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, 7 (4), 341-350

Reduction of the Morphine Maintenance by Blockade of the NMDA Receptors During Extinction Period in Conditioned Place Preference Paradigm of Rats

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Reduction of the Morphine Maintenance by Blockade of the NMDA Receptors During Extinction Period in Conditioned Place Preference Paradigm of Rats

Ali Siahposht-Khachaki et al. Basic Clin Neurosci.

Abstract

Introduction: Activation of N-methyl-d-aspartate (NMDA) glutamate receptors in the nucleus accumbens is a component of drug-induced reward mechanism. In addition, NMDA receptors play a major role in brain reward system and activation of these receptors can change firing pattern of dopamine neurons. Blockade of glutamatergic neurotransmission reduces the expression of conditioned place preference (CPP) induced by morphine. Therefore, in this study, by using an NMDA receptor antagonist, DL-2-Amino-5-phosphonopentanoic acid sodium salt (AP5), the role of NMDA receptors on the maintenance and reinstatement of morphine-CPP was investigated.

Methods: Forty-three adult male albino Wistar rats were used in this study. After subcutaneous administration of effective dose of morphine (5 mg/kg) during CPP paradigm, the animals received intracerebroventricular doses of AP5(1, 5, and 25 mM/5μL saline) during extinction period (free morphine stage). Conditioning score was recorded during extinction period and reinstatement phase. Besides, another group of the animals received a single dose administration of AP5(5 mM) just before the administration of ineffective dose of morphine (1 mg/kg) in reinstatement phase.

Results: The results revealed that two doses of this antagonist (5 and 25 mM) significantly shortened the extinction period of morphine-CPP but did not reduce reinstatement induced by priming dose of morphine. Moreover, the single dose administration of AP5(5 mM) just before prime-morphine injection decreased reinstatement of morphine-CPP.

Conclusion: These findings indicate that blockade of NMDA receptors during extinction period reduces maintenance but not reinstatement of morphine. In addition, blocking these receptors in reinstatement phase decreases reinstatement to extinguished morphine.

Keywords: Conditioned place preference; Morphine maintenance; NMDA receptor; Reinstatement; Reward.

Figures

Figure 1.
Figure 1.
Coronal photomicrograph of representative cannula placement and unilateral microinjection site (AP5 or vehicle [saline]) in the lateral ventricle of the rat brain. Abbreviations: ac: anterior commissure, cc: corpus callosum, CPu: Caudate Putamen (striatum), ec: external capsule, LV: Lateral ventricle. Scale bar=1 mm.
Figure 2.
Figure 2.
Effects of ICV injection of (A) saline or different doses of AP5 (NMDA receptor antagonist) (B) 1 mM (C) 5 mM, and (D) 25 mM/5 μL saline into the lateral ventricle on the maintenance and reinstatement of morphine in conditioned place preference paradigm. Animals received saline or AP5 during the extinction period (free morphine period). In the reinstatement day, animals received only priming dose of morphine (1 mg/kg; SC). Data are presented as mean±SEM for 6–7 rats. *P<0.05, **P<0.01, and ***P<0.001 different from the pretest day. P<0.05, ††P<0.01, and †††P<0.001 different from the posttest day. +P<0.05, ++P<0.01, and +++P<0.001 different from the reinstatement day.
Figure 2.
Figure 2.
Effects of ICV injection of (A) saline or different doses of AP5 (NMDA receptor antagonist) (B) 1 mM (C) 5 mM, and (D) 25 mM/5 μL saline into the lateral ventricle on the maintenance and reinstatement of morphine in conditioned place preference paradigm. Animals received saline or AP5 during the extinction period (free morphine period). In the reinstatement day, animals received only priming dose of morphine (1 mg/kg; SC). Data are presented as mean±SEM for 6–7 rats. *P<0.05, **P<0.01, and ***P<0.001 different from the pretest day. P<0.05, ††P<0.01, and †††P<0.001 different from the posttest day. +P<0.05, ++P<0.01, and +++P<0.001 different from the reinstatement day.
Figure 3.
Figure 3.
Effects of single dose injection of NMDA receptor antagonist (before extinction period) on the maintenance and reinstatement of morphine rewarding properties in conditioned place preference paradigm. Animals received a single injection of AP5(25 mM/5 μL saline; ICV) just after postconditioning CPP test. In this set of experiment, animals did not receive any drug (AP5) or saline/morphine during the extinction or reinstatement days. Data are presented as mean±SEM for 8 rats. **P<0.01 and ***P<0.001 different from the pretest day. †P<0.05 and †††P<0.001 different from the posttest day. +P<0.05 and +++P<0.001 different from the reinstatement day.
Figure 4.
Figure 4.
Effects of single dose injection of NMDA receptor antagonist on the reinstatement of morphine in conditioned place preference paradigm. Animals received a single injection of AP5(5 mM/5 μl saline; ICV) just prior to administration of priming dose of morphine (1 mg/kg; SC) in reinstatement day. Data are presented as mean±SEM for 8 rats. *P<0.05, **P<0.01, and ***P<0.001 different from the pretest day. †P<0.05, ††P<0.01, and †††P<0.001 different from the posttest day.

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