Retrodialysis of N/OFQ into the nucleus accumbens shell blocks cocaine-induced increases in extracellular dopamine and locomotor activity

Abstract

Nociceptin (N/OFQ) has been implicated in a variety of neurological disorders, most notably in reward processes and drug abuse. N/OFQ suppresses extracellular dopamine in the nucleus accumbens (NAc) after intracerebroventricular injection. This study sought to examine the effects of retrodialyzed N/OFQ on the cocaine-induced increase in extracellular dopamine levels in the NAc, as well as locomotor activity, in freely moving rats. 1.0μM, 10μM, and 1mM N/OFQ, in the NAc shell, significantly suppressed the cocaine-induced dopamine increase in the NAc, while N/OFQ alone had no significant effect on dopamine levels. Co-delivery of the selective NOP receptor antagonist SB612111 ([(-)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol] reversed the N/OFQ suppression of cocaine-induced dopamine in the NAc, suggesting that this is an NOP receptor-mediated effect. Using a novel system to assess locomotion, we measured various motor activities of the animals with simultaneous microdialysis from the home cage. Cocaine produced an expected increase in total activity, including horizontal movement and rearing behavior. Retrodialysis of N/OFQ with cocaine administration affected all motor activities, initially showing no effect on behavior, but over time inhibiting cocaine-induced motor behaviors. These results suggest that N/OFQ can act directly in the NAc shell to block cocaine-induced increases in extracellular dopamine levels. Extracellular dopamine and locomotor activity can be dissociated within the NAc and may reflect motor output differences in shell versus core regions of the NAc. These studies confirm the widespread involvement of NOP receptors in drug addiction and further validate the utility of an NOP receptor agonist as a medication for treatment of drug addiction.

Fig. 1. Reconstructed coronal sections showing probe placement in the NAc

The semi-permeable membrane (2 mm length tip) was largely centered in the NAc shell and dialysates obtained from this region were used to quantify dopamine. Representative probe tracts are shown as gray cylinders and depending on the anterior to posterior level, occasionally showed small portions of tract that extended into the cortex or islands of Calleja ventrally, or dorsally into the caudate putamen. Coronal sections were adapted from the atlas of Paxinos and Watson (1997). The numbers refer to the approximate anterior-posterior level, relative to Bregma. Abbreviations: NAc(c), nucleus accumbens, core; NAc(sh), nucleus accumbens, shell.

Fig. 2. N/OFQ suppresses the cocaine-induced dopamine increase in NAc shell

A. The effects of 20 mg/kg cocaine (i.p.) alone (●) or with retrodialysis delivery of N/OFQ (1 µM (▲); 10 µM (■); 1000 µM N/OFQ (◆)), on extracellular levels of dopamine (DA) in the NAc shell over time. B. The effects of various N/OFQ doses on cocaine-stimulated increases in dopamine release relative to cocaine alone and to baseline, averaged during the 60 min period of N/OFQ retrodialysis. C. The effect of 1000 µM N/OFQ retrodialyzed into the NAc shell on basal dopamine levels, in the absence of cocaine over time. Data are means ± S.E.M. *, significant difference from baseline; #, significant difference from cocaine alone (P < 0.05).

Fig. 3. NOP receptor antagonist, SB612111, reverses N/OFQ suppression of cocaine-induced dopamine in the NAc shell

The effects of cocaine alone (●), cocaine with retrodialyzed N/OFQ (■), and cocaine with retrodialyzed N/OFQ and SB 612111 (▲) on % dopamine (DA) levels in the NAc shell. Data are means ± S.E.M. #, significant difference from cocaine alone; +, significant difference from cocaine with retrodialyzed N/OFQ (P < 0.05).

Fig. 4. Retrodialyzed N/OFQ attenuates cocaine-induced behaviors

The effects of 20 mg/kg cocaine alone (■), 10 µM N/OFQ alone (◆), or cocaine with N/OFQ (▲) on percent active time (A), mean distance travelled (B), and rearing counts (C). These groups were compared to the vehicle baseline (●). Data are means ± S.E.M. *, significant difference from vehicle; #, significant difference from cocaine alone (P < 0.05).