Effects of 5-HT(3) receptor antagonists on daily alcohol intake under acquisition, maintenance, and relapse conditions in alcohol-preferring (P) rats.

Previous research indicated that 5-HT(3) antagonists can reduce ethanol drinking in rats, but drinking conditions and other environmental manipulations influenced the efficacy of these antagonists. The current experiments were conducted to examine the effects of the 5-HT(3) antagonists MDL 72222 (MDL) or ICS 205-930 (ICS) on 24-h ethanol (10% v/v) consumption during acquisition, maintenance, and following a period of deprivation in selectively bred high alcohol-preferring (P) male rats. In an analysis of the acquisition of ethanol consumption, daily injections of MDL (1 mg/kg; s.c.) or ICS (1 or 5 mg/kg) were administered to separate groups of P rats during the initial 10 days of ethanol exposure. To examine the maintenance of ethanol drinking, these same groups of rats were allowed access to ethanol for 21 days with no pharmacological manipulations, and were then administered either saline or the 5-HT(3) antagonist. To examine the effects of a 5-HT(3) antagonist on relapse of ethanol drinking, another group of P rats was allowed access to ethanol for 6 weeks and was then deprived of ethanol for 3 weeks. Prior to ethanol reinstatement, rats were treated chronically (seven daily injections) or acutely with MDL (1 mg/kg), saline, or received no injections. MDL (1 mg/kg) and ICS (1 or 5 mg/kg) reduced ethanol intake during acquisition (60-80%) and during maintenance drinking (35-70%) in P rats pretreated with saline during acquisition. However, in rats pretreated with MDL or ICS during acquisition, there was a significant reduction in the effectiveness of either MDL or ICS to reduce ongoing ethanol drinking. Neither acute nor chronic treatment with 1 mg/kg MDL altered the 80% increase in ethanol consumption observed on the first day of reinstatement following a 3-week deprivation period. However, in a follow-up study, acute treatment with MDL (3 mg/kg) or ICS (5 mg/kg) did prevent the 80% increase in ethanol consumption observed on the first day of reinstatement. Overall, the results suggest that 5-HT(3) receptors are involved in the acquisition and maintenance of 24-h ethanol drinking, and that neuroadaptations may occur as a result of chronic treatment with 5-HT(3) antagonists, or during prolonged alcohol deprivation, which alter the involvement of these receptors in regulating alcohol drinking in the P rat.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

An Investigation Into the Effects of 5-HT Agonists and Receptor Antagonists on Ethanol Self-Administration in the Rat

Pharmacological manipulation leading to altered 5-HT function has been widely demonstrated to reduce ethanol intake in free choice tests. The aim of the present study was to examine the effects of a range of compounds known to influence 5-HT neurotransmission, including selective 5-HT receptor agonists and antagonists, on ethanol ingestion and maintained behaviour in an operant self-administration paradigm. Female Sprague–Dawley rats were trained to respond for 8% ethanol (v/v) in a 60-min test by a previously described technique. The number of responses and ethanol reinforcers (dipper deliveries), ethanol consumption (g/kg of body weight), and locomotor activity (LMA) were measured following administration of 5-HT agonists (5-HT, d-fenfluramine, fluoxetine, buspirone, TFMPP, and DOI) and antagonists (metergoline, ritanserin, and ondansetron) 30 min prior to testing. d-Fenfluramine, fluoxetine, buspirone, TFMPP, and DOI all produced a reduction in ethanol ingestion and maintained behaviour at doses that failed to reduce LMA. Conversely, metergoline and ritanserin only reduced ethanol self-administration at doses that concomitantly reduced LMA. 5-HT and ondansetron were without effect on any measure. These results demonstrate that, under the present experimental conditions, activation of central 5-HT_1A, 5-HT_1B, and 5-HT₂ receptors reduced ethanol intake and reinforced behaviour in an operant paradigm.     

Voluntary consumption of ethanol and its consequences in C57 mice treated with 4-methylpyrazole

Daily injections of the alcohol dehydrogenase inhibitor 4-methylpyrazole (4MP) were administered to C57BL/6J mice offered continuous free access to food, water and 10% v/v ethanol. There was a significant correlation (r = -0.82) between the rate of ethanol consumption during pretreatment and the effect of 4MP on subsequent intake. Mice drinking more than 2.5 g/kg per day decreased their intake, while subjects drinking less than this amount increased the quantity of ethanol self-administered. The elevated concentrations of plasma ethanol which resulted from voluntary consumption were sufficient to produce intoxication but did not induce physical dependence. Presenting mice with 10% ethanol as their only fluid or offering them a choice of water and saccharin-sweetened ethanol increased intake but failed to raise plasma ethanol to the concentrations observed in mice offered unflavored ethanol and water, and treated with 4MP. The evidence suggests that plasma ethanol does not limit voluntary drinking in untreated mice and that concentrations of 135 to 250 mg/dl are not avoided by C57 mice in a free-choice situation.     

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.     

CONSTANT ABSOLUTE ETHANOL INTAKE BY SARDINIAN ALCOHOL-PREFERRING RATS INDEPENDENT OF ETHANOL CONCENTRATIONS

The present study was designed to evaluate ethanol drinkingbehaviour in Sardinian alcohol-preferring (sP) and Sardinianalcohol-non-preferring (sNP) rats in the presence of differentethanol concentrations. Ethanol intake was tested under thetwo-bottle, free-choice regimen and continuous access schedule.Ethanol-naive sP and sNP rats were initially given ethanol solutionat the standard, constant concentration of 10% (v/v) for 8 consecutivedays (Phase 1). As expected, daily ethanol intake in sP ratsrose from 4 to {small tilde}l6g/kg; in contrast sNP rats consumed<10g/kg/day ethanol. Subsequently, an ascending series ofethanol concentrations, ranging from 3 to 60% (v/v), was presentedto sP and sNP rats over a 28-day period (Phase 2). At concentrationsvarying from 7 to 30%, sP rats consumed constant amounts ofabsolute ethanol per kg of body weight ({small tilde}6.0 g/kg/day).Daily ethanol intake in sNP rats remained constantly lower than1.0 g/kg, irrespective of the ethanol concentration. Data fromPhase 2 demonstrate the ability of sP rats to precisely adjustdaily ethanol intake and support the hypothesis that voluntaryethanol drinking in sP rats is sustained by specific pharmacologicaleffects of ethanol.     

Effects of nimodipine and other calcium channel antagonists in alcohol-preferring AA rats

Several lines of evidence suggest that l-type calcium (Ca²⁺) channels play a role in excessive ethanol (EtOH) intake. In accordance with this, a considerable amount of antagonists for these ion channels has been found to suppress EtOH intake and preference in various animal models of alcoholism. The aim of the present study was to examine antialcohol effects of l-type Ca²⁺ channel antagonists in alcohol-preferring AA rats. These rats, a Wistar line selectively bred for a high 10% v/v EtOH preference in a free-choice situation, have thus far not been subjected to systematic investigations with Ca²⁺ channel antagonists. Therefore, effects on EtOH preference and intake, as well as on food and total fluid intake, were evaluated for the 1,4-dihydropyridine (DHP) derivatives nimodipine, felodipine, isradipine, nicardipine, nifedipine, and nitrendipine, as well as for the phenylalkylamine verapamil and the benzothiazepine diltiazem, utilizing a limited access, free-choice procedure. All DHPs were found to be highly effective in reducing both EtOH intake and preference, without affecting total fluid intake. Irrespective of route of application (IP or PO), the effective dose ranges were found to be very similar across compounds (10–30 mg/kg). Nevertheless, because food intake was also reduced, the effects were not completely selective. For nimodipine, the (−)-enantiomer seemed to be more effective as its (+)-enantiomer, possibly reflecting stereoselectivity at central binding sites. Compared to the DHPs, verapamil produced a similar profile of activity, but diltiazem was found to be ineffective. These results confirm and extend previous findings with l-type Ca²⁺ channel antagonists obtained in other models of alcoholism and suggest that this class of compounds offers an interesting approach for the pharmacotherapy 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.     

Histaminergic Activation of Endogenous Angiotensin II Fails to Inhibit Alcohol Intake in Rats

Demonstrations that alcohol intake can be inhibited by pharmacological activation of the renal renin–angiotensin system (RRA) or injection of angiotensin II (ANG II) in rats led to this study of a role for endogenous ANG II in inhibition of alcohol intake in rats. Relatively small doses of histamine, above threshold for eliciting drinking of water and activation of the RRA, were injected SC in adult male Sprague–Dawley rats with access to 3.0% alcohol in 45-min one-bottle alcohol tests and in two-bottle tests in which alcohol and water were available at the midpoint of the 12-h dark phase. The 0.312 and 1.25 mg/kg doses of SC histamine elevated plasma renin activity to levels similar to those in rats that had just eaten food. Neither dose of histamine affected alcohol intake in one-bottle tests. A relatively large 10 mg/kg dose of histamine increased alcohol intake in a one-bottle test, but decreased alcohol intake and increased water intake in two-bottle tests. The inhibitory effect of the 10 mg/kg dose of histamine on alcohol intake was completely blocked by SC 10 mg/kg losartan, a selective AT₁ angiotensin receptor antagonist. This 10 mg/kg dose of losartan given alone, however, failed to increase alcohol intake in one- or two-bottle tests. These results generally do not support a role for endogenous ANG II as an inhibitory physiological signal in the control of alcohol ingestion in rats, because histaminergic activation of RRA, using small but physiologically meaningful doses of histamine, failed to inhibit alcohol intake.     

Interaction of CCK and 8-OH-DPAT in the Satiation of Alcohol Intake

Administration of the neuropeptide cholecystokinin (CCK) is known to reduce food and alcohol intake and preference. The food satiation effect of CCK is reportedly dependent on serotonergic neurotransmission. Administration of 8-OH-DPAT, a serotonin_1A autoreceptor agonist, reduces the ability of CCK to inhibit feeding. We determined if CCK’s alcohol satiation effect also depends on activity of serotonergic neurons by administering 8-OH-DPAT (120–240 μg/kg) to 23-h water-deprived female and male rats, followed 1 h later by IP injection of CCK (4 μg/kg) and 30-min access to 5% w/v ethanol. 8-OH-DPAT significantly (p < 0.05) interacted with CCK, and reduced CCK’s ethanol satiation effect when given IP but increased CCK’s effect when given SC. Female rats showed this interaction of 8-OH-DPAT with CCK at a higher dose than males when given IP, but females were more sensitive to SC 8-OH-DPAT’s ability to reduce ethanol intake. Results are consistent with previous findings of dose-, sex-, and route-dependent biphasic effects of 8-OH-DPAT on feeding and ethanol intake. A partial dependence of CCK’s alcohol satiation effect on serotonergic neurotransmission is revealed in this design.     

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.     

Salvia miltiorrhiza extract inhibits alcohol absorption, preference, and discrimination in sP rats.

Experiment 1 of the present study investigated the ability of a standardized extract of Salvia miltiorrhiza in reducing voluntary ethanol intake in ethanol-preferring rats of the sP line. Ethanol intake occurred under the two-bottle free-choice regimen between 10% (v/v) ethanol and water in daily 4-h scheduled access periods; water was present 24 h/day. Intragastric administration of 200 mg/kg Salvia miltiorrhiza extract resulted in approximately 40% reduction in ethanol intake and preference throughout the 4-day treatment. This effect of Salvia miltiorrhiza extract was likely due to its ability of altering ethanol absorption from the gastrointestinal tract. Indeed, Experiments 2 and 3 of this study demonstrated that 200 mg/kg Salvia miltiorrhiza extract reduced blood ethanol levels (BELs) up to 60% in comparison to control rats, when ethanol was given IG, whereas it failed to modify BELs when ethanol was injected IP. The reducing effect of Salvia miltiorrhiza extract on ethanol absorption may have therefore resulted in an attenuated perception of the psychoactive effects of ethanol sought by ethanol-drinking rats. Consistently, the results of Experiment 4 of the present study demonstrated that a combination of 200 mg/kg Salvia miltiorrhiza extract IG and 1 or 2 g/kg ethanol IG resulted in a partial blockade of the discriminative stimulus effects of ethanol in sP rats trained to discriminate these doses of ethanol from water in a drug discrimination procedure. Collectively, the results are discussed as being suggestive that drugs curbing ethanol absorption from the gastrointestinal tract may constitute a novel strategy for controlling excessive alcohol consumption in human alcoholics.     

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.