Hallucinogen-Induced UP States in the Brain Slice of Rat Prefrontal Cortex: Role of Glutamate Spillover and NR2B-NMDA Receptors

Abstract

Psychedelic hallucinogens (eg LSD or DOI) induce disturbances of mood, perception, and cognition through stimulation of serotonin 5-HT 2A receptors. While these drugs are not proconvulsant, they have been shown by microdialysis to increase extracellular glutamate in the prefrontal cortex. Electrophysiological studies in the rat prefrontal slice have shown that both LSD and DOI enhance a prolonged, late wave of glutamate release onto layer V pyramidal neurons after an electrical stimulus. Here, we hypothesize that the network activity underlying this UP state involves glutamate spillover from excitatory synapses. To test this hypothesis, we raised the viscosity of the extracellular solution by adding the inert macromolecule dextran (B1 mM) that is known to retard glutamate overflow into the extrasynaptic space. Dextran suppressed the UP state or late excitatory postsynaptic current (EPSC), but neither the fast EPSC, the traditional polysynaptic EPSC, nor a synaptic form of 5-HT 2A -mediated transmission (serotonin-induced spontaneous EPSCs). Consistent with the previous work showing that extrasynaptic glutamate transmission in adult depends on NR2B-containing NMDA receptors, we found that NR2B-selective antagonists, ifenprodil and Ro25-6981, also suppressed the late EPSCs. The effect of psychedelic hallucinogens on UP states could be partially mimicked by inhibiting glutamate uptake but only after blocking inhibitory group II metabotropic glutamate receptors. This difference suggests that hallucinogens increase glutamate spillover in a phasic manner unlike glutamate uptake inhibitors. Increases in glutamate spillover have been suggested to recruit synapses not directly in the pathway activated by the electrical stimulus. Such recruitment could account for certain cognitive, affective, and sensory perturbations generated by psychedelic hallucinogens.

Psychedelics

“…Studies by Lambe and Aghajanian (2006) further examined the basis for the enhanced late wave of extrasynaptic transmission of glutamate in PFC brain slices of the rat. They retarded the diffusion of glutamate beyond the synapse by increasing the viscosity of the extracellular space using a solution of dextran, a procedure known to suppress glutamate spillover.…”

Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

“…The most prominent effect elicited by the activation of these receptors is an increase of both spontaneous glutamate-mediated synaptic activity and pharmacologically induced NMDA currents (20,50,51). It has been hypothesized that they result from an increase in glutamate release from thalamocortical fibers elicited by either activation of presynaptic 5-HT 2A receptors expressed on thalamocortical axons/terminals or a putative retrograde messenger produced by pyramidal neurons upon activation of postsynaptic receptors (21,23).…”

A specialized NMDA receptor function in layer 5 recurrent microcircuitry of the adult rat prefrontal cortex

“…More importantly, we propose that a higher quantity of NR2B subunits is important for online processing of PFC functions, as previous modeling predicted (10), because only the slow-decayed NR2B expression could allow greater temporal integration of asynchronous synaptic inputs (33) and cross talk among multiple synapses (30) than those with NR2A subunits. Indeed, a recent study reported that NMDAR channels with a higher proportion of NR2B subunits are critical for network activity in the prefrontal circuitry because hallucinogen-induced upstate in the PFC could be blocked by application of NR2B antagonist (37).…”