1. ¹Department of Psychiatry, University of Florida, Gainesville, FL, USA
2. ²Department of Neuroscience, University of Florida, Gainesville, FL, USA
3. ³Department of Anesthesiology, University of Florida, Gainesville, FL, USA
4. ⁴Department of Community Health and Family Medicine, University of Florida, Gainesville, FL, USA

Correspondence: Dr AW Bruijnzeel, Department of Psychiatry, McKnight Brain Institute, University of Florida, 100 S Newell Dr, PO Box 100256, Gainesville, FL 32610, USA. Tel: +1 352 294 0421, Fax: +1 352 392 8217, E-mail: awbruijn@psychiatry.ufl.edu

Received 2 December 2005; Revised 14 June 2006; Accepted 10 July 2006; Published online 30 August 2006.

Abstract

Nicotine dependence is a chronic mental illness that is characterized by a negative affective state upon tobacco smoking cessation and relapse after periods of abstinence. It has been hypothesized that cessation of nicotine administration results in the activation of brain corticotropin-releasing factor (CRF) systems that leads to the negative affective state of withdrawal. The aim of our experiments was to investigate the role of brain CRF systems in the deficit in brain reward function associated with the cessation of nicotine administration in rats. The intracranial self-stimulation procedure was used to assess to negative affective aspects of nicotine withdrawal as this procedure can provide a quantitative measure of emotional distress in rats. In the first experiment, mecamylamine induced a dose-dependent elevation in brain reward thresholds in nicotine-treated rats. In the follow-up experiment, it was shown that pretreatment with the corticotropin-receptor antagonist D-Phe CRF_(12–41) prevents the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. In the third experiment, the effect of D-Phe CRF_(12–41) on the elevations in brain reward thresholds associated with spontaneous nicotine withdrawal was investigated. Administration of D-Phe CRF_(12–41) 6 h after the explantation of the nicotine pumps, did not result in a lowering of the brain reward thresholds. These findings indicate that antagonism of CRF receptors prevents, but not reverses, the deficit in brain associated with nicotine withdrawal. These data provide support for the hypothesis that a hyperactivity of brain CRF systems may at least partly mediate the initiation of the negative affective aspects of nicotine withdrawal.