Effects of phentermine and fenfluramine on alcohol consumption and alcoholwithdrawal seizures in rats

The drug combination of phentermine plus fenfluramine has been used clinica lly in both the treatment of obesity and alcoholism. The aim of the current study was to assess the interaction of the two drugs on consumption of bot h an alcohol-containing and a nonalcoholic diet. Furthermore, the efficacy of the drug combination on suppression of withdrawal seizures was determine d. Animals were either maintained on a 6% alcohol-containing diet, free-fed an isocaloric control, or pair-fed the control diet. It was observed that, with regard to body weight growth curves, alcohol provides about 2.5 kcal/ g. Both phentermine and fenfluramine caused a decrease in consumption 1 h a fter administration; however, during the next 23 h, 4 mg/kg phentermine sig nificantly increased consumption of all diets. At doses of 1 and 2 mg/kg, f enfluramine selectively reduced consumption of the alcohol-containing diet as compared to the isocaloric diets. Lower doses of fenfluramine blocked th e increases in consumption induced by phentermine. Furthermore, in animals fed the nonalcoholic diet, the drug combination of 2 mg/kg fenfluramine plu s 8 mg/kg phentermine produced a 63-82% reduction in consumption, an effect not seen when either drug was administered alone. This greater than additi ve effect was also seen in the earlier time periods in animals pair-fed the control diet. Neurochemical analysis from these animals revealed that the alcohol-dependent animals displayed a significant reduction of DOPAC and 5- HIAA levels in the striatum, frontal cortex, and hypothalamus after a 9-h w ithdrawal period, further implicating the serotonergic and dopaminergic sys tems in mediation of withdrawal symptoms and alcohol craving. Finally, 8 mg /kg phentermine plus 8 mg/kg fenfluramine completely abolished alcohol with drawal seizures, compared to a 78% rate in saline treated rats. In conclusi on, the coadministration of phentermine plus fenfluramine produced a modera te reduction of alcohol consumption and was completely effective at reducin g alcohol withdrawal seizures. (C) 2000 Elsevier Science Inc. All rights re served.