ABSTRACT
INTRODUCTION: The atypical antipsychotic drug, quetiapine (QTP), is effective in schizophrenia and mood disorders, but induces seizures compared to typical antipsychotics. METHODS: To explore the mechanisms of action of QTP, we determined its effects on extracellular levels of norepinephrine, dopamine, serotonin, gamma-aminobutyric acid (GABA), and glutamate in the medial prefrontal cortex (mPFC) using microdialysis, and neuronal firing in the ventral tegmental area (VTA), locus coeruleus (LC), dorsal raphe nucleus (DRN), and mediodorsal thalamic nucleus (MTN) by telemetry in freely moving rats. RESULTS: QTP (10 and 30 mg/kg, i.p.) activated neuronal firing in the VTA, LC, and MTN without affecting that in the DRN. QTP increased extracellular levels of norepinephrine, dopamine, and glutamate without affecting serotonin or GABA levels in the mPFC. The stimulatory effects of QTP on norepinephrine and dopamine were mediated by positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/glutamatergic and negative GABA-mediated NMDA/glutamatergic regulation. DISCUSSION: The dopaminergic terminal projecting from the VTA received inhibitory GABA-mediated NMDA/glutamatergic regulation, but not stimulatory AMPA/glutamatergic regulation. However, both dopaminergic and noradrenergic terminals from the LC received stimulatory AMPA/glutamatergic regulation from the MTN, but not inhibitory GABA-mediated NMDA/glutamatergic regulation. These findings correlating neuronal activities in nuclei with neurotransmitter release suggested that the effects of QTP on neurotransmission in the mPFC depend on activated neuronal projections located outside the mPFC. Furthermore, positive interaction between LC and MTN afferents are potentially important in the pharmacological mechanisms of neurotransmitter regulation by QTP and hint at mechanisms underlying the atypical profile of this drug for treatment of schizophrenia and as a mood stabilizer and proconvulsive agent.
