¹Molecular and Behavioral Neuroscience Institute, The University of Michigan School of Medicine, Ann Arbor, MI, USA

Correspondence: Dr M Cecchi, Molecular and Behavioral Neuroscience Institute, The University of Michigan School of Medicine, 205 Zina Pitcher Place, Ann Arbor, MI 48109-0720, USA. Tel: +1 734 647 4465; Fax: +1 734 647 4130, E-mail: cecchi@umich.edu

²These authors contributed equally to this work.

Received 9 February 2006; Revised 8 May 2006; Accepted 15 May 2006; Published online 28 June 2006.

Abstract

The negative physical and affective aspects of opioid abstinence contribute to the prolongation of substance abuse. Withdrawal treatment is successful only in a subset of subjects, yet little is known about the neurobiological causes of these individual differences. Here, we compare the somatic and motivational components of opioid withdrawal in animals with high reactivity (HR) vs low reactivity (LR) to novelty, a phenotype associated with differential vulnerability to drug abuse. During withdrawal, HR relative to LR showed increased teeth chattering and eye twitching episodes, somatic signs associated with adrenergic modulation. Given the role of noradrenergic circuitry of the extended amygdala in opioid withdrawal, we examined adrenergic receptor gene expression in the bed nucleus of stria terminalis (BST) and central nucleus of the amygdala. Relative to LR, HR rats exhibit a selective increase in ₁ adrenergic receptor expression in lateral and medial BST. To uncover the functional relevance of this difference, we microinjected betaxolol, a selective ₁ receptor antagonist, into dorsal BST and assessed somatic and affective responses during withdrawal. Betaxolol microinjection dose-dependently decreased teeth chattering episodes in HR to levels observed in LR animals. Moreover, the antagonist blocked conditioned place aversion, a measure of negative affect associated with withdrawal, in HR but not in LR animals. Our results reveal for the first time that reactivity to novelty predicts somatic and affective aspects of opiate dependence, and that ₁ receptors in BST are implicated in opiate withdrawal but only in novelty-seeking individuals.