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_2A receptors and inhibitory influences through non-5-HT_2A receptors, including 5-HT_1A receptors. While the 5-HT_2A receptor is primarily a postsynaptic receptor on throughout the apical dendritic field of 5-HT_2A receptors, activation of a minority of 5-HT_2A 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_2A 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_2A receptors. Serotonergic hallucinogens acting on 5-HT_2A 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_2A 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_2A receptor activation and away from non-5-HT_2A receptor activation. These 5-HT_2A receptor induced responses are modulated by feedback homeostatic mechanisms through mGlu₂, mGlu₄, and mGlu₈ presynaptic receptors on thalamocortical terminals. These 5-HT_2A 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_2A receptor and mGlu autoreceptor activation (e.g., blocking 5-HT_2A receptors and enhancing activity at mGlu₂ receptors) may play a clinical role with respect to currently prescribed or novel antidepressant drugs. Thus, there is an important balance between 5-HT_2A 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.