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

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.

Glutamatergic Systems and Memory Mechanisms Underlying Opioid Addiction

“…Similar to the effects of AMPAR manipulations, NMDAR antagonists also facilitate extinction learning and reduce the reinstatement of morphine CPP (Siahposht-Khachaki et al 2016). Interestingly, GluN2B-selective antagonists also reduce morphine CPP expression when they are administered without extinction training during abstinence (Ma et al 2011b).…”

Role of AMPA and NMDA receptors on vasopressin and oxytocin secretion induced by hypertonic extracellular volume expansion

“…The experiment was conducted such that rats received a slow i.c.v. injection (1 minute) of vehicle (saline, 5 μL per rat), 2,3‐dihydroxy‐6‐nitro‐7‐sulphamoyl‐benzo[f]quinoxaline (NBQX), a selective antagonist of the AMPA receptors (#1044; Tocris Cookson Ltd, Bristol, UK), or amino‐5‐phosphonovalerate (AP5), a selective antagonist of the NMDA receptors (#A8054; Sigma Chemical Co., St Louis, MO, USA), with both treatments at 10 and 30 nmol (5 μL per rat) based on previous studies by Young and Dragunow and Ali Siahposht‐Khachaki et al …”

The Nucleus Accumbens: A Common Target in the Comorbidity of Depression and Addiction

“…A single systemic injection of the NMDA receptor antagonist ketamine at an intraperitoneal dose of 10 mg/kg produces a significant reduction in FST immobility shortly after administration (30 min to 1 h), which has been shown to persist for an average of 7 days in both rats and mice (Aleksandrova et al, 2017 ). What is more, the NMDA receptor antagonist DL-2-Amino-5-phosphonopentanoic acid sodium salt (AP5) can reduce the CPP induced by morphine (Siahposht-Khachaki et al, 2016 ).…”