The absence of 5-HT1A receptors has minor effects on dopamine but not serotonin release evoked by MK-801 in mice prefrontal cortex

Rationale Non-competitive NMDA receptor antagonists markedly increase neuronal activity in medial prefrontal cortex (mPFC), an effect which partly underlies their schizomimetic actions. Projection pyramidal neurons and local GABAergic interneurons in mPFC express 5-HT1A receptors, whose activation modulates dopaminergic (DA) and serotonergic (5-HT) activity in midbrain and the cortical release of both monoamines. Objective To examine whether the presence of 5-HT1A receptors can modulate the effect of NMDA receptor blockade with MK-801 (dizocilpine) on DA and 5-HT release in mouse mPFC. Materials and methods Brain microdialysis and locomotor activity measures in wild-type and 5-HT1A receptor knockout mice. Results Systemic MK-801 administration (0.125, 0.25, 0.50, and 1 mg/kg i.p.) induced a dose-dependent increase in mPFC 5-HT output, which was independent of the genotype. MK-801 increased DA output in a dose-dependent manner with a significant effect of genotype on low doses (0.125, 0.25 mg/kg). These differences were not paralleled by differences in gross locomotor activity. Overall, MK-801 increased more markedly DA than 5-HT output in both genotypes. Finally, the local perfusion of MK-801 in mPFC (30, 100, 300 mu M) by reverse dialysis did not elevate dialysate DA or 5-HT concentrations in mPFC. Conclusions 5-HT1A receptors partly modulate the increase in mPFC DA (but not 5-HT) release produced by NMDA receptor blockade. The lack of effect observed after the local MK-801 application suggests that the change in cortical monoamines is mainly driven by subcortical NMDA receptor blockade, without a significant involvement of PFC 5-HT1A receptors.