Abstract
BackgroundCocaine- 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).Methodology/Principal FindingsMale 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.Conclusions/SignificanceWe 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.
Highlights
Cocaine- and amphetamine-regulated transcript (CART) is a neuropeptide that was originally identified in the striatum of animals following acute psychostimulant exposure [1]
Conclusions/Significance: We show for the first time that CART signaling within the paraventricular thalamus (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 nucleus accumbens (NAC), medial prefrontal cortex (mPFC) and basolateral amygdala (BLA)
Subsequent studies have identified that CART is expressed in a number of regions known to be involved in reward and reinforcement, including the ventral tegmental area (VTA), nucleus accumbens (NAC), amygdala and hypothalamus [2,3]
Summary
Cocaine- and amphetamine-regulated transcript (CART) is a neuropeptide that was originally identified in the striatum of animals following acute psychostimulant exposure [1]. Administration of CART55-102 into the NAC or the ventral pallidum (VP) significantly attenuates the locomotor effects of acute cocaine and amphetamine administration [12,13,14], and prevents the expression of conditioned hyperlocomotion in a cocaine-paired environment [15]. Together, these data suggest that CART signaling within the NAC and VP works to negatively regulate the effects of psychostimulants. 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)
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