Elsevier

Biological Psychiatry

Volume 63, Issue 2, 15 January 2008, Pages 152-157
Biological Psychiatry

Original Article
Stimuli Linked to Ethanol Availability Activate Hypothalamic CART and Orexin Neurons in a Reinstatement Model of Relapse

https://doi.org/10.1016/j.biopsych.2007.02.002Get rights and content

Background

There has been a recent upsurge of interest in the role of hypothalamic feeding peptides, in particular, orexin (hypocretin), in drug-seeking behavior. However, the potential role of other hypothalamic feeding peptides, such as cocaine- and amphetamine-regulated transcript (CART), in conditioned reinstatement has yet to be explored.

Methods

Animals were exposed to environmental stimuli previously associated with ethanol availability (EtOH S+), and sections from the hypothalamus and paraventricular thalamus (PVT), a recipient of CART and orexin innervation, were dual labeled for Fos-protein and either CART or orexin.

Results

Significantly larger numbers of Fos-positive arcuate nucleus CART and hypothalamic orexin neurons were seen in animals exposed to the EtOH S+ compared with nonreward S animals. Presentation of the EtOH S+ also increased numbers of Fos-positive PVT neurons. Fos-positive PVT neurons were observed to be closely associated with orexin and CART terminal fields.

Conclusions

Taken together, these findings suggest that activation of hypothalamic neuropeptide systems may be a common mechanism underlying drug-seeking behavior.

Section snippets

Methods and Materials

Serial forebrain tissue encompassing the PVT and hypothalamic orexin- and CART-containing cell bodies were obtained from rats in which effects of ethanol cue exposure on c-fos expression within the prefrontal cortex, nucleus accumbens, hippocampus, central amygdala, and paraventricular nucleus of the hypothalamus has been reported previously (18). All procedures were carried out in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Scripps Research

Results

Rats exposed to the EtOH S+ demonstrated significant reinstatement of responding at the previously active lever. Responding in the presence of the S remained at extinction levels (for details see ref. 18).

Within the DMH, PF/LHA, and PVN, cytoplasmic CART and nuclear Fos-immunolabeling were rarely, if ever, colocalized. In contrast, within the ARC, significant numbers of cells dual labeled for Fos-protein and CART were observed in both S and S+-exposed animals. However, in rats exposed to the

Discussion

In this study we show for the first time that arcuate nucleus CART neurons are recruited by EtOH-associated stimuli in a conditioned reinstatement model of relapse. Furthermore, we demonstrate that these stimuli significantly increase the number of Fos-positive hypothalamic orexin neurons, consistent with recent findings of a role for orexin in morphine and cocaine reward seeking (8) and conditioned reinstatement of ethanol seeking in alcohol-preferring (P) rats (12). These findings suggest

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