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.

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

“…These results are consistent with the ability of NOP agonists to reduce extracellular dopamine levels in the nucleus accumbens, as well as their ability to block a druginduced increase (Murphy et al, 1996;Lutfy et al, 2001a). In fact, N/OFQ can block cocaine-induced increase in extracellular dopamine when administered intracerebroventricularly (Lutfy et al, 2001a) or directly into the VTA or when reverse dialized directly into the nucleus accumbens (Vazquez-DeRose et al, 2013). Based upon the ability of N/OFQ to block extracellular dopamine levels and block CPP of so many abused drugs, it is somewhat NOP Receptor Biology and Function surprising that N/OFQ was ineffective in attenuating heroin self-administration in rats (Walker et al, 1998).…”

“…NOP receptor agonists block contextual drug associations (i.e., CPP) of every drug tested, including morphine, cocaine, amphetamine, and alcohol (Ciccocioppo et al, 2000;Kotlinska et al, 2002Kotlinska et al, , 2003Zhao et al, 2003;Sakoori and Murphy, 2004). This is consistent with a NOP receptor agonist-induced decrease in extracellular dopamine in the NAc (Murphy et al, 1996;Vazquez-DeRose et al, 2013). Nevertheless, the ability of NOP receptor agonists to block self-administration of these drugs appears to be far less robust, if effective at all (Walker et al, 1998;Ciccocioppo et al, 2014;de Guglielmo et al, 2015).…”

“…For example, N/OFQ treatment has been demonstrated to inhibit norepinephrine release in cerebral cortical slices, as well as in cerebellar, hippocampal, and hypothalamic slice preparations (Siniscalchi et al, 1999;Werthwein et al, 1999;Schlicker and Morari, 2000;Lu et al, 2010). Furthermore, NOP receptor activation leads to a decrease in dopamine release in striatal slices, and most recently within the nucleus accumbens and ventral tegemental area in vivo using microdialysis approaches (Murphy et al, 1996;Vazquez-DeRose et al, 2013). The regulation of extracellular dopamine by N/OFQ has likely important implications in the NOP receptor regulation of cocaineinduced behaviors including locomotion and reward processing VazquezDeRose et al, 2013).…”

Neuropeptide systems and new treatments for nicotine addiction

“…Similar effects were observed in dependent and non-dependent rats. Nociceptin is a member of the opioid receptor family and blockade of this receptor prevents drug-induced dopamine release in the nucleus accumbens (Nacc)(Lutfy et al 2001; Vazquez-DeRose et al 2013). Dopamine release in the NAcc plays a critical role in the reinforcing properties of nicotine and therefore nociceptin receptor antagonists may decrease nicotine intake by inhibiting the nicotine-induced increase in dopamine signaling (Corrigall and Coen 1991).…”

The Nociceptin Receptor as an Emerging Molecular Target for Cocaine Addiction

“…47 Recently, Vazquez-DeRose and coworkers demonstrated that this action of OFQ/N could also be mediated locally in the NAc, as they showed that retrodialysis of OFQ/N into the NAc shell abolished cocaine-elevated extracellular dopamine in the NAc. 48 Given that the ability of cocaine to elevate extracellular dopamine levels in the NAc plays an essential role in the motor stimulatory action of cocaine, 49 we tested whether OFQ/N could also reduce hyperlocomotion induced by cocaine. Our results revealed that intracerebroventricular administration of OFQ/N dose-dependently reduced cocaine-induced motor stimulation.…”