Interactions of Hallucinogens with the Glutamatergic System: Permissive Network Effects Mediated Through Cortical Layer V Pyramidal Neurons Gerard J. Marek Abstract Recordings made from layer V (L5) pyramidal cells of the prefrontal cortex (PFC) and neocortex in rodent slice preparations have shown that serotonin (5-hydroxytryptamine, 5-HT) and serotonergic hallucinogens induce an increase in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in the apical dendritic field by activating 5-HT 2A receptors. Serotonergic hallucinogens induce late EPSCs and increase recurrent network activity when subcortical or mid-cortical regions are stimulated at low frequencies (e.g., 0.1 Hz). A range of agonists or positive allosteric modulators (PAMs) for mostly G i/o -coupled receptors, including metabotropic glutamate 2 (mGlu 2 ), adenosine A 1 , or l-opioid receptors, suppress these effects of 5-HT 2A receptor stimulation. Furthermore, a range of mostly G q/11 - coupled receptors (including orexin 2 [OX 2 ]; a 1 -adrenergic, and mGlu 5 receptors) similarly induce glutamate (Glu) release onto L5 pyramidal cells. Evidence implicates a number of brain regions in mediating these effects of serotonergic hallucinogens and G q/11 -coupled receptors including the midline and intralaminar thalamic nuclei, claustrum, and neurons in deep PFC. These effects on 5-HT 2A receptors and related GPCRs appear to play a major role in the behavioral effects of serotonergic hallucinogens, such as head twitches in rodents and higher order behaviors such as rodent lever pressing on the differential-reinforcement-of-low rate 72-s (DRL 72-s) schedule. This implies that the effects of 5-HT 2A receptor acti- vation on the activity of L5 pyramidal cells may be responsible for mediating a range of behaviors linked to limbic circuitry with connectivity between the PFC, striatum, thalamus, claustrum, striatum, amygdala, and the hippocampal formation. Keywords In vitro electrophysiology Á Layer V pyramidal neurons Á DOI-induced head-twitch response Á DRL 72-s behavior G.J. Marek (&) Global Medical Science, CNS and Pain, Astellas Pharma Global Development, 1 Astellas Way, Northbrook, IL 60062, USA e-mail: gerard.marek@astellas.com © Springer-Verlag Berlin Heidelberg 2017 Curr Topics Behav Neurosci DOI 10.1007/7854_2017_480