Cortical influences of serotonin and glutamate on layer V pyramidal neurons.

Layer V pyramidal neurons constitute principle output neurons of the medial prefrontal cortex (mPFC)/neocortex to subcortical regions including the intralaminar/midline thalamic nuclei, amygdala, basal ganglia, brainstem nuclei and the spinal cord. The effects of 5-hydroxytryptamine (5-HT) on layer V pyramidal cells primarily reflect a range of excitatory influences through 5-HT receptors and inhibitory influences through non-5-HT receptors, including 5-HT receptors. While the 5-HT receptor is primarily a postsynaptic receptor on throughout the apical dendritic field of 5-HT receptors, activation of a minority of 5-HT receptors also appears to increase spontaneous excitatory postsynaptic currents/potentials (EPSCs/EPSPs) via a presynaptic effect on thalamocortical terminals arising from the midline and intralaminar thalamic nuclei. Activation of 5-HT receptors by the phenethylamine hallucinogen also appears to increase asynchronous release of glutamate upon the layer V pyramidal dendritic field, an effect that is suppressed by 5-HT itself through non-5-HT receptors. Serotonergic hallucinogens acting on 5-HT receptors also appears to increase gene expression of immediate early genes (iEG) and other receptors appearing to induce an iEG-like response like BDNF. Psychedelic hallucinogens acting on 5-HT receptors also induce head twitches in rodents that appear related to induction of glutamate release. These electrophysiological, biochemical and behavioral effects of serotonergic hallucinogens appear to be related to modulating glutamatergic thalamocortical neurotransmission and/or shifting the balance toward 5-HT receptor activation and away from non-5-HT receptor activation. These 5-HT receptor induced responses are modulated by feedback homeostatic mechanisms through mGlu, mGlu, and mGlu presynaptic receptors on thalamocortical terminals. These 5-HT receptor and glutamatergic interactions also appear to play a role on higher cortical functions of the mPFC such as motoric impulsivity and antidepressant-like behavioral responses on the differential-reinforcement-of low rate 72-s (DRL 72-s schedule). These mutually opposing effects between 5-HT receptor and mGlu autoreceptor activation (e.g., blocking 5-HT receptors and enhancing activity at mGlu receptors) may play a clinical role with respect to currently prescribed or novel antidepressant drugs. Thus, there is an important balance between 5-HT receptor activation and activation of mGlu autoreceptors on prefrontal cortical layer V pyramidal cells with respect to the electrophysiological, biochemical and behavioral effects serotonergic hallucinogenic drugs.