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Suppression of Alcohol Preference in High Alcohol Drinking Rats Efficacy of Amperozide versus Naltrexone R. D. Myers, Ph.D., and Miles E Lankford The selectively bred high alcohol drinking (HAD) line of rat daily intake of alcohol by the HAD rats in terms of absolute is considered as a potential model of one type of alcoholism. g/kg and proportion of alcohol to water consumed. A The purpose of the present experiments was to compare the comparison of the drinking response to the higher doses of efficacy of two drugs on the volitional drinking of the HAD the two drugs showed that amperozide was more efficacious rats: the ~-HT~A receptor antagonist, amperozide, and a in suppressing alcohol intake than naltrexone. Neither nonselective antagonist of opiate receptors, naltrexone. To amperozide nor naltrexone exerted any significant effects on determine the pattern of alcohol drinking of the HAD rats, a food and water intakes or on body weight. These results standard prefererrce test was used in which water was support the concept of ajimctional link in the brain between ofleered with alcohol increased in concentrations from 3% to the serotonergic and opioidergic systems postulated to 30% over 11 days. The maximally preferred concentration underlie, in part, the aberrant drinking of alcohol. A marked of alcohol of each rat was offered for 4 days and ranged from dissociation between the temporal patterns of drinking after 7% to 20% with a mean intake of 6.9 g/kg per day. Initially, naltrexone and amperozide treatment suggests that the 1.0 mg/kg amperozide, 2.5 mg/kg naltrexone, or the saline opiate receptors mediate the immediate reinforcing effects of vehicle were injected twice daily for 4 days at 1600 and alcohol, whereas the vnore vegetative phenomena underlying 2200 hours. Secondly, 2.0 mg/kg amperozide, 5.0 mg/kg addictive properties of alcohol are regulated by ~-HT~A ualtrexone, or the saline vehicle were administered also for 4 receptors postsynaptic to serotonergic neurons. Finally, the days. After the drug sequences, alcohol preference tests inhibitory actions of both drugs imply that multiple continued for another 4 days. Whereas the saline vehicle receptor mechanisms within the mesolimbic and other was without eflect on drinking, the administration of either systems in the brain underpin the addictive liability to drug caused a significant dose-dependent reduction in the alcohol. [Neuropsychophamacology 14:139-149,1996] KEY WORDS: Alcohol preference; Drinking; HAD rats; Recently it was shown that the antagonism of the Ethanol; Opiate receptors; Naltrexone; Serotonin; ~-HT~A receptor subtype in the brain can suppress the Amperozide; ~-HT~A receptor antagonist; Genetics; volitional intake of alcohol in the rat. To illustrate, Alcogene amperozide attenuates significantly the intake of maxi- mally preferred concentrations of alcohol in the Sprague Dawley rat induced to drink alcohol by cyanamide treatment (Myers et al. 1992). Amperozide also exerts From the Departments of Pharmacology and Psychiatric Medi- the same suppressant effect on alcohol drinking in the cine, School of Medicine, East Carolina University, Greenville, North Carolina. genetic line of alcohol preferring P rats (Myers et al. Address correspondence to: R. D. Myers, Ph.D., Department of 1993a). Further, the inhibitory effect on drinking behav- Pharmacology, School of Medicine, East Carolina University, Green- ior caused by the sustained delivery of amperozide by ville, NC 27858. osmotic minipump can persist for up to 5 months after Received February 10,1995; revised April 27,1995; accepted May 3,1995. discontinuation of the drug (Myers et al. 199313). Inter- NEUROPSYCHOPHARMACOLOGY 1996~0~. 14, NO. 2 0 1996 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/96/$15.00 655 Avenue of the Americas, New York, NY 10010 SSDI 0893-133X(95)00081-N 140 R.D. Myers and M.F. Lankford NEUROPSYCHOPHARMACOLCEY~~~~VOL.~~,NO.Z estingly, treatment with amperozide for 3 days signifi- tered daily in a dose of 20 mg/kg to genetic drinkers of cantly reduces the oral consumption of a cocaine the Long Evans strain failed to lower their alcohol solution in rats (McMillen et al. 1993). A most signifi- intake (Myers and Critcher 1982). However, in other cant finding is absence of adverse side effects in the rat, strains of rat it was found that naloxone can induce a because amperozide neither impairs the intakes of food dose-dependent decline in the intake of different con- or water nor alters body weight (Myers et al. 1992) and centrations of alcohol (Myers and Critcher 1982; Froeh- is without effects on rotarod performance or the neuro- lich et al., 1990; Volpicelli et al. 1986). In the present leptic ptosis test (Gustafsson and Christensson 1990). experiments, the maximally preferred concentration of This unique action of amperozide thus differs from that alcohol was first determined individually for each HAD of other serotonergic drugs, such as p-chlorophenyl- rat. Then either one of two doses of the ~-HT~A or opi- alanine (pCPA), sertraline, buspirone (Myers 1985; Myers ate receptor antagonist was administered to the HAD and Quarfordt 1991; Privette et al. 1988), and other com- rats when alcohol was freely available. After treatment, pounds unrelated to 5-HT, which interfere with caloric intakes of preferred solutions of alcohol were recorded regulation and other functions (Myers 1994). Amper- to ascertain the subsequent effects of each drug on the ozide also is a potential antipsychotic and antidepres- patterns of drinking. sant drug (Axelsson et al. 1991; Bjork et al. 1992), which enhances the release of dopamine from mesolimbic neurons in viva (Grenhoff et al. 1990; Kimura et al. 1993; METHODS Yamamoto and Meltzer 1992). The effect of amperozide on alcohol preference implicates further the role of sero- Naive male 30-day-old HAD rats from the original N/ tonergic neurons in the brain proposed historically to Nih heterogeneous strain (Li and Lumeng 1984; Spuh- underlie aberrant drinking behavior (Myers and Mel- ler and Dietrich 1984) were obtained from the Indiana chior 1977). University Alcohol Research Center. On arrival, the rats Another neurochemical link in the central mecha- (n = 17) were quarantined until treatment with iver- nisms of alcoholism is thought to involve the in vivo mectin for pinworms was completed. At 60 days of age, formation of a family of aldehyde adducts such as a tet- 10 mg/kg cyanamide were administered subcutane- rahydro-isoquinoline (TIQ) or B-carboline (Collins 1985; ously twice daily to the rats for 3 days to sustain their Davis and Walsh 1970; Myers 1978, 1980, 1985). These preference for alcohol (Barwick and Myers 1992; Myers aldehyde adducts are synthesized in brain tissue, after and Critcher 1982). At 90 days of age, each rat was prolonged exposure to alcohol, by the condensation housed in an individual wire mesh cage at an ambient reaction between an endogenous amine and an alde- temperature of 22°C to 24°C and on a 12-hour illumina- hyde (Melchior and Collins 1982). One of the TIQ deriv- tion cycle with lights on at 0630 hours. Water and atives, tetrahydropapaveroline (THP), is the biological Purina NIH rodent chow were provided ad lib, and food precursor to morphine in the opium poppy. When THP and fluid intakes as well as body weights were recorded is infused intracerebroventricularly (ICV) in the rat or daily at 0730-0830 hours. monkey, or directly into specific structures in the meso- limbic system of the rat, abnormally high drinking of alcohol occurs spontaneously (Melchior and Myers Alcohol Preference Tests 1977; Myers and Privette 1989). As a consequence, the concept evolved that opiate receptors are involved in The pattern of preference for alcohol versus water was the pathologic development of abnormal drinking, sec- determined individually for each HAD rat using a stan- ondarily to the formation of the aldehyde adduct. Sup- dard three-bottle test procedure (Quarfordt et al. 1991). port for this viewpoint is provided by the fact that One tube contained a v/v solution of alcohol in tap opiate receptor antagonists assuage the preference for water, a second tube served as a blank, and the third alcohol in different species. For example, naloxone and tube was filled with tap water. The drinking tubes were the longer acting compound, naltrexone, significantly rotated daily on a semirandomized schedule to prevent reduce the intake of alcohol (Critcher et al. 1983; Myers the development of a position habit (Myers 1978). An et al. 1986); however, this effect depends on both the fre- 11-day preference test was carried out in which the con- quency and dose of their administration and the con- centration of alcohol was raised on each morning as fol- centration of alcohol offered to the test animal (Froeh- lows: 3%, 4%, 5%, 7%, 9%, ll%, 13%, 15%, 20%, 25%, lich et al. 1990; Hubbell et al. 1991; Myers and Critcher and 30%. After completion of the test sequence, each rat 1982; Volpicelli et al. 1986). was offered water and a solution of its maximally pre- The present study was undertaken to compare the ferred concentration of alcohol, as based on the 3% to efficacy of amperozide and naltrexone on the intake of 30% test. The individual test solution was the highest alcohol in the selectively bred high alcohol drinking concentration at which the largest volume of alcohol (HAD) rat. Initially it was found that naloxone adminis- was consumed prior to a downward shift below the NELJROPSYCHOPHARMACOLOGY 1996-vo~.14,~0.2 5-HT, Opiate Antagonists, and Drinking 141 50% level in the proportion of alcohol to the total fluid CA) to compare each value obtained under successive consumed (Lankford et al. 1991). test conditions. An F test with a p value of <.05 was considered to be statistically significant.

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