Neurokinin-3 (
NK(3)) receptor distribution and its modulatory influence on dopaminergic and noradrenergic neurotransmission have lead to the hypothesis that
NK(3) receptor antagonists may be a valid target to ameliorate the symptomatology of
schizophrenia. This hypothesis has gained some clinical support as the selective
NK(3) receptor antagonist
osanetant has shown efficacy in schizophrenic patients.
Talnetant (SB-223412) is a potent and selective
NK(3) 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.