Effects of zotepine on extracellular levels of monoamine, GABA and glutamate in rat prefrontal cortex

Abstract

Background and purpose:The atypical antipsychotic drug, zotepine, is effective in treatment of schizophrenia and acute mania, but the incidence of seizures during treatment is higher than with other antipsychotics. In addition, the mechanisms underlying the clinical actions of zotepine remain uncharacterized. Experimental approach: The effects of intraperitoneal administration of zotepine and haloperidol on the extracellular levels of noradrenaline, dopamine, 5-HT, GABA, and glutamate in the medial prefrontal cortex (mPFC) were compared. Neuronal activities induced by each drug in the ventral tegmental area (VTA), locus coeruleus (LC), dorsal raphe nucleus (DRN) and mediodorsal thalamic nucleus (MTN) were also analysed. Key results: Haloperidol did not affect extracellular neurotransmitter levels in the mPFC. In contrast, zotepine activated neuronal activities in all nuclei and increased the extracellular levels of noradrenaline, dopamine, GABA, and glutamate in the mPFC, but not 5-HT levels. The zotepine-stimulated neuronal activity in the VTA, LC, DRN and MTN enhanced the release of dopamine, noradrenaline, 5-HT, glutamate and GABA in the mPFC, although the enhanced GABAergic transmission possibly inhibited noradrenaline, dopamine and 5-HT release. The other afferent to mPFC, which releases dopamine and noradrenaline, was partially insensitive to GABAergic inhibition, but possibly received stimulatory AMPA/glutamatergic regulation from the MTN. Conclusions and implications:Our results indicated that the positive interaction between prefrontal catecholaminergic transmission and AMPA/glutamatergic transmission from MTN might explain the regulatory effects of zotepine on neurotransmitter release. A mechanism is suggested to account for the pharmacological profile of this atypical antipsychotic and for its pro-convulsive action.

Memantine protects thalamocortical hyper‐glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc−

“…Several microdialysis studies show that systemic administration of the noncompetitive NMDAR antagonists phencyclidine, ketamine, and MK801 increased glutamate release in the mPFC . However, local administration of MK801 into the mPFC did not affect glutamate levels in the mPFC . In contrast with observations in the mPFC, inhibition of NMDAR in the MDTN induced by local administration of MK801 into the MDTN increased glutamate release in the mPFC (mPFC MK801‐induced glutamate rise) .…”

“…Glutamatergic neurons in the MDTN, which receive GABAergic terminals from the reticular thalamic nucleus (RTN) and other MDTN regions, project to superficial layers in the frontal cortex . Moreover, thalamocortical glutamatergic terminals activate catecholaminergic terminals, but do not make contact with cortical GABAergic neurons . However, a large proportion of the GABAergic neurons in the frontal cortex are regulated by excitatory glutamatergic transmission from other cortical regions via activation of NMDAR .…”

Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: role of relative serotonin (5‐HT)2A and DA D2 antagonism and 5‐HT1A partial agonism

“…; Yamamura et al . and b), have comparable binding affinities for 5‐HT 7 and 5‐HT 2A receptors (Meltzer ). However, the selective 5‐HT 7 antagonist SB 269970, at a high dose of 10 mg/kg, had no effect on cortical Glu efflux (Bonaventure et al .…”

Antipsychotic Drug-Induced Somnolence: Incidence, Mechanisms, and Management

“…Clozapine has been reported to directly interact with GABA receptors [102]. Zotepine activated neuronal activities in different regions of the brain and increased the extracellular levels of noradrenaline, dopamine, GABA, and glutamate in the prefrontal cortex [103]. Interactions between orexin and dopamine systems modulated by an atypical antipsychotic, sulpiride, were observed in the nucleus accumbens in rats [104].…”