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 serotonin 1 (5-HT 1) and benzodiazepine receptors was first evaluated by computerized receptor autoradiography. The results confirmed that buspirone is a selective 5-HT 1A ligand, since it inhibited the binding of [ 3H]5-HT with lower IC 50 values (about 100 nM) in regions of the brain of the rat where this receptor subtype is predominant (such as hippocampal areas). Larger IC 50 values than 3 μM were found in areas of the brain richer in 5-HT 1 receptors, other than the 5-HT 1A subtype (e.g. striatum, substantia nigra and the ventricles). The PmP was not selective, inhibiting the binding of [ 3H]5-HT with similar affinity (about 4–10 μM) in all the regions of the brain examined. Neither buspirone nor PmP, up to 100 μM, 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 [ 3H]5-HT in all the regions of the brain studied, including those with low levels of 5-HT 1A receptors, indicating the occupancy of 5-HT 1 receptors by either buspirone or its metabolite. The binding of [ 3H]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 [ 3H]5-HT to 5-HT 1A receptors in the dorsal raphe, whereas a significant increase in binding of [ 3H]5-HT (32%) was found in the substantia nigra, which was unrelated to any modification of 5-HT 1A receptors. No significant changes were evident in the other regions of the brain.