Coactivation of kappa opioid receptors modulates sensitized responses to the dopamine agonist quinpirole

Chronic administration of psychostimulants produces a progressive increase in behavioural responses to the drug, a phenomenon known as behavioural sensitization. Behavioural sensitization is mediated probably by neuroadaptations in the dopaminergic pathways within the basal ganglia, pathways that can be modulated by other neurotransmitter systems including that of the endogenous opioids. Thus, the objective of the present thesis was to investigate the impact of kappa opioid receptor coactivation on sensitized responses to the dopamine D2/D3 agonist quinpirole (QNP).; To achieve this objective, the effects of chronic cotreatment with the kappa opioid agonist U69593 on QNP-induced locomotor activity and compulsive checking behaviour were evaluated. Behavioural studies were followed by comprehensive molecular analyses examining the activity of dopamine receptors and gene expression of dopamine receptors, the dopamine transporter and the endogenous kappa opioid prodynorphin. Results demonstrated that U69593 cotreatment induced a robust increase in both the speed and magnitude of locomotor sensitization to a high postsynaptic dose of QNP, while U69593 cotreatment with a low presynaptic dose of QNP switched the effects of QNP from locomotor depression to sensitization. In addition, chronic U69593 cotreatment accelerated the development of compulsive checking behaviour in the QNP animal model of obsessive compulsive disorder (OCD). These behaviours were associated with increased D2 receptor binding, decreased presynaptic D2 receptor mRNA and increased prodynorphin mRNA expression in specific regions of the basal ganglia.; Overall, the fmdings of the present thesis demonstrate that coactivation of the kappa opioid system has robust effects on QNP-induced sensitized locomotor responses and, moreover, implicates a role for kappa opioids in the pathogenesis of OCD. These behavioural effects appear to be partially the result of altered dopaminergic functioning within the basal ganglia, and point to the importance of opioid/dopamine system interactions in behavioural sensitization.