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The Journal of Neuroscience, August 1, 2002, 22(15):6742-6746

Differential Activation of Orexin Neurons by Antipsychotic Drugs Associated with Weight Gain

Jim Fadel*, Michael Bubser*, and Ariel Y. Deutch

Departments of Psychiatry and Pharmacology and Centers for Molecular Neuroscience and Integrative and Cognitive Neuroscience, Vanderbilt University School of Medicine, Nashville, Tennessee 37212

Weight gain is one side effect of many antipsychotic drugs (APDs). A small number of lateral hypothalamic/perifornical area (LH/PFA) neurons express the orexins, peptides that are critically involved in body weight regulation and arousal. We examined the ability of APDs to activate orexin neurons, as reflected by induction of Fos. APDs with significant weight gain liability increased Fos expression in orexin neurons, but APDs with low or absent weight gain liability did not. The weight gain liability of APDs was correlated with the degree of Fos induction in orexin neurons of the lateral LH/PFA. In contrast, amphetamine, which causes weight loss, increased Fos expression in orexin neurons of the medial but not lateral LH/PFA. We compared the effects of amphetamine and clozapine, an APD with weight gain liability, on orexin neurons innervating the prefrontal cortex. Clozapine induced Fos in 75% of the orexin neurons that project to the cortex, but amphetamine induced Fos in less than a third of these cells. These data suggest that APD-induced weight gain is associated with activation of distinct orexin neurons and emphasize the presence of anatomically and functionally heterogeneous populations of orexin neurons.

Key words: amphetamine; clozapine; dopamine; haloperidol; prefrontal cortex; weight gain

* J.F. and M.B. contributed equally to this work.

Copyright © 2002 Society for Neuroscience  0270-6474/02/22156742-05$05.00/0




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