Cocaine- and amphetamine-regulated transcript (CART) signaling within the paraventricular thalamus modulates cocaine-seeking behaviour

• Published in: PloS one Vol. 5; no. 9; p. e12980
• Main Authors: James, Morgan H, Charnley, Janine L, Jones, Emma, Levi, Emily M, Yeoh, Jiann Wei, Flynn, Jamie R, Smith, Douglas W, Dayas, Christopher V
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23-09-2010; Public Library of Science (PLoS)
• Subjects: Alcoholic beverages; Amphetamines; Amygdala; Animal behavior; Animals; Central nervous system agents; Cocaine; Cocaine- and amphetamine-regulated transcript protein; Cocaine-Related Disorders - drug therapy; Cocaine-Related Disorders - genetics; Cocaine-Related Disorders - metabolism; Disease Models, Animal; Drug abuse; Drugs; Extinction; Extinction behavior; Humans; Hypothalamus; Illegal drugs; Innervation; Male; Marine toxins; Narcotics; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - therapeutic use; Neuroscience; Neuroscience/Behavioral Neuroscience; Neuroscience/Neurobiology of Disease and Regeneration; Neurosciences; Nucleus accumbens; Pharmacology; Prefrontal cortex; Rats; Rats, Sprague-Dawley; Reinstatement; Rodents; Signal Transduction - drug effects; Signaling; Target recognition; Tetrodotoxin; Thalamus; Thalamus - drug effects; Thalamus - metabolism; Transcription
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0012980

Cocaine- and amphetamine-regulated transcript (CART) has been demonstrated to play a role in regulating the rewarding and reinforcing effects of various drugs of abuse. A recent study demonstrated that i.c.v. administration of CART negatively modulates reinstatement of alcohol seeking, however, the site(s) of action remains unclear. We investigated the paraventricular thalamus (PVT) as a potential site of relapse-relevant CART signaling, as this region is known to receive dense innervation from CART-containing hypothalamic cells and to project to a number of regions known to be involved in mediating reinstatement, including the nucleus accumbens (NAC), medial prefrontal cortex (mPFC) and basolateral amygdala (BLA).
Male rats were trained to self-administer cocaine before being extinguished to a set criterion. One day following extinction, animals received intra-PVT infusions of saline, tetrodotoxin (TTX; 2.5 ng), CART (0.625 µg or 2.5 µg) or no injection, followed by a cocaine prime (10 mg/kg, i.p.). Animals were then tested under extinction conditions for one hour. Treatment with either TTX or CART resulted in a significant attenuation of drug-seeking behaviour following cocaine-prime, with the 2.5 µg dose of CART having the greatest effect. This effect was specific to the PVT region, as misplaced injections of both TTX and CART resulted in responding that was identical to controls.
We show for the first time that CART signaling within the PVT acts to inhibit drug-primed reinstatement of cocaine seeking behaviour, presumably by negatively modulating PVT efferents that are important for drug seeking, including the NAC, mPFC and BLA. In this way, we identify a possible target for future pharmacological interventions designed to suppress drug seeking.