1. ¹Department of Pharmacology and Experimental Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA
2. ²Department of Pharmacology, Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA

Correspondence: AL Mickiewicz, Department of Pharmacology, Center for Compulsive Behavior and Addiction, Rush University Medical Center, 1735 W Harrison Street, Cohn 422, Chicago, IL 60612, USA. Tel: +1 312 563 2417/2416, Fax: +1 312 563 2403; E-mail: amanda_mickiewicz@rush.edu

Received 10 May 2008; Revised 28 June 2008; Accepted 30 June 2008; Published online 30 July 2008.

Abstract

Repeated, intermittent exposure to drugs of abuse results in response enhancements to subsequent drug treatments, a phenomenon referred to as sensitization. As persistent neuronal sensitization may contribute to the long-lasting consequences of drug abuse, characterizing the neuroanatomical substrates of sensitization is providing insights into addiction. It is known that the ventral tegmental area (VTA) is necessary for induction, and expression involves the nucleus accumbens (NAc). We reveal here that the ventral pallidum (VP), a brain region reciprocally innervated by the VTA and the NAc, is a critical mediator of opiate-induced behavioral sensitization. Blockade of VP -opioid receptors (via intra-VP CTOP injections) negated the ability of systemic administration of the opiate, morphine to induce motor sensitization, and for sensitized rats to subsequently express enhanced responding to a morphine challenge. Intra-VP morphine was sufficient to induce motor sensitization, and this sensitization was expressed following 17 days of withdrawal. Rats with a treatment history of intra-VP morphine demonstrated cross-sensitization to a challenge injection of systemically administered morphine. Conversely, repeated systemic treatments of morphine cross-sensitized to an intra-VP morphine challenge. These results indicate that activation of VP -opioid receptors is sufficient to evoke behavioral sensitization and that these receptors are necessary for sensitized responding to systemic morphine. The study pioneers the concept that both development and expression of drug-induced sensitization are regulated by the VP. Thus, the VP is likely an important contributor to neuronal adaptations that underlie addiction.