New drugs for the treatment of experimental alcoholism

Alcohol, Vol. 11, No. 6, pp. 439-451, 1994 Copyright © 1994ElsevierScienceLtd Printed in the USA. All rights reserved 0741-8329/94 $6.00 + .00

Pergamon 0"/41-8329(94)00040-9

New Drugs for the Treatment of Experimental Alcoholism R. D . M Y E R S

Departments of Pharmacology and Psychiatric Medicine, School of Medicine, East Carolina University, Greenville, NC 27858 MYERS, R. D. New drugsfor the treatment of experimental alcoholism. ALCOHOL 11(6) 439-451, 1994.-This article presents a current overview of the efforts to suppress pharmacologically the craving, dependence, or other factors associated with the self-selection of alcohol in an experimental animal. The contemporary status of the pharmacotherapy of experimental alcoholism similarly is described for different animal models of alcohol drinking. An evaluation is presented of several classes of drug for their efficacy in ameliorating the volitional ingestion of alcohol in the presence of an alternative fluid. Currently, two main experimental animal models of alcoholism are being used in this endeavor: (a) genetic lines or substrains of high alcohol preferring or high drinking rats; and (b) strains of nondrinking or low alcohol preferring rats which are induced chemically to prefer alcohol. Because of technical, methodological, and other issues surrounding the procedures used to assess the efficacy of a drug in reducing alcohol intake, several of the newer findings remain controversial. For example, serious side effects on the intake of food, caloric regulation, motor activity, or other functions would preclude the clinical utility of the drug. However, several drugs which affect monoaminergic neurons as well as opioid systems in the brain now seem to offer promise as agents which do possess clinical benefits. Two of these drugs, FG5606 (amperozide) and FG 5893 are essentially "antialcoholic" or anticraving and are without any significant side effects on cerebral mechanisms responsible for hunger, caloric intake, motor activity, or other physiological process. Amperozide, a 5-HT2 receptor antagonist with dopamine releasing properties, is particularly notable because of its irreversible nature in attenuating alcohol preference for months after its administration. It is concluded that future pharmacological research on presently available and newly developed compounds will provide exciting opportunities to the clinician who can utilize a particular drug as an adjunctive tool in the therapeutic treatment of the alcoholic individual. Alcohol preference Drinking Rats Animal models of drinking Ethanol

Alcohol intake Alcogene Food intake 5-HT receptors

O V E R the last 30 years, the novel concept that a "magic bullet" could be developed for the pharmacological treatment of alcoholism has been met by widespread skepticism. The manifold reasons for the general negativity toward this idea are not entirely unjustified. Alcoholism still is not considered by many therapists and social theorists to be a disease (18). Rather, addictive drinking is thought to be comprised of personal, psychosocial problems. By definition, therefore, a condition which is not a disease would not be amenable to pharmacological treatment. Further, a therapeutic strategy whereby one drug is used to eliminate the abuse of another drug is difficult to comprehend. Such a procedure raises the issue of substitution of one agent for another, which could

Drugs Treatment of alcoholism Serotonin antagonists

lead to subsequent dependence on the second drug and a pharmacological "revolving door." Even when alcoholism is viewed in the context of a biomedical disease, the elements underlying the disorder of chronic drinking are multifaceted, complex, and unequivocally coupled to sociological and psychological factors which impact severely on the individual. Today, unambiguous evidence still does not exist for the precise biological mechanism underlying the etiology of alcoholism. Although clear-cut chemical disturbances in specific anatomical regions of the brain are caused by alcohol, and are currently being elucidated, the question remains as to whether a single drug can reverse a biologically based psychosocial disorder. Whether or not all

Requests for reprints should be addressed to: R. D. Myers, Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27858. 439

440

x'l ~ E R S

or only a part of the neurochemical imbalance must be reversed by a drug to bring about a successful treatment of the patient also is unknown.

Animal Models For the development of a pharmacological agent to treat alcoholism, two principal animal models of alcohol drinking closely simulate the historically accepted criteria for the human disease state. One animal model developed by breeding procedures and subsequent genetic selection over successive generations, differentiates high drinking from low or nondrinking animals. Such a model is illustrated by the P (preferring) and NP (nonpreferring) lines of Wistar rat (56). The addictive drinking of alcohol by the P rat and the rejection of alcohol by the NP animal, while both are bred and raised in an identical "psychosocial" environment (52), has strengthened the concept of the existence of an "alcogene" (71). Because of these studies and the clinical findings of Cloninger (11), an inherited, genetically based condition seems to underlie, in part, the predisposition to alcohol abuse (35). A second model is based neurochemically on a unique perturbation of the aldehyde metabolizing system in the brain. The proximal metabolite of alcohol, acetaldehyde, requires the enzyme aldehyde dehydrogenase (AIDH) for its metabolism. Following the inhibition of AIDH by the drug cyanamide, aldehyde metabolites in the cerebral parenchyma are artificially elevated (88). Administration of cyanamide or injections into the brain of certain aldehyde adducts such as a tetrahydroisoquinoline (TIQ) or/~-carboline produce an aberrant preference for alcohol in the rat and other species (62,71,72). This chemically induced model o f alcohol drinking as well as the genetic model embody several of the criteria of the human alcoholic condition: an abnormally high intake of alcohol; a strong preference for alcohol in the presence of an alternative fluid or nutrient; signs of withdrawal and physical dependence on alcohol (50,57,70,71). For example, in experiments in which the P rat or TIQ treated rat is offered alcohol simultaneously with a palatable and nutrient replete fluid, alcohol is consumed in the same quantity as that when alcohol is available alone (50,79). Moreover, in both the genetic and chemically induced drinking rat, a unique pattern of alcohol preference evolves in which the intake o f alcohol rises sharply as the concentration of alcohol is increased to as high as 30070 (49,50). The purpose of this article is to evaluate the results of selected animal studies in which different classes of drugs have been tested to reduce the drinking of alcohol offered with water in a self-selection paradigm. An analysis is presented also of the vital role of food intake as related to potential nonspecific impairments by a drug of caloric intake generally, rather than its specific action on the reinforcing, addicting or other property of alcohol. Recent experiments on drugs which affect serotonergic mechanisms in the brain concomitant with alcohol drinking are also described. METHODOLOGICAL ISSUES

To evaluate the potential therapeutic value of a new or established pharmacological agent to ameliorate alcohol craving, dependence, or tolerance, it is essential that a valid animal model of alcohol drinking is utilized. A "valid" model implies an animal simulation of the human drinking condition to the greatest degree possible. The number and characteristics of the criteria required for an animal model of human alcoholism

have been enumerated, considered, and debated without a definitive consensus for over three decades (51,69,74,84). Indeed, crucial issues persist which pertain to analytical approaches and experimental techniq~es used to collect data on an alcohol drinking animal. Today, the validity of a drinking model is not simply one of an ivory tower debate among a relatively small number of laboratory scientists. Rather it has become an obligatory concern of organizations ranging from those which will support basic research on drinking to those which will ultimately embark on a clinical trial of a given drug for its potential specificity in the treatment of alcoholism. A number of critical questions relate to the pharmacotherapy of one or more of the complex facets of alcoholism. One centers on the interaction between the caloric value of both the solution of alcohol and the food offered to the animal, particularly since alcohol itself is an excellent source of calories. A second question pertains to the palatability of the concentration of alcohol used to ascertain drinking preference in a free choice situation with water. Another issue relates to the efficacy of the concentration of alcohol available to the animal and its pharmacological and behavioral significance. Yet another question concerns the pattern of alcohol intake in the presence of a flavored, nutritious ~olution offered together with alcohol and water. Each of these issues serve to determine the interpretation of alcohol drinking by an animal in response to the administration of a given dru~.

Determination of Alcohol Preferen~'e In the 1960s, a single concentrauon of alcohol, ordinarily 10070, was used to analyze the preference-avoidance or selection-rejection patterns of alcohol drinking (21). Although it was stated recently that a 10°70 solution is adequate for distinguishing alcohol preference (42), many researchers have demonstrated that in the presence of water, alcohol is preferred in concentrations ranging from 3°70 to as high as 40070 by individual test animals (69). Although the evidence for a genetic component in the volitional selection of alcohol is overwhelming in terms of rodent strains bred to prefer or avoid alcohol (23,52,101), most of these models are based methodologically on the 10070 concentration of alcohol (50,68). Recently it has been shown that the rat bred to select 10070 alcohol over water, such as the P rat or high alcohol drinking (HAD) rat, actually possesses a clear-cut preference for alcohol in very different concentrations which range from 7 070to 30070 (49,50). Since the arbitrary selection of a single 10070 concentration of alcohol imposed on the animal may not account for the possible pharmacological significance of the fluid, or lack thereof (49,84), spurious if not misleading results can be obtained by the use of one single concentration. For example, C57BL and BALB/C strains of mice ordinarily consume alcohol in concentrations other than 1007o (120). In addition, if a sweetened or nutritious fluid is available to the test animal in the presence of alcohol and water and is then preferred over the solution of alcohol, the validity of the drinking model is uncertain (49,50). Should a drug attenuate preference for alcohol to the same degree as a palatable fluid, then another factor in the self-selection paradigm such as taste is implicated in the pharmacological action of the compound. Clearly, an animal model of drinking should be utilized which is based on a determination of a specifically preferred solution or range of solutions. Moreover, the presentation of a third fluid, in addition to alcohol and water would substantiate the specificity of action of a drug if it does attenuate the

PHARMACOTHERAPY OF ALCOHOLISM drinking of alcohol. Finally, if a drug suppresses feeding and alcohol drinking concurrently, a primary action on caloric regulation is probable. DRUGS THAT MODIFY ALCOHOL DRINKING Table 1 presents a composite analysis of the effects on the self-selection of alcohol of some representative drugs that have been tested under a variety of experimental conditions. In certain studies, a proportional measure of the ratio of alcohol to water was utilized rather than the absolute intake of alcohol in grams per kilograms per time period. In other articles, the consumption of alcohol is reported in terms of the volume (e.g., millileters) consumed, irrespective of body weight, or lever responses to obtain a droplet of alcohol. Still other papers describe the measure of alcohol ingestion over a relatively short interval, while many reports overlook the caloric value of alcohol in relation to the intake of food and/or change in body weight. In relation to the ingestion of alcohol, Table 1 shows that measures of caloric intake were sometimes found to be incomplete, unclear, or not included in the results section of the article. As noted in Table 1, many studies also failed to conduct a dose response analysis of the action of the drug tested. Thus, the wide spectrum of experimental procedures having little or no uniform approach to the phenomenon of experimental drinking, can prevent a cogent interpretation of a given set of findings. An impairment by any centrally acting drug of the cerebral mechanisms responsible for hunger and eating could serve to abrogate its pharmacological specificity (2,32). That is, if a drug inhibits the ingestion of a nutrient and suppresses simultaneously the intake of alcohol, which is an excellent source of calories, its effect on drinking may be secondary to its disruption of the telencephalic mechanisms regulating the setpoint for hunger. For example, the general anorectic and hypophagic effects of the inhibitors of 5-HT reuptake alone or in the presence of alcohol are well documented (2,13). One of these drugs, sertraline, a relatively selective inhibitor of 5-HT reuptake, suppresses alcohol consumption substantially but at the same time produces a potent anorexic effect (34,82) soon after its administration (55), which parallels that of other serotonergic drugs in mutually reducing caloric intake, body weight and alcohol preference (79,82,83). Other drugs such as naloxone, morphine, and naltrexone that act on opiate receptors (104) also are well known anorexic agents that concurrently suppress the drinking of alcohol in the rat and other species (14,76,85). Table 2 presents a representative set of experimental compounds which have been examined for their capacity to alter the volitional drinking of alcohol as well as the ingestion of food. A common thread seems to run throughout the pharmacological literature on drinking in which serotonergic, dopaminergic, opioid, and other systems in the brain are altered. In virtually two-thirds of these studies, the intakes of both food and alcohol typically are suppressed concomitantly (Table 2) when the function of serotonergic neurons is modified. Those drugs which exert this dual action include: inhibitors of 5-HT synthesis such as p-chlorophenylalanine (75,81,83); enhancers of 5-HT release such as fenfluramine and p-chloroamphetamine (27,119); inhibitors of 5-HT reuptake such as doxepine, fluoxetine, and zimelidine (15,29,33,39,67,91,I00); and antagonists of one or more of the 5-HT receptor subtypes such as buspirone (12,96). These observations give rise to the viewpoint that a perturbation of telencephalic 5-HT synapses

441 involved in feeding, olfactory, and gustatory senses, water balance, sleep and thermoregulation will, therefore, produce nonspecific effects on alcohol drinking as well (2,82). It is clear also from pharmacological experiments that systems in the brain which comprise both opiate receptors and catecholaminergic neurons are involved enigmatically in the abnormal craving for alcohol (72,73,80). Because of the complexity of these systems, it has been difficult to comprehend the precise role which they may play functionally in the etiology of alcoholism. Nevertheless, recent experiments show that antagonists of both the Dl and D2 classes of dopamine receptor can reduce alcohol drinking in a free choice situation as well as in an operant responding paradigm (17). Other studies in the primate and other species show that the antagonism of the opiate receptor by naloxone or naltrexone can ameliorate the voluntary intake of alcohol (1,40,85,86,104). Following on from the animal experiments are the important clinical studies of O'Brien and others who are now using naltrexone as a part of the treatment of the alcoholic patient (O'Brien, this Issue). FUTURE PROMISE OF NEW CLASSES OF DRUGS It seems apparent that a drug which acts specifically on one type of receptor protein, or releases one transmitter, or prevents the reuptake of that transmitter is unlikely to either selectively abolish the abnormal craving for alcohol or modify its unique reinforcing qualities. Although there is now evidence that some of the compounds which possess one or more of these properties could exert an "alcoholytic" action (54), their impairment of caloric intake or interference with other related functions would tend to negate their utility in the treatment of alcoholism. On the other hand, a compound which possesses differential affinities for diverse receptors in the brain could be useful in attenuating drinking. The logic behind this concept is that the drug would act on diverse neuronal processes which underpin, at least in part, each of the multiple neurobiological components related to aberrant drinking behavior. One drug, amperozide, seems to occupy a position on this pharmacological "horizon." Amperozide is a compound which possesses certain antipsychotic, antidepressant, anxiolytic and other properties which modify both animal and human behavior (5,10). This unique drug has been under clinical trial for several years and displays a profile of therapeutic activity on behavioral symptoms which reflect many of those associated with patients having Type 1 or Type 2 alcoholism. Neurochemically, amperozide has a high affinity for cerebral 5-HT2 receptors but a far lower affinity for 5-HTjA, 5-HTla, or 5-HTlc receptors and a low affinity for a~ and 0/2 adrenoreceptors in structures of the limbic system (114). Amperozide also reduces the number of 5-HT2 binding sites following its chronic administration and inhibits both the in vitro release and reuptake of 5-HT in the rat (19,114). With respect to the central dopaminergic system, amperozide has a low affinity for Dj and O 2 receptors in structures located in the mesolimbic system (I 14). However, it does act to block the reuptake of dopamine in the corpus striatum, augments the release, and enhances the accumulation of DOPA and dihydroxyphenylacetic acid (DOPAC) within limbic and striatal tissues of the rat (20,121). Although amperozide does not alter the synthesis of dopamine in these structures, it can either intensify or stabilize the firing rate of single, identified dopaminergic neurons in the ventral tegmental area (36). Further, the drug can retard the pacemaker-like

442

MYERS

TABLE

1

SELECTED DRUGS WHICH HAVE BEEN TESTED ON ALCOHOL DRINKING IN RELATION TO ROUTE OF ADMINISTRATION, DOSE. TEST ANIMAL, FOOD INTAKE, AUTHOR, AND YEAR OF PUBLICATION Alcohol Concentrations

Alcohol Intake

Food Intake

rat C57BL mouse rat

10% 10o70

~ ~

~ ~

Mendelson et al. (63) Kakihana et al. (41)

1965 1968

5o/0

~

?

Frey et al. (271

1970

70 ~ g / k g oral 360 # g / k g oral 40 p g / k g oral 2 g / k g / i n diet 0.5-2.5 m g / k g SC 1.0-17.0 m g / k g IM 20 m g / k g IP 25 m g / k g IP 50 m g / k g IP

rat rat rat rat rat

10070 10o70 10070 10o70 4o70

~ ~ ~ ~ ~

~ ? '~ ~ ~

Eriksson (22) Eriksson (221 Eriksson (22) Sinclair (I 10) Burke & Kramer (8)

1971 1971 1971 1974 1974

monkey

3%

,*

1'

Barrett & Weinbery (4)

1975

6-30°70 6-30°70 6070

~ ~ ~

~ ? ?

Amit et al. (3) Amit et al. (3) Geller & Messiha (30)

1976 1976 1976

50 m g / k g IP

C57BL/6J mouse C57BL/6J mouse hamster rat

10070

~.

?

Sanders et al. (107)

1977

10070

,~

~

Sanders et al. (107)

1977

5% 12%

~, J,

? ?

Opitz (92) Zabik et al. (122)

1977 1978

rat & hamster

6%

~

?

Geller & Messiha (31)

1978

rat

5o70

J.

--*

Messiha (65)

1978

50 m g / k g IP 3.0 m e q / k g IP 200 m g / k g diet 200 m g / k g IP

rat rat rat rat

5o/0 10-3307o 10o70 15o7o

$ ~ J, ~

--, ~ ? ?

Messiha (65) Boland & Stern (6) Sinclair & Lindros (111) Fadda et al. (24)

1978 1980 1981 1983

12.5 & 25 m g / 100 ml oral 100 milliunits SC 100 & 200 m g / k g oral 30 m g / k g & 100 m g / k g oral 0.25, 0.50, & 1 m g / k g IP 10 m g / k g IP 0.3, 1.0, 3.0 m g / kg IP 20 # g / k g , 200 pg/kg, 1 m g / k g SC 1, 2, 4, m g / k g IP 0.125 m g / k g SC 5 & 10pg/kgSC 1.0, 2.0, 4.0 m g / kg IP 50, 100, 200 t~g/ kg SC 10 m l / k g IP 50 p g / k g IM 3.0, 5.0, 7.0 m g / kg IP

mouse

2-15070

N,

9

Chan et at. (9)

1983

rat rat

3-25°70 5°70

--* J,

--* ?

Myers et al. (86) McMillan (58)

1983 1983

rat

5070

~.

?

McMillan (58)

1983

rat

5070

~

?

Pfeffer & Samson (95)

1985

P rat rat

10070 10070

~ ~

? ?

Murphy et al. (67) Samson et al. (105)

1985 1987

rat

3 & 6070

J,

?

Grupp et al. (37)

1988

rat rat rat P rat

3070 6070 3 & 6070 10070

$ $ ~ J~

? ? ? ?

Pulvirenti & Kastin (97) Svensson et al. (115) Grupp et aL (38) Weiss et al. (118)

1988 1989 1989 1990

rat

3 & 6070

*

?

Ross et al. (102)

1990

3 & 60/0 1,2, 4 & 80/0 19070 4&8%

~ ~~

? ? ?

Lingham et al. (53) Kornet et al. (44) Fadda et al. (25)

1990 1991 1991

Drug

Route & Dose

Animal

Puromycin Goldthioglucose

40 m g / k g IP 0.6 m g / g IP

p-chloro amphetamine Clomiphen Mestranol 17-ethinylestradiol Lithium chloride Melatonin

2 m g / k g oral

Chlordiazepoxide FLA-63 Disulfiram A E T (aminoethylisothiouronium) Pargyline Lilly 51641

50 m g / k g IP

Org 6582 5-HTP

20 m g / k g oral 50, 100, 200 m g / kg IP 50-200 m g / k g IP & SC 0.5 m M / k g IP

Aminophylline VMA, 5-HIAA HVA Carbidopa Lithium Cyanamide Gammabutyrolactone Chlordiazepoxide Vasopressin Disulfiram E M D 15,700 d-Amphetamine Fluoxetine RO15-4513 Angiotensin II

Naloxone 8-OH-DPAT Isoproterenol Bromocriptine PGE2 Abutapril DGAVP M D L 72222

rat rat rat

rat monkey P rat

Author (Reference)

Year

(continued)

PHARMACOTHERAPY OF ALCOHOLISM

443 TABLE 1 CONTINUED Alcohol Intake

Food Intake

3%0

~

?

Meert & Janssen (61)

1991

5 & 8% 6% 10% 10% 3 & 6% 3% 3%

~ ~ ~ ~ ~ J. ~

? ? ? ? ? ? ?

Kostowski& Dyr (45) Knapp & Pohorecky (43) Fadda et al. (26) Rowland & Morian (103) Robertson et al. (99) Panocka et al. (94) Panocka et al. (94)

1992 1992 1992 1992 1993 1993 1993

rat

2-6%

~

?

Svenssonet al. (116)

1993

rat

5 & 8%

~

?

Kostowskiet al. (46)

1993

Drug

Route & Dose

Animal

Ritanserin

.16 mg/kg-40 mg/kg SC 0.125 mg/kg SC 0.1-10 mg/kg IP 3.0 mg/kg SC 3 mg/kg/day 20 mg/kg SC 0.1 mg/kg SC 0.0625 mg/kg SC 1.25-5.0 mg/kg 1P 0.001 mg/kg or 0.1 mg/kg SC

rat

NDO-008 Zacopride Isradipine D-fenfluramine Captopril Risperidone Haloperiodol Ipsapirone ICS 205-930

rat rat P rat P rat rat rat rat

Alcohol Concentrations

Author (Reference)

Year

"?" denotes measure not presented or incomplete data. Intragastric, intravenous, and other mode of self-administration not included.

activity of dopaminergic neurons within the ventral tegmental area following cooling of the medial prefrontal cortex (36).

A mperozide and Alcohol Drinking Recently we found that the preference for alcohol is significantly reduced by amperozide in a dose dependent manner under different experimental conditions (88). In these studies with the Sprague-Dawley rat, a standard three bottle test is always used in which water and the maximally preferred concentration of alcohol were offered to each animal. In one study, rats were induced chemically to drink alcohol by the earlier administration of the A1DH inhibitor, cyanamide, which causes an accumulation of addictive aldehyde metabolites. As shown in Fig. 1, amperozide reduced significantly the average intakes of alcohol measured according to both the absolute grams per kilogram per day and the proportion of alcohol consumed to the total intake of fluid (88). However, two findings are equally notable. In many rats, the effect of amperozide in ameliorating the consumption of alcohol persisted after its injections are terminated. Second, as illustrated in Table 3, neither the consumption of food nor level of body weight was affected by any dose of this 5-HT 2 receptor antagonist. These unusual results are in sharp contrast with those of other studies in which a sharp decline in alcohol drinking is always accompanied by a reduction in the ingestion of food (2,34,82). In the genetically bred high alcohol preferring P rat, amperozide also suppressed significantly the intake of alcohol (89). As presented in Fig. 2, the decline in drinking in terms of both proportion of alcohol to total fluid (Fig. 2, top) and grams per kilogram per day (Fig. 2, bottom) was dependent on the dose of amperozide given to this rat predisposed genetically to consume alcohol. Moreover, the amelioration of drinking persists beyond the period of treatment with amperozide, which parallels that observed in the cyanamide induced drinking rat. Thus, in an individual predisposed to drink, amperozide can exert a palliative effect on the aberrant selection of alcohol consumed in a pharmacologically significant quantity. In another study, amperozide was administered chronically over a 7-day period by an osmotic minipump to rats induced

earlier to drink alcohol by cyanamide. During the sustained delivery of amperozide in a dose of 208 izg/kg per hour, the drinking of alcohol declined significantly both in relation to the proportional measures (Fig. 3, top) and the absolute g/kg intakes (Fig. 3, bottom) per day (89), without producing any side effects on the intake of food or level of body weight. Moreover, a retest of the pattern of preference of the rats at 4, 30, 70, 110, and 140 days after the pump had exhausted the solution of amperozide revealed a continuing decline in the consumption of alcohol. This irreversible action of amperozide on the intake of alcohol is depicted in Fig. 3. Overall, this set of findings suggests a specificity of action of amperozide on the reinforcing attribute and other properties of alcohol. More important is the fact that in many of the rats, the inhibitory effect on alcohol drinking was permanent. This is illustrated in Fig. 4 for an animal which had consumed between 8.5 and 10.5 g/kg per day of its preferred concentration of 15% alcohol just prior to treatment with amperozide. Not only did the absolute gram per kilogram consumption decline over the 5-month period, but the proportion of alcohol to total fluid fell similarly (Fig. 4). This effect of the 5-HT: antagonist is the first demonstration of a potentially clinically useful agent which causes a relatively permanent diminution of alcohol drinking. Since amperozide acts centrally on the synaptic activity of dopaminergic and serotonergic neurons in the limbic system, it is envisaged that the drug ameliorates the aberrant drinking of alcohol by virtue of a direct effect on either one or both of these classes of neuron. As a consequence, amperozide apparently counteracts by its central action those functional mechanisms underlying the behavioral craving for alcohol, its potent reinforcing property or both phenomena.

A mperozide and Cocaine Drinking In relation to the vital issue of the potential pharmacological intervention of abuse of other addicting substances, a question arose as to whether amperozide can also diminish the self-administration of other addictive drugs. In a preliminary study with the rat, we found that the volitional drinking of a cocaine solution in quantities up to 35 mg/kg per day is

444

MYERS

TABLE 2 SELECTED DRUGS THAT CAN ALTER ALCOHOL DRINKING IN RELATION TO SYSTEMIC ROUTE OF ADMINISTRATION, DOSE, TEST ANIMAL, FOOD INTAKE, AUTHOR, AND YEAR OF PUBLICATION Alcohol Concentrations

Alcohol Intake

Food Intake

rat rat

3-30% 3-30% 3-30% 4, 6, & 8%

~ ~ ~ ~

~ ~ ~ ~

Myers & Veale (83) Myers & Cicero (75) Myers & Veale (83) Wilson (119)

1968 t969 1968 t971

rat rat rat rat

3-30% 10% 3-30% 5070

~ ~ T ~

-~ ~ -~ ~

Myers et al, (87) Sinclair et at. (112) Myers & Melchior (78) Messiha (64)

1972 1973 1975 1978

rat

3-t5%

J.

~

Rockman et al. (100)

1979

rat rat

t0%0 3-30%

~,

Sandberg & Stewart (106) Myers & Critcher (76)

1982 1982

rat P rat rat

10% 10% 3-30%

J, J, J,

$

Sandberg & Stewart (106) Waller et al. (117) Critcher et al. (14)

1982 1982 1983

monkey

5-15%

J,

Myers et al. (85)

1986

rat monkey rat rat

5% 3-30%0 3-30% 2-10%

J,

J,

,L

J,

Kulkosky et al, (48) Collins & Myers (12) Privette et al. (96) Gill et al. (32)

1986 1987 1988 1988

rat

7-15%

~,

Mifiano & Myers (66)

1989

rat

2.5°70

~.

Sandi et ai, (108)

1990

rat

3-30%

Myers & Quarfordt (82)

1991

rat rat rat rat

5% 5%10% 7-15%

~,

Dietze & Kulkosky (16) Dietze & Kulkosky (16) Boyle et all (7) Myers et all (88)

1991 1991 1992 1992

rat

3-3007o

J,

Singh et a1.(113)

1993

rat

10%

AT

Dyr et al. OT)

1993

rat

10%

J,

Dyr et al. (17)

1993

rat rat Nih rat P rat

10% 10% 5%

~,

Dyr et at. (17) Dyr et al. (t7) Kulkosky et al. (47)

1993 1993 1993

3-30%

Myers et al. (89)

1993

rat

3-30%

Myers et al. (90)

1993

Drug

Route & Dose

Animal

pCPA

300 mg/kg oral 300 mg/kg oral 130 mg/kg oral 20 & 40 mg/kg IP 50 mg/kg IP 60 mg/kg IP .31% in diet 1.5 m E q / k g IP

rat

aMpT Fenfluramine 5-HTP Morphine Tryptophan Cesium and rubidium salt Zimelidine Estradiol Naloxone Ethamoxytriphetol 4-Methylpyrazole Naltrexone Naltrexone CCK-8 Buspirone Sertraline R04-4602 Leu-enkephalon Sertraline Caffeine Bombesin THIP Amperozide FG 5893 Spiperone Quinpirole SCH-23390 SKF-38393 Bombesin Amperozide Amperozide

10, 20, 30 mg/kg IP 5.0 #g SC 1.5-3.0 mg/kg SC 10 mg SC 90 mg/kg IP 2.0-10 mg/kg SC 0.6 & 1.2 mg/kg SC 4 #g/kg IP 5 & 20 mg/kg IM 10, 15 & 20 mg/ kg IP 10 ng-2.0 #g ICV 0, 100, 300 #g/ kg SC 3.0 or 10mg/kg SC 0.1-50 mg/kg IP 1,2,4, #g/kg IP 16 mg/kg IP 0.5, 1.0, 2.5 m g / kg SC 0.5, 1.0. or 2.5 mg/kg IP 10 & 30/xg/kg SC 0.04-2.0 mg/kg SC 3-30 Ixg/kg SC 2-6 mg/kg SC 1,2,4, #g/kg IP 0.5.1,0, 2.5 m g / kg SC 208 # g / k g / h pump SC

J,

--,

--,

T

T

Author (Reference)

Year

PHARMACOTHERAPY OF ALCOHOLISM

445

1.0

0.5 AMP

1

1.o AMP 2.5 AMP

AMP I

o,o <0_

< z

0.0 7

>-

6

<

5

I

i i

z i_d

N.,.

/1 O •

Y L

i

i

i

i

1

2

3

4

i

0 . 5 AMP 1 . 0 AMP

z~ 2 . 5 AMP

i

i

i

5

6

7

i

i

i

8

9

,

i

10 11

sumption (116). The probable reason for the discrepancy in these findings rests, in part, in methodological differences such as the use of a weak 3°70 concentration of alcohol, which is not of pharmacological consequence to the rat (61). Alternatively, ritanserin possesses characteristics different from those of amperozide in terms of both chemical structure and pharmacological profile. Conceivably, a property of amperozide over and above its antagonism of 5-HT2 receptors may also contribute to the central amelioration of the aberrant intake of alcohol. The fact that amperozide exerts an action on dopaminergic neurons in the limbic system would suggest that this effect of the 5-HT2 receptor antagonist may contribute to the reversal of alcohol preference in the rat following the cyanamide induced inhibition of A1DH or as a result of genetic selection (77,89). On the other hand, a novel second generation amperozidelike drug, FG 5893 (2-[4-[4,4-bis(4-fluorophenyi)butyll-1piperazinyl]-3-pyridinecarboxylic acid methyl ester) also exerts a marked effect on the preference for maximally preferred concentrations of alcohol induced by cyanamide in the Sprague-Dawley rat. FG 5893 is a unique mixed 5-HTI agonist/5-HT2 antagonist, and when administered in a range of doses similar to that of amperozide, FG 5893 significantly reduced the 24 h intake of alcohol in terms of both absolute gram per kilogram and proportion o f alcohol to total fluid intake (113). Control injections of saline were without effect on alcohol consumption of the rats, and FG 5893 did not alter body weight or intake of food. As illustrated in Fig. 5, F G 5893 continued to suppress alcohol drinking during tests immediately following its injection and 40 days after treatment with the drug. Since the central action of FG 5893 is one of combined 5-HTIA receptor agonism and 5-HT 2 receptor antagonism, the addictive property of alcohol possibly may

DAYS FIG. 1. Mean + SE intakes in terms of proportion of alcohol to total fluid (top) and absolute g/kg (bottom), in rats induced to drink following pretreatment with cyanamide. Preference for the individually determined, maximally preferred concentration of alcohol vs. water was tested for 4 control days before amperozide (AMP), 3 days during AMP, and 4 control days after amperozide injections B.I.D. of 0.5 mg/kg (n = 9), 1.0 mg/kg (n = 15), and 2.5 mg/kg (n = 11). [Data from Myers et al. 1992 (88)].

equally affected by amperozide (59). The ingestion of cocaine was significantly reduced not only during a 3-day period of amperozide treatment but also during the subsequent posttreatment interval in some rats. Quite remarkable is the parallelism of the prolonged action of amperozide on the volitional ingestion of two abused substances whose characteristics are chemically and pharmacologically dissimilar. Ritanserin and FG 5893 Another 5-HT2 receptor antagonist, ritanserin, is reported to reduce the intake of alcohol in rats of a 307o solution in a self-selection situation and of 507o alcohol in rats bred for a catecholamine response to stress (61,93,98). However, other studies show that this 5-HT2 antagonist is without any significant effect on the preference for alcohol. For example, after cyanamide-treated Sprague-Dawley rats drank alcohol in maximally preferred concentrations of 9% to 15%, ritanserin in doses of up to 1.0 m g / k g failed to alter the gram kilogram or proportional intakes of alcohol (77). Other experiments also showed the lack of effect of ritanserin on alcohol con-

TABLE 3 MEAN _+ SEM INTAKES OF FOOD (g) AND WATER (ml) AS WELL AS BODY WEIGHT (g) OF CYANAMIDE TREATED RATS DURING PREFERENCE TESTING FOR THEIR MAXIMALLY PREFERRED CONCENTRATION OF ALCOHOL. INJECTIONS OF ONE OF THREE DOSES OF AMPEROZ1DE OR SALINE GIVEN OVER 3 DAYS AS DESCRIBED IN TEXT [Based on data from Myers et al. 1992 (87)]. Food (g)

Water (ml)

Weight (g)

Low dose (N = 9) Pre 0.5 mg Post

15.0 ± 0.54 15.6 ± 0.51 17.6 ± 0.65

20.6 + 0.18 20.6 ± 2.2 27.6 + 3.0

492.2 _+ 6.3 489.0 ± 7.5 497.3 ± 7.0

Intermediate dose (N = 15) Pre 1.0mg Post

15.3 ___ 0.51 15.3 ± 0.54 15.7 ± 0.49

21.0 ± 0.16 20.4 ± 1.7 20.7 ± 1.3

499.0 +__ 6.5 495.3 + 7.7 503.4 ± 7.4

16.7 _+ 0.70 16.2 _+ 0.65 18.0 _+ 0.64

16.0 _+ 0.70 15.8 ± 1.3 19.3 ± 0.86

485.3 ± 5.1 485.0 ± 5.3 490.5 ± 5.2

16.1 ± 0.47 17.4 ± 0.60 15.8 _ 0.45

22.7 ± 1.7 24.0 _+ 2.0 25.0 ± 1.8

498.8 _+ 7.2 493.3 + 9.4 493.0 _+ 7.3

High dose (N = 11) Pre 2.5 mg Post Saline control (iV= 13) Pre Saline Post

446

MYERS

involve a concurrent dysfunction in these two subtypes of serotonergic receptor as well as in the dopaminergic pathway.

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thesized endogenously in the brain (70). The finding that the opiate receptor antagonist, naloxone, attenuated the preference for alcohol induced earlier in the rat given intracerebroventricular (ICV) infusions of the aldehyde adduct provided substantive evidence for this idea (76). Later it was shown that the longer acting opioid antagonist, naltrexone, als0 significantly reduced the voluntary drinking of alcohol in rats induced chemically to prefer alcohol (I4); In later studies, naloxone was found to suppress voluntary alcohol consumption in the alcohol preferring rat (28), reduce ~ k i n g in the alcohol dependent rat, and to enhance the aversion to alcohol in the naive rat (60). In the monkey which drank copious m o u n t s of alcohol

PHARMACOTHERAPY OF ALCOHOLISM

447

after it had been injected ICV with a lumbar sample of CSF obtained from an alcoholic individual, naltrexone also significantly attenuated the voluntary drinking of alcohol (85). In addition, the drinking of alcohol continued to be suppressed in some monkeys by up to 50% of their basal intake during all or a part of the interval following the injections of naltrexone. Thus, a cerebral opiate receptor mechanism could be associated with the chemically induced imbibition of alcohol in the primate species as well as in the rat which reacts similarly to opiate receptor antagonists (72). The current interest in the use of naltrexone in the clinical treatment of alcoholism continues to expand, in that intriguing investigations are currently underway in treatment centers in North America (O'Brien this issue).

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CONCLUSION

An historical overview of the literature on the experimental pharmacotherapy of alcohol drinking has revealed the abundance and variety of drugs which have been examined. Although many of the compounds compiled in Tables 1 and 2 show some promise in ameliorating alcohol consumption, the experimental studies themselves are often difficult to interpret. The main reason for this lies in the experimental proce-

448

MYERS

dures used in the investigations. For example, the caloric value of alcohol as well as the action of the specific drug on food intake typically are not taken into account. The concentration of alcohol offered to the test animal constitutes another important concern in terms of its pharmacological significance to the animal. In addition, the measurement of alcohol intake, e.g., in milliliters or lever presses per unit time, without calculation of the grams ingested per body weight of the animal can confound the significance of the observation. For example, the ingestion of 15 ml of 14% alcohol by a 150-g rat in contrast to a 600-g rat is vastly different pharmacodynamically. Other methodological complications which preclude unambiguous evaluations of research include the lack of dose response analyses in any drug study, the grouping in one cage of animals having different patterns of preference and the control over an animal's position habit or spatial placement of drinking bottles. In spite of these difficulties, other studies point to the eventual development of a drug to counteract the components underlying the etiology of alcoholism. Such a drug would be useful in conjunction with individual or group therapy in terms of alleviating the preoccupation and craving for alcohol. However, the drug should never serve as a substitute for the euphoric, anxiolytic or reinforcing property of alcohol nor possess any indication of addictive liability on its own. In fact, the use of one drug to substitute simply for another addicting drug is scientifically illogical and clinically contraindicated.

At present, two classes of drug seem to warrant more extensive clinical investigation: the group of drugs which act on opiate receptors and those which act uniquely on monoaminergic pathways in the brain. In both instances, the complex functions of the opiate receptor subtypes as welt as serotonin and dopamine containing neurons are now believed to be critically involved in the multiple psychological and physiological actions of alcohol (54,57,72,109), Since amperozide exerts distinct effects on serotonergic and dopaminergic systems simultaneously in the brain, it could represent a prototypical compound in the exploration of efficacious agents to treat alcoholism. In any case, it seems essential that innovative clinical research be built upon the vast storehouse of experimental information collected in the past, regardless of whatever technical weakness may have characterized the earlier findings. Although the "magic bullet" may not yet be at hand, research workers in this field are now obligated to track down and follow each promising lead to a new drug in support of the treatment of the alcoholic individual ACKNOWLEDGEMENTS The research reported in this paper has been supported in part by Grant AA-04200-11 from the National Institute on Alcohol Abuse and Alcoholism to R. D. Myers. The author thanks Miles F. Lankford for his technical and other contributions and Professors W. R. Wooles and B. A. McMillen for their helpful critiques of the manuscript.

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