Local μ-Opioid Receptor Antagonism Blunts Evoked Phasic Dopamine Release in the Nucleus Accumbens of Rats

Abstract

μ-opioid receptors (MORs) in the nucleus accumbens (NAc) can regulate reward-related behaviors that are dependent on mesolimbic dopamine, but the precise mechanism of this MOR regulation is unknown. We hypothesized that MORs within the NAc core regulate dopamine release. Specifically, we infused the MOR antagonist CTAP (d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2) into the NAc core while dopamine release was evoked by electrical stimulation of the ventral tegmental area and measured by fast-scan cyclic voltammetry. We report that CTAP dose-dependently inhibited evoked dopamine release, with full blockade achieved with the 8 μg infusion. In contrast, evoked dopamine release increased after nomifensine infusion and was unchanged after vehicle infusion. These findings demonstrate profound local control of dopamine release by MORs within the NAc core, which has implications for regulation of reward processing.

Keywords: accumbens; dopamine; electrochemistry; local infusion; phasic; μ-opioid receptor.

Figure 1.

Schematic representation of the guide cannula ensemble and anatomical placements for simultaneous in vivo voltammetric measurement of evoked dopamine release and local application of a drug. (A) Guide cannula ensemble: The electrochemical measurements were performed at carbon-fiber microelectrodes lowered via the guide cannula on the left. The drug applications were performed via the injector inserted into the guide cannula on the right. Both cannulae were positioned and cemented together under a microscope prior to any experiment to ensure an approximate distance of 150 μm between the electrode and end of the injector. (B) Representations of electrode/injector placements within nucleus accumbens core.

Figure 2.

Locally applied nomifensine enhanced evoked dopamine transients. (A) Current versus time traces (top) and color plots (bottom) of evoked dopamine release from an individual rat before and after nomifensine infusion. The time of electrical stimulation is indicated by blue arrows. In the color plots, current (color) is depicted at the different applied potentials (y-axis) over time (x-axis). Dopamine oxidation is evident as positive current at ~ 0.65 V and reduction is evident as negative current at ~ −0.25 V. (B) Composite data (n=4 rats) show that nomifensine enhanced evoked [DA]_max within 5 minutes, with a peak response at 15 minutes. * different from baseline (BL), p<0.03.

Figure 3.

Infusion of CTAP to the nucleus accumbens core dose-dependently reduces evoked dopamine release. The selective MOR antagonist CTAP (2, 4, and 8 μg) or saline was infused to the area of dopamine measurement via an infusion cannula approximately 150 μm from the voltammetric electrode. (A) Current-versus-time traces at the oxidation potential of dopamine (white, 7 seconds) are overlaid on color plots of evoked dopamine release from individual rats before and after saline, 4 μg and 8 μg CTAP infusion. The time of electrical stimulation is indicated by blue arrows. Infusion of 4 μg CTAP partially blunted electrically-evoked dopamine release while 8 μg CTAP blocked it. (B) and (C): Composite data show the dose-dependent effects of CTAP on evoked dopamine release over time (B) and averaged across post-infusion time points (C). Electrically-evoked dopamine was unchanged by saline and 2 μg CTAP, but reduced by 4 and 8 μg CTAP. Statistics were calculated on the data in panel C: * different from Saline, p<0.05; # different from 2 μg CTAP, p<0.05.