Serotonin-glutamate interactions: A new target for antipsychotic drugs

Interest in the role of serotonin (5-HT) in the therapeutic effects of atypical antipsychotic drugs originated from the observations that: (1) clozapine and other atypical drugs have a high affinity for 5-HT2A relative to D-2 receptors; and (2) 5-HT2A receptors mediate the central effects of psychedelic hallucinogens. Recently, we found that 5-HT evokes a focal release of glutamate in the apical dendritic field of layer V pyramidal cells in prefrontal cortex, measured electrophysiologically by an increased frequency of spontaneous excitatory postsynaptic potentials/currents (EPSPs/EPSCs). An atypical mode of transmitter release (termed asynchronous release) scents to be involved because EPSC induction is tetrodotoxin (TTX)-sensitive but is not dependent an impulse flow and is supported by Sr2+ in the absence of external Ca2+. The 5-HT-induced increase in spontaneous EPSCs is blocked completely by the selective 5-HT2A antagonist M100907 (MDL 100,907). M100907 also blocks the enhancement by hallucinogens of a late, asynchronous component of electrically evoked EPSPs/EPSCs. Group II/III metabotropic glutamate agonists, which act downstream from 5-HT2A receptors at presynaptic inhibitory autoreceptors, markedly suppress the 5-HT-induced release of glutamate. Subtype-selective group II/III agonists, such as the group II metabotropic agonist LY354740, are particularly interesting in terms of therapeutic potential, because they are able to suppress the 5-HT2A-induced EPSCs while sparing overall glutamatergic transmission. An analysis of the mechanisms by which 5-HT2A receptors induce glutamate release suggests new targets for the design of novel treatments for schizophrenia. [Neuropsychopharmacology 21:S122-S133] (C) 1999 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.