The role of mGlu4 receptors within the nucleus accumbens in acquisition and expression of morphine-induced conditioned place preference in male rats

Abstract

Background: Several studies have shown that glutamate neurotransmission in the nucleus accumbens (NAc) is required for the development of morphine-induced conditional place preference (CPP). In addition, metabotropic glutamate receptors (mGluRs) in NAc play important roles in the reward pathways. However, the precise role of mGluR4 in different steps of the morphine-induced CPP is less well known. In the present study the effect of bilateral intra-accumbal infusion of VU0155041, as a specific mGluR4 agonist on the acquisition and expression of morphine induced CPP in male Wistar rats was investigated. The animals were bilaterally implanted with guide cannulae above the NAc. In the first step of the study, the VU0155041 was administered at doses of 10, 30 and 50 μg/0.5 μL saline per side into the NAc during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase of morphine-induced CPP. In the second step of the study, the rats bilaterally received VU0155041 at the dose of 50 μg/0.5 μL, 5 min before the post-conditioning test in order to check the effect of VU0155041 on the expression of morphine-induced CPP.

Results: The results showed that the intra-accumbal injection of VU0155041 inhibits the acquisition of morphine-induced CPP in a dose dependent manner, but had no effect on expression.

Conclusions: The data indicated that intra-NAc administration of VU0155041 dose dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine. These effects may be related to changes in glutamate activity in the NAC and/or learning dependent mechanism of glutamate neurotransmission in reward pathway(s).

Keywords: Conditioned place preference; Metabotropic glutamate receptor type 4; Morphine; Nucleus accumbens; Rat.

Fig. 1

Q-Q plot for distribution of conditioning score data in the conditioning days. These data did not pass normality test. The data normality test was performed using Shapiro–Wilk test

Fig. 2

The effects of the administration of different doses of VU0155041, as a potent and selective mGluR4 agonist, (10, 30 and 50 μg/0.5 μL) into the NAc 5 min before the injection of morphine (5 mg/kg, sc) and administration of maximum dose of VU0155041 into the NAc region alone, on the conditioning days. Bars represent mean ± S.E.M (Pre-conditioning; n = 8, Saline; n = 6, Vehicle; n = 7, different doses of VU0155041 (10 μg/0.5 μL; n = 11, 30 μg/0.5 μL; n = 10 and 50 μg/0.5 μL; n = 8). *P < 0.05, **P < 0.01, Kruskal Wallis test followed by Dunn's multiple comparisons test

Fig. 3

Q-Q plot for distribution of conditioning score data during post-conditioning (expression) phase. These data did not pass normality test. The data normality test was performed using Shapiro–Wilk test

Fig. 4

The effects of the administration of highest dose of VU0155041, as a potent and selective mGluR4 agonist, (50 μg/μL) into the NAc, 5 min before the test on the post-conditioning day. Bars represent mean ± S.E.M (Saline; n = 6, Vehicle; n = 7, VU0155041 (50 μg/side); n = 7). ns not significant, *p < 0.05. Kruskal Wallis test followed by Dunn's multiple comparisons test

Fig. 5

The effect of VU0155041 injection into the NAc on locomotor activity during morphine-induced CPP. Bars represent mean ± S.E.M (Saline; n = 7, Vehicle; n = 7, different doses of VU0155041 (10 μg/0.5 μL; n = 11, 30 μg/0.5 μL; n = 10 and 50 μg/0.5 μL; n = 8). One-way ANOVA followed by Newman-Keuls post-test

Fig. 6

Histology. a Coronal photomicrograph of the bilateral microinjection sites in the nucleus accumbens (NAc) and b schematic illustration of rat brain coronal sections showing the approximate location of the NAc injection sites. The numbers indicate the anterior–posterior coordinates relative to bregma. Atlas plates were adapted from Paxinos and Watson (Paxinos and Watson, 2007). aca, anterior commissure, anterior part; CPu, caudate putamen (striatum); gcc, genu of the corpus callosum; NAc, nucleus accumbens; scale is 1 mm. Both Fig. 1a and b shown are the authors' work. (Vehicle; n = 14 Treatment; n = 43, Misplacement; n = 7)