GABAB receptors within the central nucleus of amygdala may involve in the morphine-induced incentive tolerance in female rats

Abstract

Objectives: Central nucleus of amygdala (CeA) is the most important region for morphine-induced reward, and GABAergic system plays an important role on morphine reinforcement. The influence of CeA administration of GABA_B receptor agonist and antagonist on the expression and acquisition of morphine-induced incentive tolerance using conditioned place preference (CPP) paradigm was investigated in the present study. Our purpose was to evaluate the role of CeA GABA_B receptors in morphine tolerance.

Materials and methods: Seven days after surgery and cannulation, the experiments were begun. Subcutaneous (SC) injections of morphine induced CPP. Administration of one daily dose of morphine (12.5 mg/kg) for 3 days in order to develop tolerance to the drug reduced the conditioning induced by morphine (7.5 mg/kg, SC). GABA_B receptor agonist, baclofen (1.5, 6 and 12 µg/rat) or GABA_B receptor antagonist, CGP35348 (1.5, 6 and 12 µg/rat) were injected into the CeA 5 min before the experiments in the test day (expression of tolerance) or 5 min before each injection of morphine (12.5 mg/kg) (acquisition of tolerance).

Results: It was shown that injections of baclofen (1.5 and 12 µg/rat) reduced acquisition, whereas the dose of 6 µg/rat of the drug exacerbated the acquisition of morphine tolerance. Baclofen at all doses significantly increased the expression of tolerance to morphine. Administration of CGP35348 (1.5, 6 and 12 µg/rat) reduced the acquisition and expression of morphine tolerance.

Conclusion: These results confirmed the importance of GABA_B receptors with in the CeA in morphine tolerance in female rats.

Keywords: Central nucleus of amygdala; Conditioned place preference; GABAB receptors; Morphine; Tolerance.

Figure 1

Schematic design of the histological instauration showing the localization of the guide cannula (27); where cannula tips were correctly placed in the central nucleus of amygdala (CeA) in accordance with Paxinos and Watson Atlas (28): incisor bar (-3.3mm), -7.8 mm dorsal-ventral (DV), ±4.1 mm middle-lateral (ML) and -2.12 mm anterior-posterior (AP)

Figure 2

Conditioned place preference induced by morphine. Animals received different doses of morphine (N ≥8, data as mean ± SEM and **P<0.01, ***P<0.001)

Figure 3

Effect of morphine (subcutaneous 12.5 mg/kg) in inducing conditioned place preference in the group with induced tolerance. (N ≥8 and ***P<0.001)

Figure 4

A. Effects of the intra-central nucleus of amygdala administration of baclofen on the expression of conditioned place preference in morphine-induced tolerance. Animals received baclofen (1.5, 6 and 12 µg/rat) 5 min before the test (N ≥8, data as mean± SEM and ***P<0.001)

Figure 4

B. Effects of the intra-central nucleus of amygdala administration of CGP35348 on the expression of conditioned place preference in morphine-induced tolerance. Animals received CGP35348 (1.5, 6 and 12 µg/rat) 5 min before the test. (N ≥8 data, data as mean±SEM and ***P<0.001)

Figure 5

A. Effects of intra- central nucleus of amygdala injections of baclofen on the acquisition of morphine-induced tolerance. Animals received baclofen (1.5, 6 and 12 µg/rat) 5 min before morphine injection during the induction of tolerance. (N ≥8, data as mean±SEM and *P<0.05)

Figure 5

B. Effects of intra- central nucleus of amygdala injections of CGP35348 on the acquisition of morphine-induced tolerance. Animals received CGP35348 (1.5, 6 and 12 µg/rat) 5 min before morphine injection during the induction of tolerance (N ≥8, data as mean ± SEM and *P<0.05)