Anti-alcohol Effects Research Articles

5-HT2A and 5-HT2C/5-HT1B Receptors Are Differentially Involved in Alcohol Preference and Consummatory Behavior in cAA Rats

The present study aimed to investigate the role of serotonin 5-HT2A and 5-HT2C receptors in the control of alcohol preference and consummatory behavior in alcohol-preferring cAA rats. Effects of the 5-HT2A/2C receptor agonist, DOI, the 5-HT2C/1B receptor agonist, mCPP, the 5-HT2A/2C receptor antagonist, ritanserin, and the 5-HT2A receptor antagonist, MDL 100,907, on ethanol (EtOH, 10% v/v) preference and intake, as well as total fluid and food intake were evaluated in a 12-h limited-access two-bottle paradigm. DOI (0.3–3 mg/kg, IP) reduced EtOH intake and preference, but not total fluid or food intake; whereas mCPP (1–10 mg/kg, SC) reduced EtOH, total fluid, and food intake. Therefore, it is concluded that DOI induces a specific and selective antialcohol effect, whereas mCPP rather induces a general suppressive effect on consummatory behavior. Ritanserin (1–10 mg/kg, IP) did not affect EtOH intake and preference, nor total fluid and food consumption. MDL 100,907 (0.1–1 mg/kg, IP) induced only a small reduction of food intake at the highest dose tested. Pretreatment with ritanserin (3 mg/kg, IP) and MDL 100,907 (0.3 mg/kg, IP) blocked the effects of DOI (3 mg/kg, IP), but not those of mCPP (10 mg/kg, IP). It is suggested that activation of 5-HT2C and/or 5-HT1B receptors results in a general decrease of consummatory behavior, whereas activation of 5-HT2A receptors selectively decreases EtOH intake and preference, as assessed in the cAA rat model of alcoholism.

Lack of potentiation of the anti-alcohol effects of fluoxetine by pindolol in alcohol-preferring caa rats

1. 1. Recent clinical evidence suggests that the nonselective 5-HT 1A receptor antagonist pindolol may enhance the antidepressive efficacy of selective serotonin reuptake inhibitors (SSRIs); an effect generally ascribed to a presumed blockade of somatodendritic 5-HT 1A receptors by pindolol. 2. 2. The present study investigated whether blockade of 5-HT 1A receptors similarly potentiates the previously reported anti-alcohol effects of the SSRI fluoxetine. 3. 3. Pindolol and the selective 5-HT 1A receptor antagonist WAY-100635 were tested alone and in combination with fluoxetine in cAA rats, a genetic model of alcoholism. However, as pindolol has also a high affinity to 5-HT 1B receptors, the effects of selective 5-HT 1B receptor agonists and antagonists were evaluated as well. 4. 4. Neither pindolol (3–30 mg/kg, IP), nor WAY-100635 (1–10 mg/kg, IP) affected alcohol intake when tested alone. In contrast, the 5-HTm receptor agonists CP-94,253 and TFMPP (both 1–10 mg/kg, IP), and antagonists metergoline (1–10 mg/kg, IP) and GR 127935 (3–30 mg/kg, IP) were found to reduce alcohol intake with different degrees of selectivity (that is, the extent to which reductions in ethanol intake could be separated from reductions in food- and/or total fluid intake) and specificity (that is, the degree to which effects on ethanol intake coincided with effects on ethanol preference). 5. 5. Because the behavioral profile of pindolol resembles that of WAY-100635, and not that of the 5-HT 1B receptors ligands, combination experiments with fluoxetine were only performed with the former two compounds. Neither pindolol (30 mg/kg), nor WAY-100635 (3 mg/kg) potentiated the anti-alcohol effects of fluoxetine (10 mg/kg, IP). Moreover, WAY-100635 tended to shift the anti-alcohol effect of fluoxetine towards a less selective and specific profile. It is concluded that acute blockade of 5-HT 1A receptors does not potentiate the anti-alcohol effects of fluoxetine. In addition, it is suggested that different mechanisms underly the antidepressive and anti-alcohol effects of SSR.

Stimulus properties of the L-type calcium channel agonist BAY k 8644 in rats.

Calcium (Ca(2+)) channels appear to be involved in the regulation of ethanol (EtOH) intake, as indicated by the effectiveness of both L-type Ca(2+) channel antagonists and agonists in reducing EtOH intake in animals. The present study was aimed to investigate rewarding/aversive and discriminative stimulus effects of the Ca(2+) channel agonist BAY k 8644, a compound showing pronounced anti-alcohol effects in rats. Therefore, a series of conditioned taste aversion (CTA), conditioned place preference (CPP) and two-lever drug discrimination (DD) experiments were conducted in Wistar rats, with (+/-)-BAY k 8644 and its enantiomers. After i.p. application, (+/-)-BAY k 8644 (0.0625-1mg/kg), (-)-BAY k 8644 (0.125-1mg/kg) and (+)-BAY k 8644 (2.5-20mg/kg) all induced a dose-dependent CTA. The minimal effective doses (MED) for (+/-)-, (-)- and (+)-BAY k 8644 were 0.25, 0.25 and 10mg/kg, respectively. In a CPP study, however, (+/-)-BAY k 8644 (0.25-2mg/kg, i.p.) showed neither aversive nor rewarding stimulus properties. Rats were trained to discriminate (-)-BAY k 8644 (0.3mg/kg, i.p.), the enantiomer acting as a high potency Ca(2+) channel agonist, from vehicle, in a two-lever DD procedure (ED(50)) value: 0.05mg/kg); full generalisation: 0.1mg/kg). The (-)-BAY k 8644 cue dose-dependently generalized to (+/-)-BAY k 8644 and (+)-BAY k 8644, the enantiomer acting as a low potency Ca(2+) channel antagonist, with ED(50) values of 0.06 and 0.28mg/kg, respectively. Both (+/-)- and (+)-BAY k 8644 produced full generalization at 1mg/kg, the latter compound showing an inverted U-shaped curve (i.e., this was the only dose showing >80% drug lever selection). The stimulus patterns of BAY k 8644 and its enantiomers appear to resemble the anti-alcohol profiles of these compounds. Therefore, commonalities between the stimulus properties of the agonistic and antagonistic enantiomers might provide a clue for the mechanism underlying the anti-alcohol effects of L-type Ca(2+) channel antagonists and agonists.

O-1-8 - Cannabis withdrawal syndrome: Laboratory artifact or clinically important?

Clinical studies indicate that selective serotonin-reuptake inhibitors (SSRIs) may decrease alcohol intake and craving in particular subgroups of alcoholics. The aim of the present study was to compare the behavioral profile of various SSRIs in alcohol-preferring cAA rats, a genetic model of alcoholism. The effects of acute IP administration of fluoxetine (doses in mg/kg 1–10), citalopram (3–30), fluvoxamine (3–30) and paroxetine (1–10) on ethanol (EtOH) intake and preference, as well as food and total fluid intake, were determined in a 12-h access, water vs. 10% v/v EtOH two-bottle choice paradigm. Each compound reduced EtOH intake [Minimal Effective Doses (MEDs) 5, 10, 30 and 1 mg/kg for fluoxetine, citalopram, fluvoxamine, and paroxetine, respectively]. The degree of selectivity, that is, the extent to which reductions in EtOH intake could be separated from reductions in food and/or total fluid intake varied across the compounds. Thus, whereas EtOH intake was more markedly affected than food intake by fluoxetine, both parameters were equally affected by citalopram, and food intake was more markedly affected than EtOH intake by fluvoxamine and paroxetine. The anti-alcohol effect also differed with respect to specificity, that is, the degree to which effects on EtOH intake coincided with effects on EtOH preference. Whereas fluoxetine showed the highest level of specificity, followed by citalopram and fluvoxamine, the effect of paroxetine was nonspecific. The observed variation in the degree of selectivity and specificity of the anti-alcohol effect of SSRIs suggests that reductions in EtOH intake are not merely a consequence of a general suppressive effect on consummatory behavior. It is hypothesized that differences between the behavioral profiles of these compounds reflect a differential involvement of 5-HT receptor subtypes.

Comparison of the stimulus properties of ethanol and the Ca 2+ channel antagonist nimodipine in rats

A variety of L-type Ca 2+ channel antagonists, including the dihydropyridine derivative nimodipine, have been shown to be effective in reducing ethanol intake and preference in animal models of alcoholism. The behavioral mechanism involved in the anti-alcohol effects of nimodipine are, however, not clear yet. The aim of the present study was to investigate the possibility that the effects of nimodipine on ethanol intake are based on stimulus substitution. Therefore, rats were trained to discriminate ethanol (12.5% w/v, 1000 mg/kg i.p.) from saline in a two-level food-reinforced drug discrimination procedure (dose range of ethanol tested: 125–1000 mg/kg i.p., ED 50 value: 488 mg/kg). In cross-generalization tests with nimodipine (0.15–15 mg/kg i.p.), stimulus substitution was not noted. In addition, a cross-familiarization conditioned taste aversion paradigm was utilized. In rats, 1000 mg/kg i.p. ethanol was used as the reference drug producing a conditioned taste aversion. Effects of preexposure to ethanol (500–1500 mg/kg i.p.) and nimodipine (7.5–30 mg/kg i.p.) on the magnitude of the ethanol-induced conditioned taste aversion were investigated as an index for stimulus similarity between preexposure and reference drug. Preexposure to both ethanol and nimodipine prevented the development of a conditioned taste aversion. Contrary to the drug discrimination results, these latter findings suggest that there may be similarities between the stimulus properties of nimodipine and ethanol. Moreover, the apparent discrepancy between the results obtained in drug discrimination and cross-familiarization conditioned taste aversion suggests that different stimulus properties of ethanol control behavior in both procedures. The finding that, under particular conditions, ethanol and nimodipine appear to share common stimulus properties needs to be further evaluated, as this may be related to the reported anti-alcohol effects of nimodipine and other Ca 2+ channel antagonists.

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

Several lines of evidence suggest that l-type calcium (Ca 2+) 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ channel antagonists obtained in other models of alcoholism and suggest that this class of compounds offers an interesting approach for the pharmacotherapy of alcoholism.