Potentiation of excitatory serotonergic responses by MK-801 in the medial prefrontal cortex.
New atypical antipsychotics show a greater affinity to serotonergic rather than to dopamine receptors, suggesting that serotonin (5-HT) has a major role in the pathophysiology and treatment of schizophrenia. The goal of this study was to characterise the response of pyramidal neurons in the medial prefrontal cortex (mPFC) to 5-HT and NMDA before and after administration of the NMDA receptor antagonist, MK-801 (dizocilpine), a well-validated pharmacological model of psychosis. mPFC pyramidal (glutamatergic) neurons were recorded in urethane-anaesthetised rats. The responses to NMDA and 5-HT were assessed using in vivo electrophysiology and microiontophoresis. The 5-HT2A/2C antagonist ritanserin and the 5-HT1A antagonist WAY100635 were used to block 5-HT responses. MK-801 decreased the NMDA-induced excitatory responses and increased NMDA-evoked burst activity among mPFC pyramidal neurons. Three subpopulations of pyramidal cells were identified according to their responses to 5-HT: excitation (33%), inhibition (40%) and non-response (27%). The inhibitory responses were blocked by WAY100635 in 100% of cases, but not by ritanserin; the excitatory responses were blocked by ritanserin in 75% of cases, but not by WAY100635. The administration of MK-801 potentiated the firing rate of excitatory responses but did not modify the inhibitory responses induced by microiontophoretic application of 5-HT. These results suggest that MK-801 modifies 5-HT synapses in the mPFC by potentiating the excitatory 5-HT2A/2C responses and attenuating NMDA excitations. These data indicate that 5-HT excitatory transmission is selectively impaired at the mPFC level in this pharmacological model of schizophrenia.
Labonte
Benoit
B
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montréal, QC H3A 1A1, Canada.
Bambico
Francis Rodriguez
FR
Gobbi
Gabriella
G
D000818:Animals; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007478:Iontophoresis / Q000379:methods; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects / Q000378:metabolism; D012559:Schizophrenia / Q000503:physiopathology*; D012701:Serotonin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
D018691:Excitatory Amino Acid Antagonists; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D012701:Serotonin; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate