Corticotropin-Releasing Factor Within the Central Nucleus of the Amygdala and the Nucleus Accumbens Shell Mediates the Negative Affective State of Nicotine Withdrawal in Rats

Tobacco addiction is a chronic disorder that is characterized by a negative affective state upon smoking cessation and relapse after periods of abstinence. Previous research has shown that an increased central release of corticotropin-releasing factor (CRF) at least partly mediates the deficit in brain reward function associated with nicotine withdrawal in rats. The aim of these studies was to investigate the role of CRF in the central nucleus of the amygdala (CeA), the lateral bed nucleus of the stria terminalis (BNST), and the nucleus accumbens shell (Nacc shell) in the deficit in brain reward function associated with precipitated nicotine withdrawal. The intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In all experiments, the nicotinic receptor antagonist mecamylamine (3 mg/kg) elevated the brain reward thresholds of the nicotine-dependent rats (9 mg/kg per day of nicotine salt) and did not affect the brain reward thresholds of the saline-treated control rats. The administration of the nonspecific CRF1/2 receptor antagonist D-Phe CRF(12-41) into the CeA and the Nacc shell prevented the mecamylamine-induced elevations in brain reward thresholds in the nicotine-dependent rats. Blockade of CRF1/2 receptors in the lateral BNST did not prevent the mecamylamine-induced elevations in brain reward thresholds in the nicotine-dependent rats. These studies indicate that the negative emotional state associated with precipitated nicotine withdrawal is at least partly mediated by an increased release of CRF in the CeA and the Nacc shell. Neuropsychopharmacology (2009) 34, 1743-1752; doi:10.1038/npp.2008.231; published online 14 January 2009