Serotonin2 receptor-mediated excitation of interneurons in piriform cortex: antagonism by atypical antipsychotic drugs.
Rat piriform cortex contains a subpopulation of presumed GABAergic interneurons located near the border of layers 2 and 3 that express excitatory serotonin2 receptors. These serotonin2-responsive interneurons send axons to layer 2 pyramidal cells. Using an in vitro brain slice preparation, serotonin2 receptor-mediated excitation can be assessed either by directly recording from the interneurons or by recording the increase in inhibitory postsynaptic potentials in the pyramidal cells. Intracellular recordings from the interneurons demonstrated that compared to pyramidal cells they had a more depolarized resting membrane potential, a higher input resistance and shorter action potential duration. The serotonin2 receptor-mediated excitation was associated with a strong depolarization (range 3-22 mV). We found that the atypical antipsychotic drugs, risperidone and clozapine, which have relatively high affinity for serotonin2 receptors, each dose-dependently inhibited the serotonin2-mediated excitation of the interneurons with IC50 values of 7 nM and 1.4 microM, respectively. This antagonism was specific to the extent that excitation mediated by agonists at excitatory amino acid receptors were not blocked at concentrations of risperidone and clozapine that completely antagonized the serotonin2 receptor-mediated excitation. The typical antipsychotic drug, chlorpromazine, inhibited the serotonin2-mediated excitation of the interneurons with an IC50 of 14 microM. Haloperidol, another typical antipsychotic drug, decreased the serotonin2 response to about half of baseline at a concentration of 10 microM (the exact IC50 could not be calculated because higher concentrations produced non-specific effects on cells). Both risperidone and clozapine blocked the serotonin-elicited inhibitory postsynaptic potentials in layer 2 pyramidal cells at concentrations that approximated the IC50 for antagonizing the serotonin2-mediated excitation of the interneurons. Chlorpromazine and haloperidol, in the concentration range that blocked serotonin2 receptor-mediated excitation of interneurons, also blocked the serotonin-elicited inhibitory postsynaptic potentials in the pyramidal cells. The IC50 values for risperidone and clozapine, but not for chlorpromazine or haloperidol, for blocking serotonin2 receptor-mediated actions in rodent piriform cortical slice are in the range of the plasma concentrations of the drug that are clinically efficacious. Our data suggest that a potential site of action of the atypical antipsychotic drugs risperidone and clozapine could be antagonism of serotonin acting through serotonin2 receptors on GABAergic interneurons in cerebral cortex.
Gellman
R L
RL
Department of Psychiatry, Yale University School of Medicine, New Haven, CT.
Aghajanian
G K
GK
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D002746:Chlorpromazine / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D004594:Electrophysiology; D006220:Haloperidol / Q000494:pharmacology; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects / Q000502:physiology*; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone; D012702:Serotonin Antagonists; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D014150:Antipsychotic Agents; D007555:Isoxazoles; D010880:Piperidines; D012702:Serotonin Antagonists; D005680:gamma-Aminobutyric Acid; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone; D002746:Chlorpromazine; D001640:Bicuculline