Sites of action of ondansetron to inhibit withdrawal from drugs of abuse.

The cerebral site of action of the selective 5-HT3 receptor antagonist ondansetron to influence the behavioural consequences of withdrawal from subchronic treatment with diazepam, ethanol, nicotine or cocaine was studied in the light/dark exploration test in the mouse. The aversive response to the light compartment of the test box was reduced during a subchronic treatment with peripherally administered diazepam, ethanol, nicotine and cocaine, but was exacerbated following withdrawal from the 4 treatments. The behavioural consequences of withdrawal from diazepam (10 mg/kg IP b.i.d. 14 days), ethanol (8%/w/v drinking water for 14 days), nicotine (0.1 mg/kg IP b.i.d. 14 days) or cocaine (1.0 mg/kg IP b.i.d. 14 days) were antagonised by ondansetron injected into the amygdala and dorsal raphe nucleus (1-10 ng); injections of ondansetron (10 ng) into the median raphe nucleus, the nucleus accumbens and striatum were ineffective. It is concluded that the amygdala and dorsal raphe nucleus may be sites of action for ondansetron to antagonise the aversive behaviour caused by withdrawal from 4 common drugs of abuse in a mouse model, and that 5-HT projections from the dorsal raphe nucleus may be involved in aversive behaviour.