Endocannabinoid system as a therapeutic target for psychostimulants relapse: A systematic review of preclinical studies.

The mechanism behind the reinstament of psychostimulant, as a major obstacle in addiction treatment is not fully understood. Controversial data are available in the literature concerning the role of the endocannabinoid (eCB) system in regulating the relapse to psychostimulant addiction in preclinical studies. The current systematic review aims to evaluate eCB modulators' effect in the reinstatement of commonly abused psychostimulants, including cocaine, amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine. By searching the PubMed, Web of Science, and Scopus databases, studies were selected. Then the studies, quality was evaluated by the SYRCLE risk of bias tool. The results have still been limited to preclinical studies. Thirty-nine articles that employed self-administration and CPP as the most prevalent animal models of addiction were selected. This data indicates that cannabinoid receptor 1 antagonists and some cannabinoid receptor 2 agonists could suppress the reinstatement of cocaine and methamphetamine addiction in a dose-dependent manner. However, only AM251 was efficient to block the reinstatement of 3,4-methylenedioxymethamphetamine. In conclusion, cannabinoid receptor 1 antagonists and some cannabinoid receptor 2 agonists may have curative potential in the relapse of psychostimulant abuse. However, time, dose, and route of administration are crucial factors in their inhibitory impacts.

Insulin replacement prevents the acquisition but not the expression of morphine-induced conditioned place preference in streptozotocin-induced diabetic rats

Abstract Insulin receptors have distributed in all brain regions, including the nucleus Accumbens (NAc), and where is implicated in the reward properties of drugs. It is well known that insulin signaling can regulate dopamine release. Therefore, in the present study, we tried to examine the effect of insulin replacement on the acquisition and expression of morphine-induced conditioned place preference (CPP) in diabetic rats. Forty-eight male Wistar rats were divided into two non-diabetic (Naïve) and diabetic groups rendered by a single injection of streptozotocin (STZ). These groups separately received insulin (10U/kg) or saline (1 ml/kg) one hour prior to morphine administration (5mg/kg;s.c.) during conditioning days (acquisition phase) or post-conditioning day (expression phase) in the CPP paradigm. In this paradigm, conditioning score (CS) and locomotion activity were recorded by Ethovision. The STZ-induced diabetic rats displayed higher CS compared to naïve rats (P<0.05). This effect was abolished in all diabetic rats that received insulin during conditioning days but not the expression phase. This study has provided evidence that insulin plays a modulatory role in morphine-induced CPP, and insulin replacement during the acquisition phase could reduce the rewarding properties of morphine in diabetes conditions through a possible modulating effect on dopamine release in the NAc region

Blockade of orexin receptors in the ventral tegmental area reduced the extinction period of the lateral hypothalamic-induced conditioned place preference in rats.

The orexinergic connection between the lateral hypothalamus (LH) and the ventral tegmental area (VTA) is involved in modulating the reward circuit. The conditioned place preference (CPP) can be induced by microinjection of carbachol, a cholinergic agonist, into the LH. The current research was conducted to understand whether intra-VTA orexin receptors (OXRs) could influence the duration of the extinction period or maintenance of the intra-LH carbachol-induced CPP. To this end, the rats unilaterally received intra-LH carbachol (250 nM) within a 3-day conditioning period. Animals that have already passed the conditioning test were unilaterally administered by intra-VTA microinjection of SB334867, an OX1R antagonist, or TCS OX2 29, an OX2R antagonist during the extinction phase of the LH stimulation-induced CPP. For the first time, our data indicated that daily intra-VTA administration of either SB334867 (30 nM) or TCS OX2 29 (10 and 30 nM) during the extinction period decreased the maintenance of intra-LH carbachol-induced CPP. In conclusion, OXRs in the VTA play crucial roles in the maintenance of reward processes.

Chemical stimulation of the lateral hypothalamus induced seeking behaviors in rats: Involvement of orexin receptors in the ventral tegmental area.

Orexinergic projections originated from the lateral hypothalamus (LH) to the ventral tegmental area (VTA) play essential role in reward-related behaviors. Our previous studies show that intra-LH injection of carbachol, as a cholinergic agonist, induces conditioned place preference (CPP) in rats. This study aimed to determine whether chemical stimulation of the LH alone can induce reinstatement or not, and whether intra-VTA orexin receptors are involved in the reinstatement of intra-LH carbachol-induced CPP in the rats. The animals were unilaterally treated by carbachol (250 nM) in the LH during 3-day conditioning phase. Then, they underwent an extinction phase without receiving carbachol, and on the reinstatement day, animals received a different priming dose of carbachol in the separate groups. Extinguished animals unilaterally received intra-VTA administration of SB334867 or TCS OX2 29 as orexin-1 or orexin-2 receptor antagonists to evaluate the role of orexin receptors before effective priming dose of carbachol on the reinstatement day. Findings showed that intra-LH microinjection of a priming dose of carbachol (25 and 50 nM) induced the reinstatement of LH chemical stimulation-induced CPP. Moreover, it was indicated that, intra-VTA administration of either SB334867 or TCS OX2 29 (10 and 30 nM) before to intra-LH injection of the priming dose of carbachol (50 nM) dose-dependently inhibited the reinstatement of intra-LH carbachol-induced CPP. Also, the orexin-2 receptor antagonist was a little more effective than orexin-1 receptor antagonist for inhibiting the reinstatement of LH chemical stimulation-induced CPP. The consequences propose that both orexin receptors in the VTA play roles in the reinstatement of intra-LH carbachol-induced CPP.

Curcumin protects purkinje neurons, ameliorates motor function and reduces cerebellar atrophy in rat model of cerebellar ataxia induced by 3-AP.

BACKGROUND: Cerebellar ataxias comprise a group of terminal illnesses with ataxia as the main symptom. Curcumin as a yellow polyphenol was extracted from the rhizome ofCurcuma longa. Owing to its antioxidant, anti-inflammatory, anti-fibrotic and anti-tumor features, curcumin is considered as a potential therapeutic agent. AIM: In this study, we aim to investigate the neuroprotective effects of oral administration of curcumin on a rat model of cerebellar ataxia induced by neurotoxin 3-acetylpyridine. METHODS: The animals were randomly separated into three groups (control, 3-acetylpyridine, and curcumin + 3-acetylpyridine). Next, motor performance and muscle electromyography activity were assessed. Then, in the molecular part of the study, the anti-apoptotic role of curcumin in cerebellar ataxia and its relationship to protection of Purkinje cells were investigated. RESULTS: Curcumin treatment improved motor coordination and muscular activity, reduced cleaved caspase-3, and increased glutathione level in 3-AP-lesioned rats as well as total volumes of cerebellar granular and molecular layers. CONCLUSION: the present study implies that curcumin might have neuroprotective effects to counteract neurotoxicity of 3-AP-induced ataxia.