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

Abstract

Reinforcing properties of drugs of abuse are reduced by the coadministration of kappa opioid receptor (KOR) agonists. This effect is related to the inhibition of dopamine (DA) release in the nucleus accumbens (NAc) produced by the acute administration of KOR agonists. The present study was undertaken to investigate the in vivo effect of the repeated administration of KOR agonist on extracellular DA levels in the NAc. Rats were injected once daily with the selective KOR agonist U-69593 (0.16-0.32 mg/kg) or vehicle for 4 days. Microdialysis studies assessing extracellular concentration of DA in the NAc under basal and K(+)-stimulatory conditions were conducted 1 day later. The microdialysis studies revealed that preexposure to U-69593 had no effect on basal extracellular DA levels but significantly augmented the amount of extracellular DA induced by high K(+) compared with vehicle pretreated rats. The D2 receptor agonist quinpirole perfused through the dialysis probe in the NAc, although it produced a significant decrease on basal and K(+)-stimulated DA levels in control rats, it did not decrease significantly either basal or K(+)-stimulated DA levels in U-69593 preexposed rats. Preexposure to U-69593 did not alter the expression of tyrosine hydroxylase or dopamine transporter in the ventral tegmental area. These results show that repeated administration of U-696593 increases the amount of extracellular DA induced by high K in the NAc, an effect that may be related to decreased D2 autoreceptor function. It is suggested that repeated activation of KOR changes the response status of dopaminergic neurons in the NAc.

Effects of acute and repeated administration of salvinorin A on dopamine function in the rat dorsal striatum

“…Repeated U-69593 pretreatment attenuated the decrease in striatal DA dialysate levels produced by acute administration of the D2 receptor agonist quinpirole and reduced the locomotor stimulant effects of quinpirole (Acri et al 2001). Additionally, in the study where repeated administration of U-69593 significantly increased K + -evoked DA levels, quinpirole perfusion decreased basal and K + -evoked DA levels in control rats but not in rats pretreated with U-69593 (Fuentealba et al 2006). The impairment of D2-mediated inhibition of DA release may result from a downregulation of DA D2 autoreceptors.…”

“…Increases in cocaine-evoked DA levels have been reported in the NAC and DSTR following repeated U-69593 administration (Heidbreder et al 1998). Furthermore, repeated U-69593 administration significantly increased K + -evoked DA levels in the NAC (Fuentealba et al 2006), and chronic treatment of cultured mesencephalic DA neurons with U-69593 increased K + -evoked [ 3 H] DA release (Ronken et al 1994). Taken together, the present findings and those reported previously with U-69593 suggest that prolonged or repeated KOPr activation in the striatum or NAC sensitizes DA neurons to evoked release.…”

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

“…The present gene expression results suggest that the amount of presynaptic D2Rs may be reduced with repeated intermittent cotreatment, although a compelling demonstration of such an effect must await the measurement of the actual D2R protein as mRNAs and the associated protein may not always be regulated in a similar manner. However, evidence suggests that the chronic effects of U69593 on K + -or QNP-induced changes in extracellular DA levels may be related, at least in part, to reduced striatal presynaptic D2R function resulting from decreased cell surface expression (Acri et al 2001;Fuentealba et al 2006). Moreover, the ability of drug cotreatment to switch the locomotor inhibitory effects of low-dose QNP to excitation suggests that alterations in presynaptic D2R functioning in SN, and perhaps VTA, neurons may be of relevance to the potentiating effects of U69593 on QNP locomotion.…”

“…In addition, the DAergic system has been shown to be modulated by the endogenous opioids. For instance, acute kappa opioid administration reduces levels of extracellular DA in the nucleus accumbens (Acb; Di Chiara and Imperato 1988;Spanagel et al 1992;Maisonneuve et al 1994;Gray et al 1999; Thompson et al 2000), and chronic administration increases stimulated extracellular DA levels in this brain region (Fuentealba et al 2006). These effects may result from alterations in the activity of the presynaptic D2 receptor (D2R; Acri et al 2001;Fuentealba et al 2006), which influence the release of DA from presynaptic terminals, and/or the DA transporter (DAT; Thompson et al 2000;Shippenberg et al 2001) which modulates synaptic DA uptake.…”

“…For example, acute pre-exposure to the kappa opioid agonist U69593 attenuates amphetamine-evoked increases in DA release (Gray et al 1999), and chronic kappa opioid pretreatment has been shown to inhibit psychostimulantinduced and D1 receptor (D1R) agonist-induced striatal DYN and immediate early gene expression Gerfen 1995, 1996;Tzaferis and Mcginty 2001) and tolerate the inhibitory effects of QNP on DA release (Acri et al 2001;Fuentealba et al 2006). Behavioral studies have shown that pretreatment with kappa opioids inhibit the locomotor response to subsequent challenges with amphetamine (Gray et al 1999), cocaine Collins et al 2001a, b), or QNP (Izenwasser et al 1998;Acri et al 2001).…”