EFFECTS OF CHRONIC DIAZEPAM TREATMENT ON PRESYNAPTIC AND POSTSYNAPTIC5-HT1A RECEPTORS IN THE RAT-BRAIN

Biochemical and electrophysiological approaches were used to assess po ssible changes in 5-HT1A receptors in the rat brain after long-term tr eatment with an anxiolytic benzodiazepine. Rats were treated with diaz epam (2 mg/kg i.p. daily) during 14 days and then untreated for 1 day (protocol A) or 5 days (protocol C) until they were killed for in vitr o investigations on 5-HT1A receptors. In addition, other rats (protoco l B) received the same 14-day treatment with diazepam, followed by 1 m g/kg of the drug on days 15 and 16, and 0.5 mg/kg on days 17 and 18, a nd were killed 24 h after the last injection. In vitro binding and qua ntitative autoradiographic experiments with [H-3]8-hydroxy-2-(di-n-pro pylamino)tetralin ([H-3]8-OH-DPAT) showed that the characteristics of 5-HT1A receptor binding sites in the hippocampus and the dorsal raphe nucleus were not significantly altered by the administration of diazep am under the treatment protocols A, B and C. Furthermore, in vitro ele ctrophysiological recordings of serotoninergic neurons in the dorsal r aphe nucleus of brain stem slices revealed no modification in the sens itivity of somatodendritic 5-HT1A autoreceptors in rats treated with d iazepam according to the protocols A and B. However, under the conditi ons of protocol C, the potency of 8-OH-DPAT to depress the firing rate of serotoninergic neurons was significantly enhanced, as expected of a hypersensitivity of somatodendritic 5-HT1A autoreceptors. These data support the hypothesis that some functional changes in these receptor s could occur during benzodiazepine withdrawal. However, they do not s upport the idea of a reduced anxiolytic efficacy of 5-HT1A receptor ag onists as a result of prior treatment with a benzodiazepine. (C) 1997 Elsevier Science B.V.