Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex

doi:10.1073/pnas.0700436104

Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex

^§Department of Pharmacology,
*Department of Psychiatry and Behavioral Neurosciences, and
^‡Cellular and Clinical Neurobiology Training Program, Wayne State University School of Medicine, Detroit, MI 48201; and
^¶Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY 10032

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved April 23, 2007 (received for review January 17, 2007)

Abstract

Classic hallucinogens such as lysergic acid diethylamide are thought to elicit their psychotropic actions via serotonin receptors of the 5-hydroxytryptamine 2A subtype (5-HT_2AR). One likely site for these effects is the prefrontal cortex (PFC). Previous studies have shown that activation of 5-HT_2ARs in this region results in a robust increase in spontaneous glutamatergic synaptic activity, and these results have led to the widely held idea that hallucinogens elicit their effect by modulating synaptic transmission within the PFC. Here, we combine cellular and molecular biological approaches, including single-cell 5-HT_2ARs inactivation and 5-HT_2AR rescue over a 5-HT_2AR knockout genetic background, to distinguish between competing hypotheses accounting for these effects. The results from these experiments do not support the idea that 5-HT_2ARs elicit the release of an excitatory retrograde messenger nor that they activate thalamocortical afferents, the two dominant hypotheses. Rather, they suggest that 5-HT_2ARs facilitate intrinsic networks within the PFC. Consistent with this idea, we locate a discrete subpopulation of pyramidal cells that is strongly excited by 5-HT_2AR activation.

Footnotes

^‖To whom correspondence should be addressed at:
Department of Pharmacology, Wayne State University School of Medicine, 540 East Canfield, Detroit, MI 48201.
E-mail: randrade{at}med.wayne.edu
↵ ^†Present address: Department of Neuroscience, Johns Hopkins University School of Medicine, 918 Preclinical Teaching Building, 725 North Wolfe Street, Baltimore, MD 21205.
Author contributions: J.-C.B., M.I., and R.A. designed research; J.-C.B., M.I., L.M., and R.A. performed research; J.A.G. contributed new reagents/analytic tools; J.-C.B., M.I., and R.A. analyzed data; and J.-C.B. and R.A. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0700436104/DC1.
Abbreviations:

5-HT2AR,

5-hydroxytryptamine 2A receptor;

PFC,

prefrontal cortex;

sEPSC,

spontaneous excitatory postsynaptic current;

PLC,

phospholipase C;

DAMGO,

[d-Ala2,N-MePhe4,Gly5-ol]enkephalin.