuse in our time. Other names for the plant or its products include hemp, hashish, chasra, bhang, ganja and dagga. In the USA, the popularity of marijuana first emerged in the 192Os, at a time when the abuse potential of other drugs such as cocaine and morphine was first understood. As a consequence, marijuana was regarded as similarly dangerous and addictive. It was erroneously classified as a narcotic, and it was made illegal. In the 1960s and 1970s it became a popular drug among young people, and there were many efforts to decriminalize it. All parts of both the male and the female plant contain psychoactive cannabinoids, with the highest concentrations found in the flowering tops. Most commonly, the plant is cut, dried, chopped and incorporated into cigarettes. The hemp plant synthesizes at least 400 chemicals, of which more than 60 are structurally related to (-)-A’-tetrahydrocannabinol (A9-THC), the primary constituent in psychoactive marijuana. In addition to A9-THC, other cannabinoids found in the plant are As-THC, cannabidiol and cannabinol. In vivo, A9-THC is converted rapidly into a centrally active metabolite, 11-hydroxy-A THC. While most of the other 6. R. Martin is Professor and M. E. Abood is Assistant Professor, Department of Pharmacology and Toxicology, Box 613, MCV Station, Virginia Commonwealth University, mond, VA 232984613, USA.

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cannabinoids are either inactive or only weakly active, they have the potential of interacting with A9-THC to either increase or decrease its potency. Hundreds of additional compounds are produced by pyrolysis when marijuana is smoked, which may contribute either to acute effects or to long-term toxicity. Investigators have always been at a serious disadvantage in trying to address the science of plant material abuse. It is impossible to evaluate the pharmacological and toxicological consequences of human and animal exposure to hundreds of compounds simultaneously. Thus, the scientific community has devoted its attention to A9-THC. While this approach is quite acceptable for evaluating the biochemical and undermolecular mechanisms lying the actions of the cannabinoids, it is far less appropriate for assessing the long-term consequences of marijuana use. Psychoactive and pharmacological effects in humans The behavioral and pharmacological effects of marijuana and its active constituents have been studied extensively in humans for the past 20 years. The results have been well documented and thoroughly reviewed’“. It is not surprising that the subjective effects of marijuana vary somewhat from individual to individual. Several attempts have been made to reconcile these reported differences in marijuana’s behavioral effects. Behavioral responses may well vary as a function of dose, route of administration, setting, the ex-

perience and expectation of subjects and individual vulnerability to certain psychotoxic effects_ Furthermore, the amount of active material that reaches the bloodstream is highly dependent upon the smoking technique, the cannabinoid content of the sample, and the amount altered by pyrolysis. Despite the possible influence of any of the above factors, there are several behavioral effects that are typically ascribed to marijuana*. The most prominent feature is the initial period of euphoria or ‘high’ that has been described as a sense of well-being and happiness. Euphoria is frequently followed by a period of drowsiness or sedation. Perception of time is altered along with distortions in both hearing and vision. The subjective effects include dissociation of ideas. Illusions and hallucinations occur infrequently. A number of studies have impaired funcdemonstrated tioning in a variety of cognitive and performance tasks, including impaired memory, altered time sense and decrements in tasks such as reaction time, concept formation, learning, perception, motor coordination, attention and signal detection2. Interestingly, there are individuals in many of these studies who demonstrated increased performance in many of these tasks. They have tended to be experienced users, and the possibility that tolerance has developed, or that some other compensation has occurred, cannot be discounted. At doses equivalent to one or two cigarettes, processes involved in driving and flying are impaired; the impairment persists for 4-8 hours, long after the user perceives the subjective effects of the drug3. Conversely, there are examples where driving ability is enhanced in some subjects2. The impairment produced by alcohol is additive to that induced by marijuana. At higher doses, acute panic reactions or mild paranoia have been observed; these may be due to the alterations in perception produced by the drug. Some subjects do panic when perceiving a loss of mental control. The paranoia has been harder to document; to some extent it may be due to the illegal status of the drug, or it may be a compensatory

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Fis_ 1. ~t&rxs&~ in vivo ad in vitro activities of cartnabinoids. The abilities of over25 car?abinoid analogs to inhibit locomotor a&v@~ andproduce anMx@ption (taNlick latency), hypothermia, and ring immobility (catalepsy) In mice ?re plotted as log EO, values m&g tf& &KS in the [%t]W5594O @and-binding assay. Data from Martin et a/. (1991) Pharmacol. Blochem. Behav. 40,471-478, with permission.

reaction for the paniP. With extremely high doses, an acute toxic psychosis accompanied by depersonalization and loss of insight has been reported3. This is a short-lasting condition, its frequency is quite low in Western societies, and it seems to affect mainly heavy user@. Common predisposing factors are preexisting personality disturbances. Considerable attention has focused on potential psychopathological effects of continued mari+na use. An ‘amotivational syndrome’ has frequently been described in the literature, where chronic marijuana users have been noted to exhibit apathy, dullness and impairment of concentration and judgement, memory, along with loss of interest in personal appearance and pursuit of conventional goal& Well-controlled clinical studies, however, have failed to provide strong evidence that an amotivational syndrome is a direct consequence of marijuana us612. There is also little, if any, evidence to support the early contentions that marijuana induces aggression. There are a number of c0nfOunding factors in examining the psychopharmacology of marijuana, such as cultuml influences including socialization 2nd expectations of the user. In addition, there is the question of marijuana’s influence on preexisting psychiatric illness, as well as the documentation of ‘selfmedication’ of depressed individuaG2. In summary, while there is no conclusive evidence for a chronic psychopathology of marijuana, it is premature to conclude that there is none. The most consistent acute pharmacological effects of Ag-THC

are dilation of conjuctival blood vessels and tachycardial. These are observed in both naive and experienced marijuana smokers. Blood pressure remains relatively unchanged unless high doses are used, in which case orthostatic hypotension ensues. Although increased appetite is frequently attributed to smoking marijuana, appetite has not been consistently enhanced when controlled studies have been carried out with either marijuana or A’-THC. Mariju2n2 differs from many other drugs of abuse in its lack of effect on respiratory rate, even at very high doses. As for toxicity associated with chronic marijuana use, there has been some evidence of alterations in the reproductive system, immune system 2nd lungs. However, convincing evidence has yet to emerge from well-controlled studies that marijuana is solely responsible for any alterations that have been observed in these organ systems. Pharmacological effects in laboratory animals Cannabinoids have been shown to produce a unique syndrome of behavioral effects in 2 wide variety of animal species. At low doses, they produce 2 mixture of depressant and stimulatory effects, and at higher doses, predominantly CNS depression. The depressant effects of the psychotomimetic cannabinoids differ from other CNS depressants. A state of hyperreflexia or hyperstimulation is observed during the depressive portion of the syndrome4. This unique syndrome has been useful as a model for predicting psychotomimetic activity. Higher doses of cannabinoids produce a more classical

type of depression in rodents, including catalepsy. Martin et al5 have demonstrated that cannabinoids that produce 2 combination of hypoactivity, hypothermia, antinociception and catalepsy in mice are very likely to be psychoactive. Other animal models that correlate with psychoactivity are dog static ataxia, monkey overt and drug discrimibehavior, natio&‘. Hundreds of synthetic cannabinoid compounds have been evaluated for pharmacological activity in these procedure& (Fig. 1). In fact, the strict structureactivity relationship for the cannabinoids was for many years the only evidence to support the existence of 2 cannabinoid receptor. The development of novel potent analogs has played 2 major role in the characterization and cloning of the cannabinoid receptorssg. Some of the more interesting new analogs are presented in Table I and Fig. 2. The bicyclic Cl’55940 and derivatives were Melvin 2nd developed by Johnson”; the aminoalkylindoles were developed by the research group at Sterling**, the dimethylheptyl derivatives of As-THC and A’-THC by Mechoulam et aZ.l* and Razdan et a1.13, respectively. The data presented in Table I demonstrate the dramatic increase in potency exhibited by some of these analogs. However, these data also suggest some possible differences between A’-THC and these novel compounds. A’-TI-IC is almost equipotent in producing all of these effects whereas the analogs exhibit differing potencies in the various measures. One of the most notable differences is their greater potency in depressing spontaneous activity. For

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example, CP55940 is almost 10 times more effective in reducing motor activity than in producing catalepsy, and WIN55212 is four times more potent in producing hypoactivity than antinociception. These differences may well result from these analogs activating multiple biochemical processes rather than a single system. Many drugs abused by humans have been shown to augment brain reward circuits, via mesocorticolimbic dopamine pathways14 (see also Koob, this issue). Gardner et al.1517 have found, in Lewis rats, that A9-THC augments intracranial electrical self-stimulation in the median forebrain bundle, and also enhances presynaptic basal dopamine efflux in the nucleus accumbens and prefrontal cortex. Since these effects have only been reported in one strain of rat, their extrapolation to human abuse is tentative at best.

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Tolerance and dependence in animals

Determination of dependence, either physical or psychological, is not easy in a human population, given the plethora of social and legal factors that impact on the drug abuser, and the fact that few users abuse just one drug. Therefore, animal studies are important in assessing drug dependence (for a recent review, see Pertwee”). Studies conducted with A9-THC have not provided consistent evidence that dependence occurs with the cannabinoids. Although there are several strategies for assessing dependence liability of drugs in laboratory animals, the most prominent procedure is continual drug exposure, cessation of treatment, and observation of the animal for signs of withdrawal. Using an aggressive intravenous treatment regimen of A9THC in monkeys, Kaymakcalan” demonstrated that significant effects occurred during drug abstinence. However, it is not clear that the observed behaviors represented withdrawal, since A9THC did not reverse these effects unequivocally. On the other hand, Beardsley et aLzO showed that upon cessation of continuous intravenous infusion of A9-THC, monkeys suffered a disruption of schedule-controlled behavior, which could be reversed by readministration of A9-THC. HOW-

ever, similar withdrawal symptoms were not always reproduced in .other laboratories or when other routes of administration were employed. One of the first definitive studies was conducted by McMillan et aLzl, who showed that administration of increasingly large doses of A9-THC to either dogs or pigeons on a continual basis resulted in profound tolerance, yet withdrawal symptoms did not occur when the drug was removed. While self-administration of drugs has been taken as an indication of psychological dependence and/or abuse potential, few reports claim to have established experimental models for selfadministration of A9-THC. The inability to maintain self-administration of A9-THC was shown long ago by Kaymakcalan”. Additional evidence was provided by Carney et al.=, who showed that A9-THC would not substitute for drugs with strong reinforcing properties. This observation suggests limited potential for development of physical crossdependence, as well as limited psychological dependence due to the weak reinforcing properties of A’-THC. The observation that dependence and tolerance develop con-

comitantly with many centrally acting drugs led to the assumption that tolerance may provide indirect support for the development of dependence. In some cases, the severity of the withdrawal syndrome can be correlated with the degree of tolerance development. Tolerance development has been shown to occur to A’-THC-induced anticonvulsant activity, catalepsy, depression of locomotor activity, hypothermia, immunosuppreshypotension, sion, static ataxia in dogs and alteration of response rates and accuracy of schedule-controlled behaviors4=. A 100-fold development of tolerance has been observed in pigeons, dogs and rodents, and some reports indicate an even greater degree of tolerance. It is clear that tolerance develops differentially in all species as a function of the parameter measured. There is no indication that the causes of tolerance can be explained by altered pharmacokinetics but rather, development of tolerance must be described as a pharmacodynamic event. The evidence so far suggests that a tremendous degree of tolerance to A9-THC can be observed in the absence of a similar degree of withdrawal symptomatology.

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Biochemical tolerance has been documented in many systems used to study receptor-regulated adenylyl cyclase activity. The cellular response to agonists declines reversibly after drug addition, and upon continued exposure, the cell loses its ability to respond to that ligand. Short-term of NlSTG2 neuroExK cells to A’-THC, while not affecting cell morphology or growth, produced an attenuation of cannabinoid-inhibited adenylyl cyclase activity’“. Cells pretreated for 24 hours with 1 pM A9-THC showed control levels of basal and sea&n-stimulated cAMP accumulation, but A9-THC produced only a 17% decrease (vs. 35% in vehicle-treated cells) in cAMP accumulation. Carbachol, a muscarinic acetylcholine receptor agonist that also inhibits adenylyl cyclase, produced its normal response in the A’-THC-treated cells. Thus, the desensitization produced here was specific for the cannabinoid receptor-mediated response. The desensitization process was time- and dose-dependent, and reversible - features characteristic of biochemical tolerance. Another response of cells to continued presence of agonist is receptor downregulation. In most systems this process follows desensitization, and is characterized by a loss of ligand binding at cell surface receptors. This phenomenon has not yet been demonstrated for cannabinoid receptors. It has been shown that chronic exposure to A’-THC fails to alter irreversibly brain cannabinoid receptorsZ. Tolerance and dependence in humans It is well established that chr~nk heavy use of cannabis does not result in a withdrawal

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syndrome with severe symptomatology. However, the occurrence of some form of psychological dependence or craving is more probable than physical dependence. There are numerous case reports of psychological dependence to cannabis, each with unique features26. The initial evidence for ‘dependence’ upon cannabis arose from uncontrolled clinical observations following cessation of long-term use in countries such as India, Greece or Jamaica where the available cannabis has high potencf6. Jones and colleagues2629 studied the development of tolerance and dependence to cannabis and A’THC under a more rigorous treatment paradigm. A’-THC (doses of 10 or 30 mg) or cannabis extract was administered orally to volunteers every 3 or 4 hours around the clock, for up to 21 days. Upon cessation of treatment, the most prominent and frequent symptoms were increased irritability and restlessness. Other prominent symptoms were insomnia, anorexia, increased sweating and mild nausea. Objective changes included reduction in body weight, increased body temperature and hand tremor. Both the subjective and objective changes could be diminished by re-administration of A9-THC, suggesting a withdrawal syndrome. The intensity of the effects observed was dependent upon the length of the treatment time and the dose. Jones26 also reported development of tolerance to the behavioral and pharmacological effects in these subjects. Tolerance to A9-THC was best summarized by Hollister’, who concluded that relatively little tolerance develops when the doses are small or infrequent and the drug exposure is of limited duration. Tolerance

forms of leaf and resin.

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clearly develops when individuals are exposed to high doses for a sustained period of time. The relative intensity of the withdrawal syndrome is dependent upon the quantity (or dose) as well as the frequency and duration of use. Under the most intense exposure regimen, the symptoms of withdrawal are relatively mild in most subjects. There are few reports in which an abrupt interruption in marijuana use has led to incapacitation of the individual abusing this substance. The number of people who have difficulty in controlling their abuse of cannabis to the extent that they require professional treatment is relatively small. Characterization of the cannabinoid receptor In vitro, cannabinoids have been shown to inhibit adenylyl cyclase activity in membranes from N18TG2 neuroblastoma cells and NGIOS-15 neuroblastoma x glioma hybrid cells, and cAMP production is inhibited via a pertussis toxin-sensitive G protein30. These cells also contain opioid receptors and muscarinic acetylcholine receptors, but the effects of cannabinoids are not inhibited by antagonists of either receptor type, Inhibition of adenylyl cyclase is stereoselective as well as specific for psychoactive cannabinoids, since cannabinol and cannabidiol produce minimal response. Furthermore, cannabinoids inhibit CAMP production in rat brain31. The aminoalkylindole analogs have recently been shown to inhibit adenylyl cyclase activity in rat brain membranes and to corn ete for cannabinoid-binding sitesP2 . These compounds are interesting in that they were initially developed as nol,ste-oidal anti-inflammatory agents apd some analogs have demonstrable in vitro cannabinoid receptor antagonist effects. Receptor binding studies indicate that the tritiated aminoalkylindole WIN55212 (Fig. 2) shares a common site of action with the cannabinoids33. Radioligand binding studies with [3H]CP55940 (Fig. 2) in tissue homogenates and in tissue slices have shown that the receptor is localized primarily in the brain. Autoradiographic studies by Herkenham et al.34*35 have shown a heterogenous distribution that is

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conserved throughout a variety of mammalian species, including humans, with most of the sites in the basal ganglia, hippocampus and cerebellum. Binding sites are also abundant in the cerebral cortex and striatum. It is interesting to speculate that these sites correlate with some of the pharmacological effects of marijuana, for example, cognitive impairment (hippocampus and cortex), ataxia (basal ganglia and cerebellum) and low toxicity (lack of receptors in the brainstem). Recently, Matsuda et d9 reported the molecular cloning of the receptor for cannabinoids. Using an oligonucleotide probe based on another G proteincoupled receptor, substance K, they isolated a clone from a rat brain library that had homology with other G protein-coupled receptors, but was unique. Identification of the ligand for this ‘orphan receptor’ involved screening many candidate ligands, including opioids, neurotensin, angiotensin, substance P and NPY, among others, until cannabinoids were found to act via this molecule. In cells transfected with the clone, (3’55940, A9-THC and other psychoactive cannabinoids, but not cannabidiol and cannabinol were (inactive cannabinoids), found to inhibit adenylyl cyclase, whereas in untransfected cells no such response was found. Furthermore, the rank order of potency for inhibition of adenylyl cyclase in transfected cells correlated well with results for cell lines previously shown to possess cannabinoid-inhibited adenylyl cyclase activity. Distribution of the mRNA of the clone also paralleled that of the cannabinoid receptor. Knowledge of the structure of the cannabinoid receptor provides the opportunity to raise antibodies to this molecule in order to further probe its function. In addition, it raises a most interesting question: what is the natural ligand(s) for this receptor? Therapeutic uses Throughout its history, cannabis has been reported to have clinicai utility36; the literature is replete with anecdotal reports of the therapeutic usefulness of the plant material. It was not until pure active principles and syn-

thetic analogs became available, however, that folklore could be tested clinically. There have been reports to indicate that the cannabinoids may be effective in treating pain, convulsions, glaucoma, muscle spasticity, bronchial asthma, nausea and vomiting*. These disorders are currently treated with drugs that are structurally distinct from cannabinoids. Developing an effective cannabinoid analog for treating any of these conditions most likely would involve a mechanism of action distinct from that of the agents that are now employed. Obviously, new strategies are crucial for treating patients who are unresponsive to current therapy or suffer severe side-effects. Among these therapeutic indications, only one has resulted in practical utility. Nabilone, a synthetic cannabinoid, was marketed in Canada in 1981 as an antiemetic adjunct to cancer chemotherapy, but it gained little clinical acceptance. Despite the development of analogs with extremely high potency, none has been devoid of the characteristic cannabinoid behavioral effects. A therapeutic agent is not likely to emerge until appropriate pharmacological selectivity has been achieved. Although the behavioral effects of A9-THC and its status as an abused substance have discouraged its use as a therapeutic agent, a few clinical uses have emerged. In 1987, A9-THC (under the name dronabinol) was introduced in the USA for use as an anti-emetic in patients receiving cancer chemotherapy who were refractory to the usual anti-emetics. The drug has been well received by physicians in the USA and there is little evidence that it is being abused. More recently, marijuana has been used by acquired immune deficiency syndrome (AIDS) victims to block the nausea of chemotherapy and in attempts to stimulate their appetite. Clinical trials with dronabinol in AIDS patients have suggested improved appetite at a dose that was tolerated during chronic administration3’. However, it would appear that sanctioning the use of marijuana and A9-THC for appetite stimulation was based more on political expediency than on sound scientific principles.

Despite lack of conclusive evidence that A9-THC adversely affects the immune system in healthy adults, there is a wealth of information demonstrating cannabinoid-induced alterations in the immune system in laboratory anirm@. It should be obvious that AIDS patients are at a higher risk than the normal population to drugs that are potentially immunosuppressive. As with the development of any therapeutic agent, the next required step is evaluation of the drug in the targeted population for both efficacy and adverse effects. 0

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While marijuana has enjoyed varying degrees of popularity among selected populations throughout antiquity, there has been a marked rise in popularity world-wide over the past 25 years. It is by far the most widely used illegal drug of abuse in the USA. Marijuana is likely to remain a major drug of abuse for years to come because of its pleasurable effects and relatively low toxicity. With the recent advances in the characterization of a cannabinoid receptor and the development of new synthetic probes, scientists now have the opportunity to reexamine many of the issues that have proved elusive. Elucidation of the functional role of the cannabinoid receptor should provide new insights into the biochemical processes responsible for pain perception, behavior and memory. New treatment strategies and medications should emerge from these findings. References 1 Hollister, L. E. (1986) PhammcvJ. Rev. 38,1-20 2 Fehr, K. 0. and Kalant, H. (1983) in Cannabis and Health Hazards: Proceedings of an ARNWHO Scientific Meeting on Adverse Health and Behavioral Consequences of Cannabis Use (Fehr, K. 0. H., eds), pp. l-65, and Kalant, Addiction Research Foundation Press 3 Maykut, M. 0. (1985) Prog. Neurovsvchovharmacol. BioJ. Pswhintnl _ _ 9, iop-238 4 Dewey, W. L. (1986) Phatmacol. Rev. 38, 151-178 5 Martin, B. R. (1985) in Marihuana ‘84, Proceedings of the Oxford Symposium on Cannabis (Harvey, D. J., ed.), pp. 685-692, IRL Press 6 Razdan, R. K. (1986) PharmacoJ. Rev. 38, 75-149 7 Balster, R. L. and Prescott, W. R. (1992) Neurosci. Biobehav. Rev. 16, 55-61 8 Howlett, A. C. et al. (1990) Trends Neuro-

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204 sci. 13,420-423 9 Matsuda, L. A., Lolait, S. J., Bmwnstein. M. J., Young, A. C. and Bonner, T. I. (1990) Nature 346, 561-564 10 Johnson, M. R. and Melvin, L. S. (1986) in Cannabinoids as Therapeutic Agents (Mechoulam,R., ed.), pp. 121-144, CRC Press 11 Bell, M. R. et al. (1991) 1. Med. Chem. 34, 1099-1110 12 Mechoulam, R. et al. (1987) NIDA Res. Mono~. Ser. 79,15-30 13 Razd&, R. K. (1987) NIDA Res. Monogr. Ser. 79,3-14 14 Di Chiara, G. and Imuerato, A. (1988) Proc. Nat1 Acad. Sci. USA 85,5274-&278. 15 Chen, J_ et al. (1990) PFychophannacolopv 102.156-162 16 Che& J., &&es, W., Lowinson, J. H. and Gardner, E. L. (1990) Eur. I. Pharmuco!. 190,2S9-262 17 Gardner, E. L. et al. (1988) Psychouhannucoloav %, 142-144 18 &wee, R.ud. (l&l) in TheBiologicalBasis of Drux Tolerance and Dependence (F%att, J: A., &i.). pp. 232-263, Academic Press 19 Kaymakcakm, S. (1973) Bull. NIX. 25, 39-47

20 Beardsley, P. M., Balster, R. L. and Harris, L. S. (1986) 1. Pharmacol. Exp. Ther. 239,311-319 21 McMillan, D. E., Dewey, W. L. and Harris, L. S. (1971) Ann. NY Acad. Sci. 191,699 22 Camey, J. M., Uwaydah, I. M. and Balster. R. L. (1977) Phurmacol. Biochem. Behuv.~7,357~364 23 Harris, L. S., Dewey, W. L. and Razdan, R. K. (1977) in Handbook of Experimental Pharmucology (Born, G. V. R., Eichler, 0.. Farah. A. and Welch. A. D., eds), DD. r. 1’ 371-429, Springer-Verlag 24 Dill, J. A. and Howlett, A. C. (1988) 1. Ph&mucol. Exp. Ther. 244, 1157~1163~ 25 Westlake, T. M. et aI. (1991) Brain Res. X4.14.5-149 26 Jon&, R. T. (1983) in Cannabis and Heulth Huzurds (Fehr, K. 0. and Kalant, H., eds), pp: 617-689, Addiction Research Foundation 27 Jones, R. T., Benowitz, N. and Bachman, J. (1976) Ann. NY Acad. Sci. 282,221-239 28 Jones, R. T. and Benowitz, N. (1976) in Phurmucology of Murih&n &aide, M. C. and Szara, S., eds), pp. 627-642, Raven Press

Neurobiology of alcohol abuse Herman H. Samson and R. Adron Harris Excessive consumption of beverage alcohol (ethanol) is a major health concern worldwide. Understanding the mechanisms by which ethanol affects neural functioning, after both acute and chronic exposure, has become a major goal in the study of alcoholism. With such an understanding, we should be able to institute more effective treatments and preventative measures for alcohol abuse problems. Recent studies have found, contrary to earlier assumptions, that ethanol has selective, dose-dependent effects on various neurotransmitter systems within the CNS. These effects are observed at all levels of analysis, from molecular to behavioral. This review by Herman Samson and Adron Harris covers these recent findinps. with the intent of generating questions that will focus further resedrch efioks. Alcohol is the second most widely used psychoactive substance in the world after caffeine. While most societies approve of moderate alcohol use, chronic and/or excessive drinking is considered a hazard to both health and public safety. In the USA, the cost of alcohol-related problems was estimated at over $136 billion in 1990, and unless changes in drinking patterns occur, or better treatment and prevention approaches H. H. Samson is Director at the Alcohol and Drug Abuse Institute and Professor in the Depurfment of Psychiatry and Behavioral Sciences, University of Washington School of Medicine. Seattle, Washington, and R. Adron Harris is a Research Career Scientist at the VA Medic42 Center and Professor in the Department of Pharmacology, University of Colorado School of Medicine, Denver, Colorado, USA. 0 1992.Elsevier

Science Publishers Ltd (UK)

are found, health costs will be over $150 billion in 1995l. In order to both treat and prevent alcoholrelated problems, basic research into the mechanisms by which alcohol produces its psychotropic activity is essential. Ethyl alcohol (ethanol), unlike most psychoactive drugs, has no known specific receptor system within the CNS. However, it is clear that ethanol can affect a variety of neurotransmitter systems and understanding how this occurs is most likely to be the key to explaining the psychoactive actions of ethanol. It is impossible to cover all of the neurotransmitter systems known to be affected by ethanol within the space limitations of this review. While important findings related to many transmitter

29 Jones, R. T., Benowitz, N. L. and Heming, R. I. (1981) 1. Clin. Pharmacol. 21,143S-1525 30 Howlett, A. C., Qualy, J. M. and Khachatrian, L. L. (1986) Mol. PharmacoI. 29,307-313 31 Biduat-Russell, M., Devane, W. A. and Howlett, A. C. (1990) /. Neurochem. 55, 21-26 32 Pacheco. M.. Childers. S. R.. Arnold. R.. Casiano; F: and Ward, 6. J. (lb91j 1. Phnrmacol. Em. Ther. 257,170-183 33 Eisenstat, M. A: et nf. (1990) NIDA Res. Monogr. Ser. 105,427-428 34 Herkenham. M. et al. (1991) . ,, 1. Neurosci. ~~~ 11.563-583. 35 Herkenham, M. et al. (1990) Proc. Nat! Acad. Sci. USA 87,1932-193& 36 Harris, L. S. (1978) in Psvchovharmacology, A Generation of Progress ilipton, M. A., DiMascio, A. and Killam, K. F., eds). UD. __ 1565-1574. Raven Press 37 Plasse, T. F. et ui. (1991) Pharmucof. Biochem. Behuv. 40.695-700 38 Munson, A. E. and Fehr, K. 0. (1983) in Cannabis and Health Hazards (Fehr, K. 0. and Kalant, H., eds), pp. 257-354, Addiction Research Foundation

systems have been delineated (see Ref. 2 for a more complete discussion of other transmitter systems), this review highlights the recent findings related to the excitatory and inhibitory amino acid transmitters and to dopamine and 5-HT. Molecular pharmacology The search for moiecular actions of alcohol has focused mainly on mechanisms of intoxication and development of tolerance and dependence. A key, and unanswered, question is how these actions are related to alcohol selfadministration in laboratory animals and to alcohol abuse and alcoholism in humans. Membrane actions Alcohols (typified by ethanol) are members of the family of intoxicant anesthetics that includes volatile anesthetics, barbiturates and benzodiazepines; drugs that display a similar spectrum of intoxication as well as substantial cross-tolerance and cross-dependence. Because of the chemical structural diversity of these intoxicant anesthetics, it is difficult to imagine a single receptor that could be responsible for actions of ethanol as well as these other related drugs. Based on the pioneering work of Meyer and Overton carried out 100 years ago, the idea that alcohol acts by partitioning into neuronal mem-