Differential efficacy of serotonergic drugs FG5974, FG5893, and amperozide in reducing alcohol drinking in P rats

Amperozide (FG5606), a 5-HT₂ receptor antagonist, is well known to suppress alcohol consumption in different rat models of drinking. The present study compared the efficacy of three drugs, FG5974, FG5893, and amperozide, which have differential affinities for 5-HT_1A and 5-HT_2A receptors, on alcohol drinking in the genetic alcohol-preferring (P) rat. After preference for alcohol vs. water was determined over 10 days when concentrations of alcohol were increased from 3% to 30%, the maximal concentration of alcohol preferred by each animal was selected for drug testing. A 4-day predrug preference test was followed by SC injection of the saline control vehicle or doses of 1.0 and 2.5 mg/kg FG5974, FG5893, or amperozide given at 1600 and 2200 h for 4 days. Alcohol preference testing concluded with a final 4-day interval. A total daily dose of 5.0 mg/kg FG5974 reduced absolute g/kg intake of alcohol and proportional intakes of the P rats significantly; the lower dose of FG5974 also reduced alcohol drinking significantly following treatment. The mixed 5-HT_1A agonist/5-HT_2A antagonist, FG5893, which suppresses drinking in cyanamide-treated rats, was without effect on alcohol ingested by the P rats. However, amperozide caused a dose-dependent decline in both absolute intakes and proportion of alcohol that was more intense than that of FG5974. The control vehicle failed to alter alcohol drinking and, like the FG compounds, did not affect food intake or body weight. Although the inhibition of alcohol drinking by amperozide corresponds precisely with previous findings, the effect of FG5974 contrasts to results obtained with a structurally analogous drug FG5893. Thus, the genetic strain of rat as well as the nature of the chemical characteristics of a 5-HT agonist/antagonist will determine the differential efficacy of a drug in influencing the volitional drinking of alcohol.     

Alcohol drinking in rats is attenuated by the mixed 5-HT1 agonist/5-HT2 antagonist FG 5893

Over the last three decades, the neurotransmitter serotonin (5-HT) has been implicated in the etiological mechanisms underlying the excessive drinking of ethyl alcohol. Recently, the 5-HT₂ antagonist amperozide was found to reduce selectively the high intake of alcohol in the cyanamide-induced drinking rat without any adverse side effects. The purpose of the present study was to determine the action on alcohol drinking of the novel second-generation amperozide-like drug, which is a mixed 5-HT₁ agonist/5-HT₂ antagonist, FG 5893 (2-[4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazinyl]-3-pyridinecarboxylic acid methyl ester). To induce preference for alcohol in Sprague-Dawley rats, the enzyme aldehyde dehydrogenase was inhibited by cyanamide administered in the absence of alcohol in a dose of 10 mg/kg twice a day over three days. A standard three-bottle preference test was used in which water and a maximally preferred concentration of alcohol were offered to each animal. Following control tests of alcohol preference for 3 days, either a saline control vehicle or FG 5893 in a dose of 0.5, 1.0, or 2.5 mg/kg was administered subcutaneously at 1600 and 2200 for 3 consecutive days. Whereas control injections of saline were without effect on alcohol consumption, all doses of FG 5893 significantly reduced the 24-h intake of alcohol in terms of both absolute g/kg and proportion of alcohol to total fluid intake. Further, the 1.0 and 2.5 mg/kg doses of FG 5893 continued to suppress alcohol consumption over two 4-day tests immediately following the injection sequence and after a 40-day interval. Neither body weights nor intakes of food of the rats were affected by FG 5893 either during or after its administration. Thus, it is proposed that this putative anxiolytic and antidepressant drug causes a prolonged modification in the function of serotonergic synapses in the mesolimbic system of the brain. Because FG 5893 possesses combined 5-HT_1A agonist and 5-HT₂ antagonist characteristics, it is envisaged that the addictive property of alcohol may in part involve a concurrent perturbation in the function of these two subtypes of serotonergic receptors.     

Irreversible suppression of alcohol drinking in cyanamide-treated rats after sustained delivery of the 5-HT2 antagonist amperozide

The purpose of this study was to evaluate the long-term effect of sustained treatment with amperozide, which has been shown to attenuate the volitional drinking of ethyl alcohol in the rat without side effects. Preference for alcohol first was induced pharmacologically in Sprague-Dawley rats by the inhibitor of aldehyde dehydrogenase, cyanamide, administered in a dose of 10 mg/kg twice daily for 3 days. Then following a standard preference test, each rat was offered water and its maximally preferred concentration of alcohol which ranged from 7% to 15%. Following a 4-day pre-drug test, saline control vehicle or amperozide was administered for 7 days by an osmotic minipump implanted in the intrascapular space. A single dose of 208 μg/kg/h (i.e., 5.0 mg/kg/day) was selected on the basis of a prior dose response study of amperozide. During the interval of sustained release of amperozide, the consumption of alcohol declined significantly in terms of both absolute g/kg intake and proportion of alcohol to water. When the preference of the rats was retested at 4, 30, 70, 110, and 140 day intervals after the pump had exhausted amperozide, the absolute g/kg consumption of alcohol continued to decline significantly. Unlike other drugs, amperozide did not produce any side effects, particularly on the intake of food or water or on body weight, which suggests a pharmacological specificity of its action. Because amperozide acts centrally on 5-HT₂ receptors as well as on dopaminergic synapses in the limbic system, it is envisaged that the drug exerts a unique effect on reward systems in the brain by affecting their receptor reuptake mechanisms, release of the respective transmitters, or other processes potentially involved in the abnormal imbibition of alcohol. Finally, because the effect of amperozide on alcohol drinking is progressive and irreversible, it thus may serve as a pharmacological adjunct to current therapy used in the clinical treatment of the disease of alcoholism.     

The mixed 5-HT1A2A receptor drug FG5938 suppresses alcohol drinking while enhancing feeding in P rats

The neurotransmitter serotonin (5-HT) has long been implicated in the etiology of aberrant consumption of alcohol. Several compounds thought to possess a potential therapeutic value to counteract drinking have high affinities for 5-HT_1A and 5-HT_2A receptors in the brain. For example, amperoxide and FG5865 significantly reduce the volitional intake of alcohol, without altering food intake, both in rats genetically predisposed or chemically induced to drink alcohol. The present study was undertaken in the alcohol-preferring (P) rat to determine whether an amperozide-like drug. FG5938 (1-[4-(p-fluorophenyl)butyl]-4-(6-methyl-2-pyridinyl)-piperazine fumarate), exerts an action on the volitional drinking of alcohol as well as on the intakes of food and water. In 11 male P rats, the pattern of preference for different concentrations of alcohol was determined by an 11-day test for water vs. 3 to 30% alcohol solutions. After maximally preferred alcohol concentrations, i.e., 9 to 15%, had stabilized for 4 days, saline of FG5938 was injected subcutaneously at 1600 and 2200 h in a dose of 2.5, 5.0, or 10.0 mg/kg over 4 consecutive days. Following treatment, preference testing for the same concentrations of alcohol was continued for 5 additional days. FG5938 caused a significant suppression in alcohol drinking in terms of both absolute g/kg and proportion to total fluid intake. During its administration, FG5938 also enhanced the ingestion of food and water of the P animals significantly, with the largest intake occurring on the initial day, while body weights increased. After FG5938 injections, food and water intakes returned to predrug levels. The saline control vehicle had no significant effect on the intakes of alcohol, food, or water of the P rats. Overall, these results show that FG5938 acts to attenuate alcohol preference while simultaneously increasing the ingestion of food paradoxically. To our knowledge, this is the first known drug to possess this unique property. Finally, these findings support the view that a compound having affinities to both 5-HT_1A and 5-HT_2A receptors may be useful as a therapeutic agent in the treatment of alcoholism.     

Volitional consumption of ethanol by fawn-hooded rats: Effects of alternative solutions and drug treatments

Behavioral and neurochemical measures of brain 5-hydroxytryptamine (5-HT) function in the Fawn-Hooded rat are abnormal relative to outbred strains of rats. Fawn-Hooded rats freely drink large amounts of 10% ethanol in the presence of water and have been proposed to be an animal model for studies related to alcoholism. In this study, Fawn-Hooded rats were given solutions of ethanol increasing in concentration from 3% to 30% (w/v in tap water) over 10 days with tap water in a second drinking tube and a third tube left empty. The solutions of ethanol that produced maximal drinking with a preference (ml ethanol/ml total fluid) near 50% ranged from 5% to 13%, which became: the fixed individual concentrations for each rat. After a 5-day baseline period the rats were offered a solution in the third drinking tube of either 0.5% aspartame or chocolate Ultra SlimFast (diluted with water 2: 1). The chocolate drink, but not aspartame, significantly reduced the consumption of alcohol by 73%. For the drug experiments, the rats were given successive 4-day periods of: baseline drinking; drug or saline injections b.i.d.; and a posttreatment period. Neither ipsapirone, a 5-HT_1a partial agonist, nor naltrexone injected inhibited the intakes of ethanol solutions. Treatment with 2.5 mg/kg of amperozide, a 5-HT₂ antagonist, decreased the consumption of ethanol by 38%, but also caused a decrease in consumption of food. These results show a pattern of drinking of increasing concentrations of ethanol different than other strains of rats. Because ethanol intakes of the Fawn-Hooded rat decline precipitously when offered palatable chocolate drink and fail to respond to drugs known to decrease human ethanol intake, this strain may not be a valid model for testing the effects of centrally acting drugs on the consumption of ethanol.     

Involvement of the serotonergic system in ethanol intake in the rat

A two-bottle, free-choice paradigm was used to investigate the influence of the serotonergic (5-HT) system on ethanol intake in genetically heterogeneous Wistar rats. Systemic administration of the 5-HT_1A agonist ipsapirone (1.25–5.0 mg/kg) caused a dose-dependent decrease in ethanol preference and intake, while the 5-HT₂ antagonist ritanserin (1.25–5.0 mg/kg) and the 5-HT₃ antagonists ondansetron (0.01–1.0 mg/kg) and granisetron (0.5–1.0 mg/kg) failed to alter ethanol consumption. The effect of ipsapirone treatment on ethanol intake was more pronounced in high-preferring animals than in low-preferring. A closer look at the microstructure of the rat's drinking behaviour by means of a microcomputer-controlled data acquisition system showed that ipsapirone treatment caused a significant decrease in the number of licks recorded at the ethanol-containing bottle and a decrease in the time spent at this bottle. Furthermore, ipsapirone treatment caused a significant increase in the number of breaks in licking behaviour recorded at this bottle. The drinking behaviour at the water-containing bottle was not affected by the ipsapirone treatment. Neither was the rat's eating behaviour altered by this treatment. These findings support the hypothesis that the 5-HT system is involved in the regulation of ethanol intake, with special emphasis on the involvement of the 5-HT_1A receptor subtype, and may indicate that central reward-mediating mechanisms are influenced.     

New drugs for the treatment of experimental alcoholism

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.     

Nefazodone attenuates the behavioral and neurochemical effects of ethanol

This study evaluated the influence of nefazodone, a combined 5-HT_2A receptor antagonist and 5-HT reuptake inhibitor, on the behavioral and neurochemical effects of ethanol in nonselected male Wistar rats. In microdialysis experiments, ethanol (2.5 g/kg, IP) increased extracellular accumbal dopamine levels by 36% (p = 0.0073) compared to baseline levels, and elevated the maximal DOPAC and HVA levels by 26% (p = 0.0093) and 52% (p = 0.0010), respectively. Nefazodone (50 mg/kg, SC) per se increased accumbal dopamine levels by 28% (p = 0.0199), but, when injected 40 min before ethanol, reduced the ethanol-induced elevation of accumbal dopamine overflow (p = 0.0132) and decreased the ethanol-induced HVA levels (p = 0.0159). In an ethanol(6% v/v)/water free-choice paradigm, nefazodone (50 mg/kg, SC) decreased ethanol intake by 51% (p = 0.0251) and preference by 22% (p = 0.0251) in high- but not low-preferring rats from a nonselected Wistar strain. These results show that nefazodone modulates the mesolimbic dopamine system in a dopamine activity-dependent manner, and influences the neurochemical and behavioral effects of ethanol in the rat.     

Serotonin3 Receptor Antagonism of Alcohol Intake: Effects of Drinking Conditions

McKINZIE, D. L., R. EHA, R. COX, R. B. STEWART, W. DYR, J. M. MURPHY, W. J. McBRIDE, L. LUMENGAND T.-K. LI. Serotonin₃ receptor antagonism of alcohol intake: Effects of drinking conditions. ALCOHOL 15(4) 291–298, 1998.—The effects of 5-HT₃ receptor antagonists on ethanol intake were examined in the selectively bred alcohol-preferring P line of rats under continuous and limited access to 10% (v/v) ethanol with food and water ad lib. Single daily injections of either MDL 72222 (MDL) or ICS 205-930 (ICS) (0.01–3.0 mg/kg, SC) given 60 min before a 4-h scheduled access period for 4 consecutive days failed at all doses to alter the intake of a 10% (v/v) ethanol solution by P rats. However, multiple daily injections of either MDL (1–3 mg/kg, SC) or ICS (3.0 and 5.0 mg/kg, SC), given three times daily at 4-h intervals, significantly reduced ethanol intake under 24-h free-choice conditions on the first treatment day. Additionally, a single administration of 1.0 mg/kg MDL reduced 24-h free-choice ethanol intake by approximately 50% of control values and had no effect on 24-h saccharin intake. The effects of MDL were further examined in a 2-h schedule access paradigm in which rats received the access period at the same time every day (Fixed) or randomly during the dark cycle (Variable). Although 1.0 mg/kg MDL had little effect on ethanol drinking in the Fixed group, ethanol intake was reduced by 55% of control levels in the Variable group. Overall, the data indicate that drinking conditions influence the effectiveness of 5-HT₃ antagonists to reduce ethanol consumption. Furthermore, the results suggest that conditions, associated with limited access ethanol drinking, markedly reduce the actions of 5-HT₃ antagonists on ethanol intake.     

Taste reactivity to ethanol in rats: Influence of adrenalectomy or ipsapirone

The affective mimetic responses of male Wistar rats with prior access to 6% ethanol in their home cages were observed during intraoral infusions of an equivalent alcohol solution. Ethanol preference in the home cage appeared unrelated to measures of aversion and ingestion in the taste reactivity tests in normal rats. Adrenalectomy, which significantly reduced home cage ethanol preference, failed to influence the taste reactions elicited by ethanol or water. On the other hand, treatment of intact rats with the 5-HT_1A receptor agonist ipsapirone (2.5 mg/kg), a drug that also decreases ethanol drinking in two-bottle intake tests, did increase the duration of aversive groomings, whereas measures of ingestion remained unaffected. These results suggest that ipsapirone, but not adrenalectomy, may alter the palatibility of ethanol; this perceptual change may partly underlie the ability of ipsapirone to reduce home cage alcohol drinking in the rat.     

The 5-HT1A receptor agonist 8-OH-DPAT reduces ethanol intake and maintained behavior in female Sprague-Dawley rats

Agents affecting serotonergic (5-hydroxytryptamine, 5-HT) function influence ethanol consumption in rats and primates. In the present study female Sprague-Dawley rats were trained to orally self-administer 8% ethanol (v/v) in a large operant chamber in a 60-min test period by a prandial drinking technique. The number of responses, ethanol reinforcers (dipper deliveries), and ethanol consumption (g/kg) were measured following administration of the 5-HT_1A agonist 8-OH-DPAT (0.001–1.0 mg/kg, ip) 30 min prior to testing. Locomotor activity (LMA) was also measured to assess activity changes induced by 8-OH-DPAT. 8-OH-DPAT selectively reduced ethanol ingestion from 17.1±3.2 dipper deliveries under vehicle conditions to 6.6±3 at a dose of 0.1 mg/kg. Higher doses of 8-OH-DPAT (0.5 and 1.0 mg/kg) significantly reduced both ethanol ingestion and LMA. Lower doses of 0.001–0.01 mg/kg of 8-OH-DPAT were without effect on ethanol intake and maintained behavior. These results demonstrate that, under the present experimental conditions, the 5-HT_1A receptor agonist 8-OH-DPAT reduced ethanol self-administration in the rat, and support a role for 5-HT_1A receptors in the mediation of ethanol reinforcement.     

Effects of D1 and D2 dopamine receptor agents on ethanol consumption in the high-alcohol-drinking (HAD) line of rats

Dopamine receptor agonists and antagonists were tested for effects on alcohol drinking in female HAD rats (n = 10) given limited access (4 h/day) to a 10% (v/v) ethanol solution. Food and water were available ad libitum. Subcutaneous drug injections were given 30–60 min before the ethanol access periods. The D₂ agonist quinpirole (0.04–2.0 mg/kg) caused a dose-dependent decrease in alcohol drinking throughout the 4-h period. Spiperone, a D₂ antagonist, had no effect during the initial part of the session, but by the fourth hour, the 10 μg/kg dose tended to increase alcohol intake and the 30 μg/kg dose reduced intake. The D₁ antagonist SCH-23390 (3–30 μg/kg) dose-dependently decreased ethanol drinking during the first hour of access. The D₁ agonist SKF-38393 (2–6 mg/kg) also decreased alcohol intake, but it was less effective than SCH-23390. The findings implicate both D₁ and D₂ receptors in the reinforcing effects of alcohol drinking by the HAD line of rats.     

Antagonism by naltrexone of voluntary alcohol selection in the chronically drinking macaque monkey

An opiate receptor antagonist can reduce excessive alcohol drinking in the rat previously given intracerebroventricular (ICV) infusions of a tetrahydroisoquinoline. Recently, it was found that cerebrospinal fluid (CSF) obtained from volunteers or human patients and subsequently injected ICV in macaque monkeys markedly alters the voluntary consumption of ethyl alcohol in certain of these primates. The purpose of the present study was to determine whether an opioid antagonist would affect the pattern of alcohol intake in selected monkeys which drank excessive amounts of alcohol. Initially, the preferred concentration of alcohol was determined individually for each monkey which consistently drank from 3.0-6.0 g/kg alcohol per day. Subsequently, the single concentration, which ranged from 5-15%, was offered together with water during three consecutive periods as follows: (1) 4-day control baseline period; (2) a 3-day interval during which a saline control vehicle or 0.6 or 1.2 mg/kg naltrexone was administered subcutaneously at 0900 and 1700 hours; and (3) a final 4-day post-injection period during which the alcohol-water preference test was continued. The results showed that both doses of naltrexone significantly attenuated voluntary alcohol drinking up to 60% of the baseline intake during the 3 days of its administration. In two monkeys, alcohol drinking continued to be suppressed up to 50% of basal intake during all or a part of the 4-day post-naltrexone interval. These findings suggest that an opiate receptor mechanism in the brain could be partially involved in the action of the chemical constituents of the human's CSF which serve to induce an abnormally high intake of alcohol in the infra-human primate.     

5-HT1A receptor agonists reduce ethanol-induced locomotor activity in mice

Animal studies as well as clinical studies have suggested that the brain 5-HT system is important for the regulation of voluntary ethanol intake and preference. Previous studies have suggested that 5-HT_1A receptor agonists may reduce ethanol preference in rats. In the present study on mice, the 5-HT_1A receptor agonists (8-OH-DPAT), ipsapirone, and buspirone all antagonized the locomotor activity (LMA) stimulatory effect of ethanol (2.5 g/kg). The present results provide further support for the notion that the LMA-increasing effect of ethanol may be homologous to its reinforcing properties and that 5-HT_1A receptor agonists may counteract these properties as well.     

Serotonin 5-HT3 antagonists fail to affect ethanol self-administration of rats

Five Long-Evans hooded rats were trained to lever press according to fixed-ratio 5 reinforcement schedules for 0.06 ml dipper deliveries of 8% w/v ethanol during daily (M-F) 0.5-h experimental sessions. After ethanol self-administration was established, doses of the serotonin 5-HT₃ antagonists, ondansetron (0.03–3.0 mg/kg), granisetron (0.01–1.0 mg/kg), and SC-51296 (0.1–10.0 mg/kg) were administered prior to ethanol sessions to determine their effects on ethanol self-administration. None of the doses of the antagonists had significant effects on numbers of obtained ethanol deliveries. Subsequently, each antagonist (ondansetron, 0.1 mg/kg; granisetron, 0.3 mg/kg; SC-51296, 0.1 mg/kg) was administered b.i.d. for five consecutive daily sessions. During none of these chronic tests with the 5-HT₃ antagonists were there significant main effects of drug administration. Overall, these results do not support the hypothesis that the serotonin 5-HT₃ antagonists would have robust therapeutic efficacy in the treatment of alcoholism.     

Effects of fenfluramine, 8-OH-DPAT, and tryptophan-enriched diet on the high-ethanol intake by rats bred for susceptibility to stress

The swim-test susceptible (SUS) line of rats has been bred in our laboratory for the characteristic of reduced motor activity in the swim test following exposure to an acute stressor. Testing of multiple generations of SUS rats has also revealed that they consume large amounts of ethanol voluntarily. As reported for lines of rats that show a propensity for high-ethanol intake, the SUS rats show evidence of low serotonergic function. Because serotonergic function has often been shown to be involved in the regulation of alcohol consumption, here we examined the effects of manipulations of serotonin transmission on intake of ethanol by SUS rats. Fenfluramine, a serotonin-releasing drug, was injected at various doses (0.625, 1.25, 2.5, and 5.0 mg/kg) twice per day and ethanol intake was measured using a two-bottle free-choice method. The 8-OH-DPAT, a 5?HT_1A agonist, was injected at various doses (0.03125, 0.0625, 0.125, 0.25, 0.5, and 1.0 mg/kg) before a 1-h session of exposure to ethanol (single-bottle test, water available the other 23 h per day). A diet enriched with 3% tryptophan (TRP), the amino acid precursor for serotonin synthesis, was administered in a restricted feeding schedule (5 h per day) with ethanol intake measured the last 4 h. Fenfluramine decreased ethanol intake at all doses tested. The 8-OH-DPAT increased ethanol intake at lower doses, presumably acting at autoreceptors, which inhibit serotonergic neurons, and decreased intake at higher doses, presumably acting at postsynaptic 5-HT_1A receptors. TRP-enriched diet also significantly decreased ethanol intake. Food and water intake were less or unaffected by these three manipulations. With all three manipulations, ethanol intake remained suppressed one or more days after the day of tests that decreased ethanol intake. These data suggest that SUS rats, like many other lines/strains of rodents that consume large amounts of alcohol, show an inverse relationship between serotonin transmission and voluntary intake of ethanol.     

The novel, selective, brain-penetrant neuropeptide Y Y2 receptor antagonist, JNJ-31020028, tested in animal models of alcohol consumption, relapse, and anxiety

Neuropeptide Y (NPY) signaling has been shown to modulate stress responses and to be involved in regulation of alcohol intake and dependence. The present study explores the possibility that blockade of NPY Y2 autoreceptors using a novel, blood-brain barrier penetrant NPY Y2 receptor antagonist, JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), may achieve a therapeutically useful activation of the NPY system in alcohol- and anxiety-related behavioral models. We examined JNJ-31020028 in operant alcohol self-administration, stress-induced reinstatement to alcohol seeking, and acute alcohol withdrawal (hangover)-induced anxiety. Furthermore, we tested its effects on voluntary alcohol consumption in a genetic animal model of alcohol preference, the alcohol-preferring (P) rat. Neither systemic (0, 15, 30, and 40 mg/kg, subcutaneously [s.c.]) nor intracerebroventricular (0.0, 0.3, and 1.0 nmol/rat) administration of JNJ-31020028 affected alcohol-reinforced lever pressing or relapse to alcohol seeking behavior following stress exposure. Also, when its effects were tested on unlimited access to alcohol in P rats, preference for alcohol solution was transiently suppressed but without affecting voluntary alcohol intake. JNJ-31020028 (15 mg/kg, s.c.) did reverse the anxiogenic effects of withdrawal from a single bolus dose of alcohol on the elevated plus-maze, confirming the anxiolytic-like properties of NPY Y2 antagonism. Our data do not support Y2 antagonism as a mechanism for reducing alcohol consumption or relapse-like behavior, but the observed effects on withdrawal-induced anxiety suggest that NPY Y2 receptor antagonists may be a putative treatment for the negative affective states following alcohol withdrawal.     

Serotonin-3 receptors in the posterior ventral tegmental area regulate ethanol self-administration of alcohol-preferring (P) rats

Several studies indicated the involvement of serotonin-3 ([5-hydroxy tryptamine] 5-HT₃) receptors in regulating alcohol-drinking behavior. The objective of this study was to determine the involvement of 5-HT₃ receptors within the ventral tegmental area (VTA) in regulating ethanol self-administration by alcohol-preferring (P) rats. Standard two-lever operant chambers (Coulbourn Instruments, Allentown, PA) were used to examine the effects of seven consecutive bilateral microinfusions of ICS 205-930 (ICS), a 5-HT₃ receptor antagonist, directly into the posterior VTA on the acquisition and maintenance of 15% (vol/vol) ethanol self-administration. P rats readily acquired ethanol self-administration by the fourth session. The three highest doses (0.125, 0.25, and 1.25 μg) of ICS prevented acquisition of ethanol self-administration. During the acquisition postinjection period, all rats treated with ICS demonstrated higher responding on the ethanol lever, with the highest dose producing the greatest effect. In contrast, during the maintenance phase, the three highest doses (0.75, 1.0, and 1.25 μg) of ICS significantly increased responding on the ethanol lever; after the 7-day dosing regimen, responding on the ethanol lever returned to control levels. Microinfusion of ICS into the posterior VTA did not alter the low responding on the water lever and did not alter saccharin (0.0125% wt/v) self-administration. Microinfusion of ICS into the anterior VTA did not alter ethanol self-administration. Overall, the results of this study suggest that 5-HT₃ receptors in the posterior VTA of the P rat may be involved in regulating ethanol self-administration. In addition, chronic operant ethanol self-administration and/or repeated treatments with a 5-HT₃ receptor antagonist may alter neuronal circuitry within the posterior VTA.     

Naltrexone treatment produces dose-related effects on food and water intake but daily alcohol consumption is not affected

Abstract

There is evidence that naltrexone, an opioid antagonist, affects alcohol and food consumption. Though food intake is inherently involved when naltrexone effects on alcohol consumption have been studied, the differential effect of this opioid antagonist on both food and alcohol intake has not yet been reported. The present study analyzed the effect of a single daily dose of naltrexone on alcohol, food and water intake when these substances were available on a continuous basis. Wistar male rats were treated with s.c. injections of either naltrexone (2 or 10 mg/kg/day/rat) or a saline solution, 0.2 ml/day/rat for 7 days. This period was followed by a lapse of 7 days with no treatment (PT period), and this sequence of naltrexone or saline treatment followed by a period without treatment was repeated four times. Neither 2 mg/kg nor 10 mg/kg of naltrexone affected alcohol consumption, though the higher dose of naltrexone (10 mg/kg) increased food intake with respect to both the PT periods and the saline group and decreased water consumption with respect to the corresponding PT periods. Naltrexone at 2 mg/kg produced a decrease in food intake but only with respect to the PT periods. These results suggest that the effects of a single dose of naltrexone on alcohol consumption may not be evident when 24-h access to alcohol is assessed; however, naltrexone may produce different dose-related effects on food and water intake, suggesting that they may be mediated by distinct opioid system mechanisms.     

Cyanamide given ICV or systemically to the rat alters subsequent alcohol drinking

Cyanamide or disulfiram serves to suppress volitional intake of alcohol presumably because of the toxic build-up of acetaldehyde dehydrogenase (AIDH). However, the presence of acetaldehyde systemically favors the in vivo synthesis of addictive-like metabolites in the brain which in turn enhance alcohol drinking. The purpose of this investigation, therefore, was to determine whether cyanamide administered to the rat, which did not have access to alcohol during treatment, would nevertheless affect the subsequent preference for alcohol. In the first experiment, cannulae were implanted bilaterally above the cerebral ventricle of 33 adult male Sprague-Dawley rats so that an artificial CSF or a solution of cyanamide could be infused intracerebroventricularly (ICV). Following post-operative recovery, each rat was tested for its alcohol preference by offering it water and a solution of ethyl alcohol which was increased over 8 days from 3-20%. After a single test concentration of alcohol (range of 5-9%) was selected for each individual animal presented with water over a 5-day interval, cyanamide was infused in a volume of 2.5 microliters per side three times daily for 4 days in one of the following total doses: 0.03, 0.1, 0.3, 0.5 or 1.0 mg. A second five-day preference test was run, and 6 weeks following cyanamide infusions a final 3-20% alcohol preference screen was run over 8 days. The results showed that a long-term, dose-dependent increase or decrease in alcohol intake occurred in those rats reactive to the drug.(ABSTRACT TRUNCATED AT 250 WORDS)