Differential activation of orexin neurons by antipsychotic drugs associated with weight gain

Abstract

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.

Fig. 1.

Orexin-li neurons expressing Fos were counted in the medial and lateral LH/PFA at two levels of the hypothalamus (bottom). The percentages of orexin neurons expressing Fos were significantly greater after administration of APDs with high weight gain liability (CLZ, clozapine;OLA, olanzapine; RIS, risperidone;CPZ, chlorpromazine) than after challenge with APDs that cause relatively little weight gain (ZIS, ziprasidone;FLU, fluphenazine; HAL, haloperidol).^*p ≤ 0.01;^**p ≤ 0.001;^***p ≤ 0.0001.

Fig. 2.

Amphetamine induced Fos in orexin neurons of the medial but not lateral LH/PFA. ^*p ≤ 0.02.

Fig. 3.

Clozapine induced Fos to a significantly greater degree in orexin neurons that project to the prefrontal cortex than did amphetamine (AMPH) (top left). There was no difference in the degree to which the two drugs induced Fos in non-orexin LH/PFA cells that innervate the PFC (top right). Chartings of representative sections from animals treated with clozapine or amphetamine (middle row) show retrogradely labeled orexin neurons that expressed Fos as filled circles; open circles mark orexin neurons that project to the cortex but do not express Fos. Maximal (stipple) and minimal (black) cholera toxin B deposits into the PFC are shown at the bottom.^*p ≤ 0.01.

Fig. 4.

Photomicrographs showing Fos-li nuclei in orexin-li neurons. In a vehicle-treated rat only one orexin cell contains a Fos-li nucleus (arrow), although many orexin-li cells (arrowheads) are visible. In contrast, many Fos positive orexin neurons (arrows) are seen in a section from a clozapine-treated animal. Clozapine does not induce Fos in MCH-li neurons (C). D shows cells retrogradely labeled from the prefrontal cortex (green) and orexin-li neurons (red). An orexin neuron that expresses Fos but does not innervate the PFC is marked by an arrowhead. Orexin cells that project to the PFC appear yellow–orange, and one of these (arrow) contains a clearly visible Fos-li nucleus.