Augmentation of antipsychotic-induced neurochemical changes by the NK3 receptor antagonist talnetant (SB-223412)

Neurokinin-3 (NK3) receptor distribution and its modulatory influence on dopaminergic and noradrenergic neurotransmission have lead to the hypothesis that NK3 receptor antagonists may be a valid target to ameliorate the symptomatology of schizophrenia. This hypothesis has gained some clinical support as the selective NK3 receptor antagonist osanetant has shown efficacy in schizophrenic patients. Talnetant (SB-223412) is a potent and selective NK3 receptor antagonist able to modulate monoaminergic neurotransmission in both cortical and subcortical brain structures. Here we have used in vivo microdialysis to investigate the adjunctive effects of talnetant (10 and 30 mg/kg; i.p.) on typical (i.e. haloperidol, 0.3 and 1 mg/kg; i.p.) and atypical (i.e. risperidone, 0.3 and 1 mg/kg; i.p.) antipsychotic drug-induced changes in monoaminergic neurotransmission in forebrain structures of the guinea pig. As seen previously talnetant, produced a dose dependent increase in extracellular levels of both dopamine (DA) and norepinephrine (NE) in both prefrontal cortex (PFC) and hippocampus in a similar manner to the atypical risperidone. Combination studies revealed an additive effect of talnetant on risperidone-induced changes in both NE and DA levels in the PFC but not the hippocampus. Furthermore, addition of talnetant converted the neurochemical profile of the typical antipsychotic, haloperidol, to a profile more akin to that induced by an atypical antipsychotic. These data suggest that addition of talnetant to antipsychotic drugs may facilitate monoaminergic neurotransmission and hence potentially improve their clinical efficacy.