EFFECT OF ACUTE AND CHRONIC ADMINISTRATION OF BUSPIRONE ON SEROTONIN AND BENZODIAZEPINE RECEPTOR SUBTYPES IN THE RAT-BRAIN - AN AUTORADIOGRAPHIC STUDY

The affinity of buspirone and its main metabolite 1-(2-pyrimidinyl)piperazine (PmP) for serotonin1 (5-HT1) and benzodiazepine receptors was first evaluated by computerized receptor autoradiography. The results confirmed that buspirone is a selective 5-HT1A ligand, since it inhibited the binding of [H-3]5-HT with lower IC50 values (about 100 nM) in regions of the brain of the rat where this receptor subtype is predominant (such as hippocampal areas). Larger IC50 values than 3-mu-M were found in areas of the brain richer in 5-HT1 receptors, other than the 5-HT1A subtype (e.g. striatum, substantia nigra and the ventricles). The PmP was not selective, inhibiting the binding of [H-3]5-HT with similar affinity (about 4-10-mu-M) in all the regions of the brain examined. Neither buspirone nor PmP, up to 100-mu-M, were active on benzodiazepine receptors. The autoradiographic technique was therefore used to evaluate the effects of acute (10 mg/kg, p.o., 1 hr before killing) and chronic (10 mg/kg, i.p., twice a day for 21 days, 24 hr washout) treatment with buspirone in male rats. Acute treatment reduced the binding of [H-3]5-HT in all the regions of the brain studied, including those with low levels of 5-HT1A receptors, indicating the occupancy of 5-HT1 receptors by either buspirone or its metabolite. The binding of [H-3]flunitrazepam was decreased (16%) only in the substantia nigra. The benzodiazepine/GABA receptors present in the substantia nigra, also undergo adaptive changes after chronic treatment with buspirone: only in this region was binding to benzodiazepine receptors increased by 41% (mainly due to type I receptors) and GABA partly lost its enhancing efficacy. Moreover, chronic administration of buspirone significantly reduced (21%) the binding of [H-3]5-HT to 5-HT1A receptors in the dorsal raphe, whereas a significant increase in binding of [H-3]5-HT (32%) was found in the substantia nigra, which was unrelated to any modification of 5-HT1A receptors. No significant changes were evident in the other regions of the brain.