Effect of the acute and chronic administration of the selective 5-HT6 receptor antagonist SB-271046 on the activity of midbrain dopamine neurons in rats:: An in vivo electrophysiological study

This study examined the effect of the acute and repeated per os (p.o.) administration of the selective 5-HT6 receptor antagonist SB-271046, on the number, as well as the firing pattern of spontaneously active dopamine (DA) neurons in the rat substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized male Sprague-Dawley rats. This was accomplished using the technique of extracellular in vivo electrophysiology. A single p.o. administration of either 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active SNC DA neurons per stereotaxic electrode tract compared to vehicle-treated animals. The acute administration of either 1 or 3 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons. In contrast, a significant decrease in the number of spontaneously active VTA DA neurons was observed after a single administration of 10 mg/kg of SB-271046 compared to vehicle-treated animals. The acute p.o. administration of SB-271046 significantly altered the firing pattern parameters of all (bursting + nonbursting DA neurons) DA neurons, particularly those in the VTA, compared to vehicle-treated animals. The repeated p.o. administration (once per day for 21 days) of 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons compared to vehicle-treated animals. The repeated administration of 3 or 10 mg/kg of SB-271046 significantly increased the number of spontaneously active SNC DA neurons compared to vehicle controls. Overall, the repeated administration of SB-271046 had relatively little effect on the firing pattern of midbrain DA neurons. The results obtained following the chronic administration of SB-271046 show that this compound has a profile different from that of typical or atypical antipsychotic drugs in this model. Clinical studies are required to understand what role 5-HT6 receptor blockade might eventually play in the treatment of schizophrenia. (C) 2004Wiley-Liss,Inc.