title: The physiological role of 5-HT2A receptors in working memory.
abstract: Dorsolateral prefrontal cortex has an essential role in the cognitive process of working memory, dysfunction of which is considered to be a core deficit in schizophrenia. Although this cortical region is densely innervated with 5-HT2A receptors to which atypical antipsychotic drugs bind with high affinity, little is known of the influence of this serotonin receptor subtype on prefrontal function. We addressed this issue by examining the effects of iontophoresis of selective receptor ligands on prefrontal neurons possessing spatially tuned delay activity, or "memory fields," in monkeys performing a delayed-response task. Memory fields of putative pyramidal cells were attenuated by iontophoresis of 5-HT2A antagonists, which primarily produced a reduction in delay activity for preferred target locations. Conversely, 5-HT2A stimulation by alpha-methyl-5-HT or 5-HT itself, accentuated the spatial tuning of these neurons by producing a modest increase in activity for preferred target locations and/or a reduction in activity for nonpreferred locations. The agonist effects could be reversed by the selective antagonist MDL100,907, and were dose-dependent, such that high levels attenuated spatial tuning by profoundly reducing delay activity. A role for feedforward inhibitory circuitry in these effects was supported by the finding that 5-HT2A blockade also attenuated the memory fields of putative interneurons. We conclude that prefrontal 5-HT2A receptors have a hitherto unrecognized role in the cognitive function of working memory, which involves actions at both excitatory and inhibitory elements within local circuitry.
authors.affiliation: Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA. graham.williams@yale.edu
authors.forename: Graham V
authors.initials: GV
authors.lastname: Williams
authors.forename: Srinivas G
authors.initials: SG
authors.lastname: Rao
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Goldman-Rakic
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D005403:Fixation, Ocular / Q000502:physiology; D007478:Iontophoresis; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010775:Photic Stimulation; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000378:metabolism*; D012438:Saccades / Q000502:physiology; D012702:Serotonin Antagonists / Q000008:administration & dosage; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage
chemical_list: D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists