The Ventral Pallidum is Critically Involved in the Development and Expression of Morphine-Induced Sensitization

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 m-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 m-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.

Blockade of Ethanol-Induced Behavioral Sensitization by Sodium Butyrate: Descriptive Analysis of Gene Regulations in the Striatum

“…To our knowledge, this latter finding is original because only 2 studies already showed reversal of EIBS, but with a nonpharmacological approach (Fallopa et al, 2012;Rueda et al, 2012). Altogether, these data suggest that NaB prevented or reversed neuroadaptations underlying EIBS, despite the fact that these neuroadaptations may be distinct between both induction and expression phases (Mickiewicz et al, 2009). Conversely, because NaB has no effect on 2.0 g/kg-EIBS induction or expression, we hypothesized that these apparent disparate findings may result from profound dissimilar neuroadaptations induced by both EtOH doses.…”

“…Different studies suggest that the 2 phases may involve distinct brain structures. The ventral tegmental area may be involved in the induction, while the nucleus accumbens may be more involved in the expression (Mickiewicz et al, 2009).…”

Mouse model ofOPRM1(A118G) polymorphism has sex-specific effects on drug-mediated behavior

“…S3 c and d). Morphine has been shown to elicit enhanced locomotor-activating effects (behavioral sensitization) with repeated, intermittent administrations (22,23). Indeed, A/A animals showed behavioral sensitization following repeated morphine injections, while G/G animals did not (day ϫ genotype ϫ treatment interaction, F 6,138 ϭ 9.688, P Ͻ 0.0001; Fig.…”

Drug Wanting: Behavioral Sensitization and Relapse to Drug-Seeking Behavior

“…Ibotenate lesions of the amygdala have been reported to either block or have no effect on the development of amphetamine sensitization (Wolf et al, 1995;Cador et al, 1999). Finally, studies with -opioid agonists and antagonists suggest that ventral palladium is involved in both the initiation and expression of behavioral sensitization to morphine (Mickiewicz et al, 2009). As will be discussed further below, it is likely that each of these brain regions affects the development of sensitization by influencing the mesocorticolimbic dopamine system.…”