Cotreatment with the kappa opioid agonist U69593 enhances locomotor sensitization to the D2/D3 dopamine agonist quinpirole and alters dopamine D2 receptor and prodynorphin mRNA expression in rats

Abstract

Rationale: The repeated coadministration of the kappa opioid receptor agonist U69593 with the D2/D3 dopamine (DA) agonist quinpirole (QNP) potentiates locomotor sensitization induced by QNP. Behavioral evidence has implicated both pre- and postsynaptic changes as being involved in this augmentation.

Objectives: The objectives of this study were to obtain supporting molecular evidence of pre- and/or postsynaptic alterations in the DA system with U69593/QNP cotreatment and to examine the relationship of such changes to locomotor sensitization.

Materials and methods: Gene expression of D1 and D2 receptors (D1R and D2R), the DA transporter, as well as the endogenous opioid prodynorphin (DYN), in the basal ganglia was examined by in situ hybridization in rats after one or ten drug injections.

Results: After one injection, changes that were specific to U69593/QNP cotreatment were decreased D1R and D2R messenger RNA (mRNA) in the nucleus accumbens (Acb) shell and increased DYN mRNA in the dorsal striatum (STR). After ten injections, U69593/QNP-specific changes were decreased D2R mRNA in substantia nigra (SN) and increased DYN mRNA in STR and Acb core. Only in U69593/QNP rats was the sensitized locomotor performance on injection ten positively correlated with DYN mRNA levels in Acb and STR.

Conclusions: Distinct alterations of D2R and DYN mRNA levels in SN and Acb/STR, respectively, strengthen the evidence implicating pre- and postsynaptic changes in augmented locomotor sensitization to U69593/QNP cotreatment. It is suggested that repeated U69593/QNP cotreatment may augment locomotor sensitization to QNP by activating D1R-expressing DYN neurons and attenuating presynaptic D2R function.