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.     

Comparison of the action of the 5-HT2 antagonists amperozide and trazodone on preference for alcohol in rats

Previous studies in the rat demonstrated that the 5-hydroxytryptamine₂ (5-HT₂) antagonist amperozide attenuates the volitional intake of both alcohol and cocaine solutions in a free-choice situation. However, another 5-HT₂ antagonist, ritanserin, has not been found to reduce alcohol drinking consistently in the rat. In this study, trazodone was compared to amperozide for its effect on the volitional consumption of alcohol because, like amperozide, trazodone is a potent 5-HT₂ receptor antagonist but a weak inhibitor of 5-HT reuptake. Male Sprague-Dawley rats were induced to drink alcohol by 10 mg/kg cyanamide injected for 3 days b.i.d. One week later the rats were offered a choice of water and increasing concentrations of alcohol solutions ranging from 3% to 30% v/v in a three-bottle two-choice paradigm. After the concentration of alcohol that produced maximal daily intake was determined for each rat, trazodone or amperozide was injected b.i.d. SC in doses of 1.0 mg/kg or 2.5 mg/kg for three days. Whereas the higher dose of amperozide produced a significant, 55.6% decrease from pretreatment baseline of alcohol intake, trazodone did not alter alcohol preference at either the 1.0- or 2.5-mg/kg dose. These results are discussed in terms of whether the antagonism of 5-HT₂ receptors by amperozide is critical to its attenuating effect on preference for alcohol solutions.     

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.     

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.     

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.     

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 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.     

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.     

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.     

Glycyl-l-Glutamine Injected Centrally Suppresses Alcohol Drinking in P Rats

Recent reports show that central β-endorphin (1–31) injection augments the volitional intake of alcohol. Correspondingly, alcohol drinking stimulates β-endorphin (1-31) release from the hypothalamus of the rat. Glycyl-l-glutamine (Gly-Gln) is produced in β-endorphin-containing neurons and is coreleased with β-endorphin(1–31) and other processing products. Because Gly-Gln is apparently an endogenous antagonist of β-endorphin(1–31) in several systems, the present study was designed to investigate the hypothesis that Gly-Gln injected ICV would alter voluntary alcohol drinking in the genetic, high-alcohol-preferring P rat. After a guide tube was implanted stereotaxically above the lateral cerebral ventricle, the rats were offered 3–30% alcohol over 10 days, and then given their maximally preferred concentration of alcohol in the presence of water for the remainder of the experiment. Gly-Gln or artificial cerebrospinal fluid (CSF) vehicle then was injected ICV in a dose of 10 or 100 nmol for 3 consecutive days, which was followed by a 7-day postinjection interval. Gly-Gln suppressed significantly the intakes of alcohol in terms of both g/kg and proportion to total fluid. During the postinjection days, alcohol drinking continued to be suppressed, whereas neither the daily intakes of food or water nor the body weights of the rats were changed. The present results are consistent with the concept of a functional antagonism by Gly-Gln of the role of β-endorphin(1–31) in mediating certain central functions. These results demonstrate that alcohol consumption is suppressed by the direct intracerebral application of this unique peptide.     

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.     

Age dependent development of ethanol drinking in rats after inhibition of aldehyde dehydrogenase.

The purpose of this experiment was to determine the temporal characteristics associated with the age-related development of volitional consumption of ethanol induced by the pharmacological inhibition of aldehyde dehydrogenase (AlDH). To induce preference for ethanol, the AlDH inhibitor, cyanamide, was administered to male Sprague-Dawley rats which were 30 days of age. Cyanamide (n = 8) was injected subcutaneously twice daily in a dose of 10 mg/kg over a period of 3 days while the control group (n = 6) received the saline vehicle solution according to the same schedule. Then at 50, 70, 90, and 110 days of age, both groups of rats were given a standard 11-day test of preference for water versus ethanol offered in concentrations ranging from 3% through 30%. The results showed that at 70 days of age the preference for ethanol increased above the level of the 50-day test in terms of absolute g/kg intakes and proportion of ethanol to water consumed over the lower range of 3% through 15% concentrations. During the tests at 90 and 110 days of age, the cyanamide-treated rats further increased their preference for ethanol significantly over the levels at the 70-day test in terms of both g/kg and proportional intakes. The pattern of drinking of ethanol offered in the higher concentrations of 25% and 30% was unrelated to the age of the rats and the overall intakes were significantly higher than those of the lower concentrations. These findings demonstrate that the enzymatic inhibition of AlDH systematically acts in a delayed fashion to shift the pattern of preference for ethanol which is contingent on the maturation of the animal. In this instance, the volitional intake of ethanol in the cyanamide-treated rats reached its maximal level by 90-110 days of age. It is proposed that an endocrine mechanism involved in gonadal maturation may function in the intense shift in alcohol drinking.     

Effects of purified puerarin on voluntary alcohol intake and alcohol withdrawal symptoms in P rats receiving free access to water and alcohol

Alcohol preferring (P) rats, given "free choice" of water, exhibited daily intake of 60-75 g of water/kg of body weight. When given "free choice" of water and 15% ethanol, P rats consumed 7-13 g of alcohol/kg. Their water intake decreased proportionally to the alcohol intake, but total fluid intake did not differ significantly. Alcohol withdrawal after 50 days of alcohol drinking caused withdrawal symptoms such as hypersensitivity, poor coordination, and tremors. A daily 50 mg/kg dose of puerarin (PU) caused approximately 50% suppression in alcohol intake, but did not affect body weight and food and total fluid intake in P rats receiving "free choice" of water and 15% ethanol. Alcohol ingestion gradually returned to the control level despite consistent PU intake. However, alcohol intake following alcohol withdrawal was suppressed in PU-fed P rats. PU suppressed the severity of alcohol withdrawal symptoms. Thus, withdrawal symptoms do not occur in PU-fed rats even though their alcohol ingestion is comparable to that in control P rats. Brain, plasma, and liver samples were analyzed for the presence of kudzu root isoflavones, which are mostly PU (>90% of total isoflavones) and a trace amount of daidzin. Liver samples obtained from PU-fed P rats contained 20-30 microg/g of PU. An important observation was that plasma or brain samples obtained from PU-fed or alcohol + PU-fed rats did not contain PU. This study indicated that PU feeding transiently suppressed alcohol intake and abolished withdrawal symptoms at a time when alcohol intake had returned to the control level. The absence of PU in plasma and brain indicates the possibility that some nonspecific mechanism may be involved in the anti-alcoholism effects of PU in P rats.     

Evidence that the amygdala is involved in the inhibitory effects of 5-HT3 receptor antagonists on alcohol drinking in rats

Two 5-HT₃ receptor antagonists, tropisetron (1 and 10 ng) and ondansetron (10 and 100 ng) were tested for effects on ethanol drinking in Wistar male rats after bilateral microinjection into the amygdala. The animals had limited access (2 h/day) to the 10% (v/v) ethanol solution, food and water were available ad lib during the scheduled access period. Both drugs caused a decrease in ethanol drinking. Tropisetron (1 and 10 ng) decreased ethanol intake during the first hour of access. The lower dose (10 ng) of ondansetron was more effective than the higher (100 ng) dose. The finding implicates amygdaloid 5-HT₃ receptors in the mechanism of ethanol intake in Wistar rats.     

Sex differences in alcohol drinking patterns during forced and voluntary consumption in rats.

Wistar rats were studied during forced and voluntary alcohol consumption, and continuous or periodic access to ethanol (6%) v/v with different availability of fluids. Absolute volume of alcohol consumption was not different between sexes in any condition; however, females consumed significantly more alcohol than males on a g/kg basis in all conditions. These differences were significantly more extensive during continuous free-choice to alcohol and water than during forced alcohol consumption. Females showed greater alcohol preference than males only during continuous free-choice to alcohol and water. During periodic free-choice to alcohol and water condition, alcohol consumption was distributed during more hours throughout the day in females than males. During periodic free-choice to alcohol and to an isocaloric sweetened solution (ISS), intakes of ISS were very high compared to regular intakes of daily water; nevertheless, alcohol consumption was maintained to similar levels observed in continuous free-choice to alcohol and water and represented almost 50% of regular daily consumes of water in males and females. Free-choice for alcohol and ISS modified the usual pattern of alcohol consumption during the daily light-dark cycle in males and females and reduced the time devoted to drinking alcohol compared to other conditions, in which similar intakes were observed. Results show that the extent of the higher alcohol consumption in females than males and the changes in patterns of alcohol intake were dependent on the nature of the ingestion schedule.     

Apomorphine and 7-OH DPAT reduce ethanol intake of P and HAD rats

Adult male rats of the alcohol-preferring (P) line (N = 10) and high alcohol drinking (HAD) line (N = 12) were used to study the effects of IP administration of 0.125–0.50 mg/kg 7-OH DPAT (a putative D₃ agonist) and 0.25–1.0 mg/kg apomorphine (a dopamine agonist with 50-fold higher affinities for the D₁ and D₂ receptors than for the D₃ receptor) on the concurrent intakes of 10% (v/v) ethanol and 0.0125% (g/v) saccharin during a daily 4-h scheduled access period. Control intakes by the P rats for the 4-h period were 17.9±0.5 and 7.2±0.4 ml for the ethanol and saccharin solutions, respectively. For the HAD line, ethanol consumption was 18.7±0.2 ml and saccharin intake was 8.7±1.6 ml for the 4-h period. In terms of grams ethanol/kg body wt., the 4-h intakes were 2.2±0.2 for the P line and 3.0±0.3 for the HAD rats. Both P and HAD rats consumed approximately 40% of their total ethanol intake in the first 15 min of access while consuming only about 15% of their total saccharin intake during this 15-min period. The putative D₃ agonist 7-OH DPAT produced a decrease in ethanol intake in the first h to 45–55% of control levels for the P rat (p < 0.01) and to 25–70% of control values in the HAD line (p < 0.001). Apomorphine caused a dose-dependent decrease in ethanol intake in the first hour to 15–70% of control values in the P rat (p < 0.001) and to 25–60% of control levels in the HAD line (p < 0.001). Saccharin and 4-h food intakes for both lines were not altered by either 7-OH DPAT or apomorphine. Overall, these results suggest that D₂ and D₃ dopamine receptors may play a role in mediating alcohol drinking behavior of the selectively bred HAD and P lines of rats.     

Sex differences in pattern of drinking.

Drinking patterns of male and female Long-Evans rats were compared during a 15-day drinking period. All animals were tested for preference for alcohol for 24 h during which food, water, and beer containing 5% ethanol were freely available. Animals drinking 50 ml or more of beer were chosen for the experiments. On days 1-5, animals were offered food, water, and beer containing 5% ethanol (v/v). On days 6-15, the concentration of ethanol in the beer was doubled to 10% (v/v). Preference ratios (beer/total fluid) were higher for females than males, and females consumed more grams of alcohol per unit of body weight. When alcohol concentration was doubled, females increased alcohol intake (g/kg), while males tended to titrate alcohol intake to levels consumed at 5% concentration. Female patterns of drinking differed from male patterns of drinking.     

Alcohol drinking in rats injected ICV with 6-OHDA: Effect of 8-OHDPAT and tropisetron (ICS 205930)

6-Hydroxydopamine (6-OHDA) was administered ICV to Wistar male rats. Lesioned animals displayed lower preference for ethanol (ETOH) than sham-operated rats. Among 6-OHDA lesioned rats only 9% became high-preferring whereas 20% of sham-operated animals became high-preferring ones. Both tropisetron (the antagonist of 5-HT₃ receptors) and 8-OHDPAT (the 5-HT_1A receptor agonist) reduced ETOH drinking in high-preferring rats. However, in 6-OHDA lesioned rats the effect of tropisetron was reduced although 8-OHDA retained its effect on ETOH consumption. These results suggest that brain DA neurons are involved in tropisetron action but are not responsible for antipreference effect of 8-OHDPAT.     

Sham ingestion of alcohol in rats.

Sprague-Dawley rats were surgically fitted with gastric fistulas and their intakes of 6% ethanol measured first with the fistula closed (normal drinking) and then on three test sessions with the fistula open (sham drinking). The rats were water deprived prior to the 1-h test sessions. On the second and third sham drinking sessions, intakes of alcohol were significantly increased above those in both the closed and first open fistula session. The effectiveness of the sham ingestion preparation to minimize absorption was shown by the much lower blood alcohol levels in sham compared with real drinking rats. Thus, reduction of the postingestive effects of alcohol leads to an acquisition of increased oral consumption. The similarities and differences between sham intakes of water and alcohol are discussed.