Hallucinogen-induced UP states in the brain slice of rat-prefrontal cortex: Role of glutamate spillover and NR2B-NMDA receptors

Psychedelic hallucinogens (eg LSD or DOI) induce disturbances of mood, perception, and cognition through stimulation of serotonin 5-HT2A 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 (similar to 1 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-HT2A-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.