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Addiction is a chronic relapsing disorder and is one of the most important issues in the world. Changing the level of neurotransmitters and the activities of their receptors, play a major role in the pathophysiology of substance abuse disorders. It is well-established that N-methyl-d-aspartate receptors (NMDARs) play a significant role in the molecular basis of addiction. NMDAR has two obligatory GluN1 and two regionally localized GluN2 subunits. This study investigated changes in the protein level of GluN1, GluN2A, and GluN2B in the prefrontal cortex of drug abusers. The medial prefrontal cortex (mPFC), lateral prefrontal cortex (lPFC), and orbitofrontal cortex (OFC) were dissected from the brain of 101 drug addicts brains and were compared with the brains of non-addicts (N = 13). Western blotting technique was used to show the alteration in NMDAR subunits level. Data obtained using Western blotting technique showed a significant increase in the level of GluN1 and GluN2B, but not in GluN2A subunits in all the three regions (mPFC, lPFC, and OFC) of men whom suffered from addiction as compared to the appropriate controls. These findings showed a novel role for GluN1, GluN2B subunits, rather than the GluN2A subunit of NMDARs, in the pathophysiology of addiction and suggested their role in the drug-induced plasticity of NMDARs. [ABSTRACT FROM AUTHOR]

Background and aims: Repeated performance of some behaviors such as playing computer games could result in addiction. The NMDA receptor is critically involved in the development of behavioral and drug addictions. It has been claimed that the expression level of neurotransmitter receptors in the brain may be reflected in peripheral blood lymphocytes (PBLs). Methods: Here, using a real-time PCR method, we have investigated the mRNA expression of GluN2A, GluN2D, GluN3A, and GluN3B subunits of the NMDA receptor in PBLs of male online computer game addicts (n = 25) in comparison with normal subjects (n = 26). Results: Expression levels of GluN2A, GluN2D, and GluN3B subunits were not statistically different between game addicts and the control group. However, the mRNA expression of the GluN3A subunit was downregulated in PBLs of game addicts. Discussion and conclusions: Transcriptional levels of GluN2A and GluN2D subunits in online computer game addicts are similar to our previously reported data of opioid addiction and are not different from the control group. However, unlike our earlier finding of drug addiction, the mRNA expression levels of GluN3A and GluN3B subunits in PBLs of game addicts are reduced and unchanged, respectively, compared with control subjects. It seems that the downregulated state of the GluN3A subunit of NMDA receptor in online computer game addicts is a finding that deserves more studies in the future to see whether it can serve as a peripheral biomarker in addiction studies, where the researcher wants to rule out the confusing effects of abused drugs. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) have been recently shown to improve functional recovery in animal models of CNS disorders and are currently being examined in clinical studies for sclerosis, stroke, and CNS lesions. The activation of endogenous CNS protection and repair mechanisms is unclear. MSC-based approaches are considered a new potential target for neurodegenerative disorders. This study was designed to discover the effect of MSCs injection in the nucleus accumbens (NAc) on the reinstatement of behavior in morphine-induced conditioned place preference (CPP) in male rats. The CPP was induced via intra-peritoneal (i.p.) morphine injection (5 mg/kg) for three consecutive days. After being tested for CPP induction, animals received MSCs or culture medium (DMEM F-12) in their NAc using stereotaxic surgery. Following extinction, a priming dose of morphine (2 mg/kg) was administered to induce reinstatement. Expression of GluN1, GluN2A, and GluN2B subunits of the NMDA receptor and the NT-3 gene in the NAc was assessed on the last day of extinction and following CPP reinstatement. The results showed that local injection of MSCs attenuated reinstatement after receiving a priming dose of morphine, and also shortened the period of CPP extinction. The mRNA expression of the NT-3 gene in the group receiving MSCs was increased compared to control animals, as was observed for GluN1 and GluN2B, but not GluN2A. It is concluded that intra-NAc injection of MSCs may facilitate morphine extinction and alleviate reinstatement behavior which may be via expression changes in NMDA receptor subunits and NT-3 gene. • Intra-NAc injection of MSCs could attenuate morphine reinstatement behavior in CPP. • Administration of MSCs in NAc reduces the period of CPP extinction. • NT-3 expression in the MSCs-treated group is increased compared to control animals. • Expression of NMDA receptor subunits GluN1 and GluN2B is elevated in the MSCs group. [ABSTRACT FROM AUTHOR]

• Intra-NAc shell infusion of CART induced CPP or CPA dose-dependently. • Aversive CART + rewarding morphine produced neither CPP nor CPA. • IHC showed NR1 reduction in NAc and hippocampus, but not in PFC in above experiment. • Sub-rewarding both CART and morphine induced CPP, NR1 increased in all above areas. • There might be an interaction between opioids, CART and NMDA in NAc-shell framework. The addictive properties of opioids may be mediated to some extent by cocaine-and amphetamine-regulated transcript (CART) in the reward pathway. Moreover, some claims CART interacts with the glutamate system. Here, we evaluated whether intra-nucleus accumbens (NAc) shell infusions of CART induces Conditioned Place Preference (CPP) or Conditioned Place Aversion (CPA) and affects morphine reward. We also measured NR1 subunit expressions of the N -methyl- d -aspartate (NMDA) receptor in various parts of the reward pathway (NAc, prefrontal cortex and hippocampus) after conditioning tests. Animals with bilateral intra-NAc shell cannulas were place-conditioned with several doses of subcutaneous morphine prior to intra-NAc shell infusions of artificial cerebrospinal fluid (aCSF). Immunohistochemistry (IHC) showed a dose-dependent increase in the NR1 expression in all examined parts. When rats were conditioned with intra-NAc shell infusions of CART, CPP and CPA induced with 2.5 and 5 μg/side respectively and IHC showed NR1elevation with 2.5 and reduction with 5 μg/side in all areas. Sub-rewarding dose of CART administration (1.25 μg/side) prior to sub-rewarding dose of morphine (2.5 mg/kg) induced CPP and NR1 increased in all examined tissues in IHC. However, infusion of an aversive dose of CART (5 μg/side) prior to the rewarding dose of morphine (5 mg/kg) produced neither CPP nor CPA and NR1 in the NAc and hippocampus decreased significantly. It seems that the rewarding or aversive effects of intra-NAc shell CART and its facilitating or inhibiting effects on morphine reward are dose-dependent. Additionally, NMDA may be closely involved in the affective properties of opioids and CART in the reward pathway. [ABSTRACT FROM AUTHOR]

A combination of cannabis and ecstasy may change the cognitive functions more than either drug alone. The present study was designed to investigate the possible involvement of dorsal hippocampal NMDA receptors in the interactive effects of arachidonylcyclopropylamide (ACPA) and ecstasy/MDMA on memory retrieval. Adult male Wistar rats were cannulated into the CA1 regions of the dorsal hippocampus (intra-CA1) and memory retrieval was examined using the step-through type of passive avoidance task. Intra-CA1 microinjection of a selective CB1 receptor agonist, ACPA (0.5–4 ng/rat) immediately before the testing phase (pre-test), but not after the training phase (post-training), impaired memory retrieval. In addition, pre-test intra-CA1 microinjection of MDMA (0.5–1 μg/rat) dose-dependently decreased step-through latency, indicating an amnesic effect of the drug by itself. Interestingly, pre-test microinjection of a higher dose of MDMA into the CA1 regions significantly improved ACPA-induced memory impairment. Moreover, pre-test intra-CA1 microinjection of a selective NMDA receptor antagonist, D-AP5 (1 and 2 μg/rat) inhibited the reversal effect of MDMA on the impairment of memory retrieval induced by ACPA. Pre-test intra-CA1 microinjection of the same doses of D-AP5 had no effect on memory retrieval alone. These findings suggest that ACPA or MDMA consumption can induce memory retrieval impairment, while their co-administration improves this amnesic effect through interacting with hippocampal glutamatergic-NMDA receptor mechanism. Thus, it seems that the tendency to abuse cannabis with ecstasy may be for avoiding cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Abstract Working memory (WM) system, temporarily stores information and uses this information for complex cognitive tasks. WM connects memory, emotional feelings and perception. Evidence compelling that N -methyl d -aspartate receptor (NMDAR) expression relatively affect WM performance in animal models. It has been suggested some peripheral blood lymphocyte's (PBL) receptors are similar with neuronal receptors in the brain, so we measured PBL's receptors changes as a marker of the neuronal receptor. In this study, we examined one hundred adult men with Wisconsin Card Sorting Test (WCST) as a tool for primary screening for executive function (EF) which include WM. Then, we selected fifty individuals with high and low WCST scores. With digit span and symmetry span tasks, we screened 20 samples for high WM group and 19 samples for low WM group. After separating PBL, we measured mRNA expression level changes in NMDAR subunits with Reverse transcription-polymerase chain reaction method. We demonstrated that GluN2D increased and GluN3A decreased in individuals with high WM compared with the low WM (P <.01 and P <.001, respectively). The expression levels of GluN2A, GluN2B, and GluN3B were not altered between two groups (P >.05). Modifying the PBL receptors could be future approaches to defend memory loss and concentrate the senses over WM-related processes in physiological and pathological statuses. We hypothesized that increasing in GluN2 subunits and decreasing in GluN3 subunits led to improving current via NMDAR and subsequently affect WM. Highlights • GluN2A and GluN2C subunits mRNA expression have not changed in individuals with high working memory. • GluN2D subunit mRNA expression was changed in individuals with high working memory. • GluN3A subunit mRNA expression was altered in the high working memory subjects. • GluN3B subunit mRNA expression was not altered in the high working memory subjects. [ABSTRACT FROM AUTHOR]