Reducing effect of Salvia miltiorrhiza extracts on alcohol intake: influence of vehicle.

A previous study demonstrated that an extract of Salvia miltiorrhiza, a medicinal herb highly valued in Chinese folk medicine for the treatment of different pathologies, including insomnia, was capable of reducing voluntary alcohol intake in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to evaluate the suitability of different emulsifying, suspending agents and solvents as vehicles through which Salvia miltiorrhiza extracts can exert their reducing effect on alcohol intake. A single dose (100 mg/kg) of a standardised extract of Salvia miltiorrhiza was dissolved in either pure Polysorbate 80, arachis oil, PEG 400, or Polyoxyl 35 castor oil, or suspended in 0.5% CMC in water, and administered acutely by gavage to sP rats. A significant and specific reduction in alcohol intake was recorded only in rats treated with the combination of Polysorbate 80 plus the Salvia miltiorrhiza extract. A further experiment demonstrated that the ability of the combination of Polysorbate 80 in water plus the Salvia miltiorrhiza extract to decrease alcohol intake was dependent upon the concentration of Polysorbate 80. The results of the present study demonstrate that Polysorbate 80 is a proper vehicle for unravelling the reducing effect of Salvia miltiorrhiza extracts on alcohol intake. The ability of Polysorbate 80 to form micelles with the active ingredient(s) of the Salvia miltiorrhiza may explain these results. They may also offer relevant information for pharmaceutical preparation of Salvia miltiorrhiza extract to be used in future clinical trials.

Differences in ethanol-induced conditioned taste aversion in Sardinian alcohol-preferring and Sardinian alcohol-nonpreferring rats.

In the present study, we investigated whether aversion to the pharmacological effects of ethanol developed to a differential extent in selectively bred Sardinian alcohol-preferring (sP) and Sardinian alcohol-nonpreferring (sNP) rats, and whether this different response was consistent with their genetically determined differences in ethanol preference and consumption. To this purpose, a conditioned taste aversion paradigm was used. Male sP and sNP rats were exposed to five sessions in which a 20-min availability of a saccharin solution (1 g/l) was paired to the injection of ethanol (0, 0.5, or 1 g/kg, i.p.), delivered immediately after removal of the saccharin bottle (conditioning phase). Subsequently, the choice between saccharin solution and water was offered for 18 consecutive daily 20-min sessions (postconditioning phase). Ethanol at 1g/kg produced a marked aversion to saccharin in sNP rats: The reduction in saccharin intake was already evident on the second day of the conditioning phase and lasted for 15 days of the postconditioning phase. In contrast, this dose of ethanol elicited a modest, if any, conditioned taste aversion in sP rats, although blood ethanol levels were comparable to those assessed in sNP rats. These results indicate the existence of a differential degree of aversion to the postingestional effects of ethanol between sP and sNP rats, and support the suggestion that it may contribute, at least in part, to the opposite preference for and consumption of ethanol monitored in these rat lines.

Gamma-hydroxybutyric acid versus alcohol preference in Sardinian alcohol-preferring rats.

Previous experiments demonstrated that the selectively bred Sardinian alcohol-preferring (sP) rats possess a genetically based proclivity to consume pharmacologically relevant doses of gamma-hydroxybutyric acid (GHB). The present study was aimed at comparing the reinforcing properties of GHB and ethanol, measuring the propensity of sP rats to consume GHB and ethanol when both drugs were concomitantly available. Initially, two groups of sP rats (ethanol-naive and ethanol-experienced, respectively) were forced to consume GHB in order to help them discover the reinforcing properties, which could then prevail over the unpleasant taste of the GHB solution. Subsequently GHB (at concentrations increasing from 1 to 6% w/v) was offered in free choice with water and all rats consumed pharmacologically relevant amounts of GHB. Finally, under the free-choice regimen between GHB (presented to each rat at its preferred concentration), ethanol and water, daily ethanol intake averaged approximately 6 g/kg (i.e. the amount of ethanol usually consumed by sP rats), whereas GHB intake declined by approximately 75%. In the few rats showing a high intake of GHB, ethanol intake was not altered. No difference in GHB drinking behaviour was ever recorded between ethanol-naive and ethanol-experienced rats. The results of the present study demonstrate that freely available GHB is not capable of altering ethanol preference and consumption in sP rats and suggest that the postulated reciprocal substitutability of the two drugs does not completely include the reinforcing properties, at least in sP rats and when oral self-administration of GHB is considered. The results also provide a model of the low abuse liability of GHB observed in human alcoholics.

Stimulation of voluntary ethanol intake by cannabinoid receptor agonists in ethanol-preferring sP rats.

RATIONALE: Recent studies have shown that the cannabinoid CB1 receptor antagonist, SR 141716, is capable of reducing voluntary ethanol intake in rodents, suggesting the involvement of the CB1 receptor in the neural circuitry mediating the positive reinforcing properties of ethanol. OBJECTIVES: The present study extended to the agonists the investigation on the pharmacological manipulation of ethanol intake by cannabinoid agents. METHODS: Selectively bred, Sardinian alcohol-preferring (sP) rats were offered ethanol and water under the two-bottle free choice procedure with unlimited access for 24 h/day. RESULTS: The acute administration of WIN 55,212-2 (0.5-2 mg/kg; IP) and CP 55,940 (3-30 microg/kg; IP) induced a significant, dose-dependent increase in ethanol intake. Conversely, water consumption and intake of regular food and a highly palatable sucrose solution were not affected by treatment with WIN 55,212-2 and CP 55,940. The stimulatory effect of WIN 55,212-2 and CP 55,940 on ethanol intake was completely prevented by administration of SR 141716 (0.3 mg/kg; IP) and the opioid receptor antagonist, naloxone (0.1 mg/kg; IP). CONCLUSIONS: Administration of WIN 55,212-2 and CP 55,940 promoted voluntary ethanol intake in sP rats. This effect was mediated by stimulation of the cannabinoid CB1 receptor and required the activation of the endogenous opioid system. The results of the present study add further support to the hypothesis that the cannabinoid CB1 receptor is part of the neural substrate regulating ethanol intake. These results are also discussed in terms of WIN 55,212-2 and CP 55,940 administration possibly fixing to a higher level the hedonic set-point mechanism regulating ethanol drinking behavior in sP rats.