Differential activation of orexin neurons by antipsychotic drugs associated with weight gain.
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.
Fadel
Jim
J
Department of Psychiatry and Center for Molecular Neuroscience and Integrative, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA.
Bubser
Michael
M
Deutch
Ariel Y
AY
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D002452:Cell Count; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D020712:Fornix, Brain / Q000187:drug effects / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015430:Weight Gain / Q000187:drug effects* / Q000502:physiology
D014150:Antipsychotic Agents; D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos; D000661:Amphetamine; D003024:Clozapine; D006220:Haloperidol