Kappa-Opioid Agonist U69593 Potentiates Locomotor Sensitization to the D2/D3 Agonist Quinpirole: Pre- and Postsynaptic Mechanisms

Abstract

To assess whether the development and expression of behavioral sensitization to the dopamine D2/D3 agonist quinpirole (QNP) is influenced by coadministration of the kappa opioid receptor agonist U69593, rats received every 3-4 days for a total of 10 treatments an injection of U69593 (0.3 mg/kg) together with an injection of either a postsynaptic (0.5 mg/kg) or a presynaptic dose of QNP (0.05 mg/ kg); locomotor activity was measured after each treatment. Control rats were injected as appropriate with QNP, U69593, and vehicle/ saline. Following chronic treatment, dose-response profiles to QNP were obtained to assess the expression of sensitization; the effect of U69593 on locomotor activity in animals already sensitized to QNP was also assessed. Results showed that cotreatment of U69593 with a postsynaptic dose of QNP doubled the speed and magnitude of sensitization to QNP, while U69593 cotreatment with a presynaptic dose of QNP switched the effects of QNP from locomotor depression to locomotor sensitization. However, U69593 cotreatment with a presynaptic dose of QNP changed a different set of measures of sensitization than did cotreatment with a postsynaptic dose of the dopamine agonist. Together, findings suggest that sensitization to QNP is not a unitary phenomenon but has components that are relatively independent, mediated by distinct pre-and postsynaptic mechanisms and modulated by kappa receptor activity.

Repeated administration of the selective kappa-opioid receptor agonist U-69593 increases stimulated dopamine extracellular levels in the rat nucleus accumbens

“…Indeed, Perreault et al showed that the repeated administration of U-69593 together with quinpirole significantly potentiates rats' locomotor activity induced by high doses of quinpirole. Moreover, they showed that the same treatment switched the effect of low doses of quinpirole from locomotor depression to locomotor excitation (Perreault et al, 2005). We suggest that the locomotor sensitization induced by the chronic treatment with kappa opioid agonist observed by Perrault and coworkers could be mediated in part by the impairment of D2 presynaptic control induced by chronic activation of KORs that we show here.…”

The role of the dynorphin–κ opioid system in the reinforcing effects of drugs of abuse

“…For example, although a single treatment of dynorphin or salvinorin A decreased dopamine release in the dorsal striatum (Zhang et al 2004, 2005), three to five repeated injections of κ agonists had either no effect or augmented cocaine-, amphetamine-, and K + -evoked dopamine release (Fuentealba et al 2006, 2007; Gehrke et al 2008; Heidbreder et al 1998). Additionally, three days of U69593 administration had no effect on basal dopamine dynamics in rats although it attenuated the quinpirole (a D 2 agonist)-induced decrease of dopamine level (Acri et al 2001) while it potentiated quinpirole -induced locomotor sensitization in rats (Perreault et al 2006). More importantly, whereas κ agonists can reinstate responding for extinguished cocaine self-administration, dopamine antagonists only inhibit context- or cocaine-induced reinstatement of responding for cocaine (Anderson et al 2003, 2006; Crombag et al 2002).…”

Psychosis pathways converge via D2High dopamine receptors

“…In fact, although it is generally assumed that dopamine supersensitivity is related to postsynaptic alterations, it is known that altered dopamine sensitivity of the presynaptic system does occur (King et al, 1994). Such presynaptic alterations may underlie the enhancement of quinpirole sensitization by the j opiate agonist (Perreault et al, 2005).…”