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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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