ABSTRACT
The Chinese herbal medicine, NPI-028, has been used for centuries in China to counteract alcohol intoxication. The present study used a number of different experimental conditions to determine whether NPI-028 and its derivatives might selectively influence alcohol intake in rodents that naturally exhibit high alcohol intakes. It was determined that intraperitoneal (i.p.) injections of NPI-028 (0.5, 0.75, and 1.0 g/kg) suppressed alcohol intake by up to 30% in both alcohol-preferring P and Fawn-Hooded (FH) rats during a continuous access schedule. These injections did not significantly affect food or water intakes, nor did the highest dose of NPI-028 (1 g/kg) alter blood ethanol levels after an i.p. injection of 2.5 g/kg of ethanol. In P rats, it was found that NPI-028 was orally active with the dose of 1.5 g/kg having a greater effect on ethanol intake than the 1.0 g/kg dose; once again, food and water intakes were not significantly altered. In FH rats maintained on a limited access schedule (1 hr/day), alcohol intake was completely abolished by 1.5 g/kg of NPI-028. Chronic i.p. administration of NPI-028 (0.75 g/kg) for four consecutive days in FH rats maintained on a continuous access schedule did not lead to any diminution of its alcohol-suppressant effects. Thus, NPI-028 has significant effects on alcohol intake without much effect on water and food intake, and tolerance does not readily develop to these effects. The i.p. administration of a partially purified extract (NPI-031) of NPI-028, obtained by countercurrent chromatography, also dose-dependently suppressed ethanol intake in FH rats, but the highest dose 200 mg/kg) also significantly decreased food intake. Finally, the i.p. administration of puerarin (NPI-31G), an isoflavone isolated from NPI-031 by countercurrent chromatography, significantly reduced ethanol intake in FH rats without affecting food or water intake. Therefore, NPI-028 and one of its pure components, NPI-031G, selectively reduced ethanol intake in alcohol-preferring rats.
Subject(s)
Alcohol Deterrents/pharmacology , Alcohol Drinking/prevention & control , Drugs, Chinese Herbal/pharmacology , Animals , Dose-Response Relationship, Drug , Ethanol/pharmacokinetics , Injections, Intraperitoneal , Isoflavones/pharmacology , Rats , Rats, Inbred Strains , Structure-Activity RelationshipABSTRACT
The Flinders Sensitive Line (FSL) was derived from the Sprague-Dawley rat by selectively breeding those animals exhibiting a high level of sensitivity to an anticholinesterase. The Flinders Resistant Line (FRL) was simultaneously developed as a control line. These lines exhibit nonoverlapping distributions of their thermic responsiveness to oxotremorine. Bright light prevents the development of supersensitivity to oxotremorine occurring as a result of forced stress or treatment with a muscarinic receptor antagonist in the rat. The authors now report that treatment with bright light during the regular photoperiod (i.e., a time that does not produce a phase-shift or free-running) differentially affects the hypothermic response and activity-suppressing effect of oxotremorine in both the FSL and FRL. Both lines exhibit decreased hypothermia without reduction in motor activity in response to oxotremorine following 6 days of treatment with bright light. The magnitude of blunting of the hypothermic response was greater in the FSL than the FRL. These findings suggest that (1) studies of the effects of bright light are contingent on the end point one measures and (2) the capacity of this treatment to blunt the hypothermic response to a muscarinic agonist is greater in an animal model with endogenously hyperactive muscarinic cholinergic systems.
Subject(s)
Arousal/drug effects , Body Temperature Regulation/drug effects , Hypothalamus/drug effects , Light , Oxotremorine/pharmacology , Receptors, Muscarinic/drug effects , Animals , Atropine Derivatives/pharmacology , Motor Activity/drug effects , Parasympatholytics , Rats , Rats, Inbred Strains , Social EnvironmentABSTRACT
Flinders Sensitive and Resistant Lines of rats, which are differentially sensitive to the hypothermic effects of both muscarinic agonists and ethanol, were exposed to full spectrum artificial bright light for eight days, because exposure to bright light has been shown to blunt hypothermic responses to muscarinic agonists. There was a selective blunting of the hypothermic effects of ethanol, but no significant change in the intoxicating effects of ethanol, as measured by evaluation of the righting reflex. The selective effect of exposure to bright light on the hypothermic actions of ethanol suggests that bright light may be modifying the function of only a limited number of brain regions, including the hypothalamus.