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The Journal of Neuroscience, May 27, 2009, 29(21):6973-6981; doi:10.1523/JNEUROSCI.6144-08.2009

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Behavioral/Systems/Cognitive
Hindbrain Cocaine- and Amphetamine-Regulated Transcript Induces Hypothermia Mediated by GLP-1 Receptors

Karolina P. Skibicka, Amber L. Alhadeff, and Harvey J. Grill

Graduate Group of Psychology and Graduate Group of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Karolina P. Skibicka, Graduate Group of Psychology and Graduate Group of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104. Email: skibicka{at}mail.med.upenn.edu

Cocaine- and amphetamine-regulated transcript (CART) peptides are widely distributed throughout the neuraxis, including regions associated with energy balance. CART's classification as a catabolic neuropeptide is based on its inhibitory effects on feeding, coexpression with arcuate nucleus proopiomelanocortin neurons, and on limited analysis of its energy expenditure effects. Here, we investigate whether (1) caudal brainstem delivery of CART produces energetic, cardiovascular, and glycemic effects, (2) forebrain–caudal brainstem neural communication is required for those effects, and (3) glucagon-like peptide-1 receptors (GLP-1Rs) contribute to the mediation of CART-induced effects. Core temperature (Tc), heart rate (HR), activity, and blood glucose were measured in rats injected fourth intracerebroventricularly with CART (0.1, 1.0, and 2.0 µg). Food was withheld during physiologic recording and returned for overnight measurement of intake and body weight. CART induced a long-lasting (>6 h) hypothermia: a 1.5°C and 1.6°C drop in Tc for the 1.0 and 2.0 µg doses. Hindbrain CART application reduced food intake and body weight and increased blood glucose levels; no change in HR or activity was observed. Supracollicular decerebration eliminated the hypothermic response observed in intact rats to hindbrain ventricular CART, suggesting that forebrain processing is required for hypothermia. Pretreatment with the GLP-1R antagonist (exendin-9–39) in control rats attenuated CART hypothermia and hypophagia, indicating that GLP-1R activation contributes to hypothermic and hypophagic effects of hindbrain CART, whereas CART-induced hyperglycemia was not altered by GLP-1R blockade. Data reveal a novel function of CART in temperature regulation and open possibilities for future studies on the clinical potential of the hypothermic effect.

Received Dec. 24, 2008; revised March 30, 2009; accepted April 21, 2009.

Correspondence should be addressed to Karolina P. Skibicka, Graduate Group of Psychology and Graduate Group of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104. Email: skibicka{at}mail.med.upenn.edu






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