Orphanin FQ/Nociceptin Modulation of Mesolimbic Dopamine Transmission Determined by Microdialysis

Abstract

Orphanin FQ has been reported to suppress extracellular dopamine levels in the nucleus accumbens after intracerebroventricular administration. This study sought to provide evidence for an intra-ventral tegmental site of action for this effect using a dual-probe microdialysis experimental design. Orphanin FQ was applied to the ventral tegmental area of anesthetized rats by reverse dialysis while extracellular dopamine was sampled with a second dialysis probe in the nucleus accumbens. Orphanin FQ at a probe concentration of 1 mM (but not at 0.1 mM) significantly reduced nucleus accumbens dialysate dopamine levels. The receptor-inactive analogue, desPhe 1 -orphanin FQ (1 mM), produced a small but significant increase in nucleus accumbens dialysate dopamine levels. Simultaneous measurement of ventral tegmental area dialysate amino acid content revealed significant increases in both GABA and glutamate during infusion of orphanin FQ (1 mM). To determine if increased GABA overflow mediates the action of orphanin FQ on mesolimbic neurons, orphanin FQ (10 nmol) was microinjected directly into the ventral tegmental area in the presence or absence of the GABA A receptor antagonist, bicuculline (1 nmol). Bicuculline transiently blocked the suppressive action of orphanin FQ on accumbens dialysate dopamine levels. These data indicate that orphanin FQ decreases dopamine transmission in the nucleus accumbens by inhibiting dopamine neuronal activity in the ventral tegmental area through a mechanism that may involve an increased overflow of GABA. Key Words: Dopamine -Mesolimbic-Microdialysis-Orphanin FQNociceptin-GABA.

Orphanin FQ/nociceptin attenuates motor stimulation and changes in nucleus accumbens extracellular dopamine induced by cocaine in rats

“…Similarly to dynorphin A (1−17) and other kappa opioid receptor agonists, OFQ has been shown to decrease extracellular DA in the Nuc Acc after intracerebroventricular (i.c.v. ; Murphy et al 1996) or intra-VTA injection (Murphy and Maidment 1999). Consistent with these neurochemical studies, behavioral experiments have shown that OFQ suppresses basal motor activity in rats (Devine et al 1996b).…”

“…Seven more samples were collected. All samples were stored at −70°C prior to assay for DA by highperformance liquid chromatography with electrochemical detection as described previously (Murphy and Maidment 1999).…”

“…with either aCSF (10 μl; n=5 rats) or OFQ (30 nmol/10 μl, n=6 rats) and three further samples were then collected. Samples were frozen and stored at −70°C prior to DA analysis as described (Murphy and Maidment 1999).…”

The Nociceptin/Orphanin FQ Receptor Agonist Ro 64-6198 Reduces Alcohol Self-Administration and Prevents Relapse-Like Alcohol Drinking

“…The dopamine (DA) and opioid systems regulating ethanol-related behaviors may be involved. Nociceptin has been found to reduce DA release in the nucleus accumbens by acting on GABAergic interneurons in the ventral tegmental area (VTA) (Murphy and Maidment, 1999;Murphy et al, 1996). This may occur through modulation of the enkephalinergic fibers projecting to the VTA and synapsing with GABA neurons (Sesack and Pickel, 1995;Zheng et al, 2002).…”

Nociceptin/Orphanin FQ Modulates Motor Behavior and Primary Motor Cortex Output Through Receptors Located in Substantia Nigra Reticulata

“…The neurobiological substrate(s) underlying motor actions of exogenous and endogenous N/OFQ have been investigated. The N/OFQ-induced hypolocomotion has been related to inhibition of mesencephalic mesoaccumbal (Murphy and Maidment, 1999) and/or nigrostriatal (Marti et al, 2004a) DA neurons. Consistently, injections of the NOP receptor antagonist [Nphe 1 Arg 14 ,Lys 15 ]N/OFQ-NH 2 (UFP-101) in substantia nigra reticulata (SNr) elevated rotarod performance and striatal DA release (Marti et al, 2004a).…”