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Several studies indicated that morphine administration impairs cognitive brain functions. Therefore, in the current study, we investigated the effect of subchronic exposure to morphine and its withdrawal on effort- and/or delay-based forms of cost-benefit decision making and alterations in p-CREB/CREB ratio, p-GSK3β/GSK3β ratio, and BDNF level during decision making in the amygdala. Our data displayed an impairment of both forms of cost-benefit decision making following subchronic exposure to morphine. However, preference of high reward/high effort and/or high delay reward increased after naloxone injection. In molecular section, levels of BDNF and p-CREB/CREB ratio increased during cost-benefit decision making while p-GSK3β/GSK3β ratio decreased in both forms of decision making. In morphine-treated rats, level of BDNF and p-CREB/CREB ratio reduced during both forms of decision making while p-GSK3β/GSK3β ratio increased during delay-based and did not have a significant difference with the control group during effort-based decision making. On the withdrawal day, BDNF level raised while p-GSK3β/GSK3β ratio attenuated compared to morphine-treated group in both form of decision making. In addition, p-CREB/CREB ratio increased only during delay-based decision making on the withdrawal day. In conclusion, our data revealed that subchronic exposure to morphine interferes with the cost-benefit decision making may be via changes in level of BDNF, p-CREB/CREB and p-GSK3β/GSK3β ratio in the amygdala.

Previous studies indicate that metabotropic glutamate receptor type 2/3 (mGluR2/3) has a key role in the rewarding properties of morphine-induced conditioning place preference (CPP). Group II mGluR2/3 agonists are offered as a drug addiction treatment. The nucleus accumbens (NAc), which is one of the important areas involved in the reward circuitry, also expresses these receptors. In this study, we evaluated the effects of mGluR2/3 agonist, LY379268, on the extinction and reinstatement of morphine-induced CPP, following its microinjection into the NAc. Adult male Wistar rats (220-250 g) were implanted bilaterally by two separate cannulae into the NAc. After the acquisition of morphine CPP, different doses of LY379268 (0.3, 1 and 3 µg/0.5 μl saline) were microinjected into the NAc every day during the extinction period and, in a different set of experiments, on the reinstatement test day, 60 min before the infusion of a priming dose of morphine (1 mg/kg; subcutaneous). Thereafter, the animals were tested for place preference by the Ethovision software. The intra-accumbal injection of the mGluR2/3 agonist, LY379268, significantly decreased the extinction latencies and reinstatement of morphine-induced CPP at higher doses. It seems that the NAc might be a functional region for mGluR2/3 to play a regulatory role for decreasing drug-seeking behavior in rats. Furthermore, it can be said that mGluR2/3 agonists have a potential role in the treatment of drug-seeking behaviors.

Orexinergic projections originating from the lateral hypothalamus (LH) have an important role in the acquisition of the LH-stimulation conditioned place preference (CPP). Among the brain areas associated with reward processing, LH orexinergic neurons send projections to the dentate gyrus (DG) region of the hippocampus, and it has been shown that orexin receptors are expressed in the DG. In this study, we investigated the role of intra-DG orexin-1 (OX1) and orexin-2 (OX2) receptors on acquisition, expression and extinction of CPP induced by stimulation of the LH. Rats were unilaterally implanted by two separate cannulae into the LH and DG. The CPP paradigm was done; conditioning scores and locomotor activities were recorded by Ethovision software. The results showed that intra-DG administration of SB334867, a selective OX1r antagonist, and TCS OX2 29, a selective OX2r antagonist, (0.5, 5, 12.5 and 50nM/0.5µl DMSO) before carbachol microinjection (250nM; effective dose) during the 3-days conditioning phase, dose-dependently inhibited the development of LH stimulation-induced CPP in the rats. However, this reduction in OX1r antagonist treated groups was more than that in OX2r antagonist treated animals. In addition, these antagonists decreased the expression of LH-induced CPP. Moreover, OX1r but not OX2r antagonist could shorten the extinction duration of place preference. We conclude that the orexinergic projections from the LH to DG are involved in the development, expression and extinction of CPP induced by LH stimulation.

The ventral tegmental area (VTA) as a major source of dopamine neurons projecting to cortical and limbic regions has a crucial role in reward as well as stress processes. Dopamine is a predominant neurotransmitter in the reward system, which plays an important role in both drug priming-induced and cue-induced reinstatement of cocaine and heroin seeking. It has been shown that this neurotransmitter has a role in stress-induced relapse to drug seeking. Therefore, the present study aims to evaluate the effects of intra-VTA administration of SCH-23390, as a dopamine D1-like receptor antagonist, and sulpiride, as a dopamine D2-like receptor antagonist, on drug priming-induced and food deprivation (FD)-induced reinstatement. The rats were bilaterally implanted by two separate cannulae into the VTA. After the acquisition and extinction of morphine-conditioned place preference, the animals received different doses of SCH-23390 or sulpiride (0.15, 0.4, 1.5 and 4 mg/0.3 µl vehicle per side) into the VTA on the reinstatement day and tested for drug priming-induced reinstatement of morphine (1 mg/kg) or FD-induced reinstatement facilitated by an ineffective dose of morphine (0.5 mg/kg) in separate groups. Our findings indicated that the D1/D2-like receptor antagonists attenuated the drug priming-induced and FD-induced reinstatement. However, these decrements were more significant in groups of animals that received a 24-h FD as a stressor. The data may suggest a role for the VTA dopaminergic system in relapse to drugs of abuse, which may be induced either by re-exposure to morphine or exposure to a stressor.

Orexinergic projections derived from the lateral hypothalamus (LH) to the ventral tegmental area (VTA) and the nucleus accumbens (NAc), play a key role in the acquisition of conditioned place preference (CPP) induced by LH stimulation. On the other hand, there are several studies which support the idea of the existence of a cross-talk between the orexinergic and cannabinoid systems. Nevertheless, the function and how both systems interact in the reward circuit remain unknown. In this study, the authors tried to clarify the role of orexin-2 receptor (OX2r) within the VTA and NAc in the development of reward-related behaviors after chemical stimulation of the LH and also find out the involvement of CB1 cannabinoid receptors in this phenomenon. Animals were implanted by two separate cannulae into the LH and VTA or NAc, unilaterally. The CPP paradigm was done; and conditioning scores were recorded. The results showed that administration of TCS OX2 29 as a selective OX2r antagonist (1, 3 and 10 nM/rat) into the VTA or NAc just 5 min before microinjection of carbachol (250 nM/0.5 μl saline), a cholinergic agonist, into the LH during the 3-day conditioning phase, could dose-dependently inhibit the development of LH stimulation-induced CPP. Furthermore, concurrent injection of ineffective doses of TCS OX2 29 and AM251, as a CB1 receptor antagonist, into the NAc could reduce conditioning scores. The findings of this study showed that the OX2 receptor has a critical role in modulating reward circuit in the VTA and NAc, when the LH was stimulated by carbachol. Moreover, we suggest the existence of an interaction between orexinergic and cannabinoid systems within the VTA and NAc in place preference induced by LH stimulation.

Methamphetamine (METH) is a psychostimulant drug with significant abuse potential and neurotoxic effects. A high percentage of users relapse to use after detoxification and no effective medication has been developed for treatment of METH addiction. Developing evidences indicated the role of glial cells in drugs abused related phenomena. However, little is known about the role of these cells in the maintenance and reinstatement of METH-seeking behaviors. Therefore, the current study was conducted to clarify the role of glial cells in the maintenance and reinstatement of METH-induced conditioned place preference (CPP) in rats. Astrocyte condition medium (ACM) and neuroglia conditioned medium (NCM) are liquid mediums prepared from primary astrocyte and neuroglia cells. These mediums seem to contain many factors that release by glia cells. CPP was induced by systemic administration of METH (1mg/kg for 5days, s.c.). Following the establishment of CPP, the rats were given daily bilateral injections (0.5μl/side) of either vehicle, ACM or NCM into the nucleus accumbens (NAc) and then were tested for the maintenance and reinstatement. Intra-NAc administration of ACM treated with METH, could extend the extinction period and also, intensified the magnitude of METH reinstatement. Furthermore, intra-accumbal administration of NCM treated with METH notably delayed the extinction period by four days and significantly increased the magnitude of CPP score in the reinstatement phase compared to the post-test phase. Collectively, these findings suggested that activation of glial cells may be involved in the maintenance and reinstatement of METH-seeking behaviors. It provides new evidence that glia cells might be considered as a potential target for the treatment of METH addiction.

It was established that stimulation of the lateral hypothalamus (LH) can induce antinociception. Previous studies showed a role for the ventral tegmental area (VTA) and nucleus accumbens (NAc) in antinociception induced by LH stimulation through the orexinergic system. In this study, we tried to assess the involvement of dopamine D1-like receptors within the VTA and NAc in the LH stimulation-induced antinociception. Male Wistar rats were unilaterally implanted with two separate cannulae into the LH and VTA or NAc. Animals received intra-VTA or intra-accumbal infusion of SCH-23390, as a D1-like dopamine receptor antagonist (0.125, 0.25, 1 and 4 μg/rat), 2 min before intra-LH administration of carbachol (125 nM/rat). The antinociceptive effects of SCH-23390 were measured by using a tail-flick analgesiometer and represented as maximal possible effect (%MPE). Results showed that intra-VTA and/or accumbal administration of SCH-23390 could prevent carbachol-induced antinociception. These findings revealed that D1-like dopamine receptors within the VTA and NAc play an important role in antinociceptive effect induced by chemical stimulation of the LH.

Several lines of evidence have shown that stimulation of the lateral hypothalamus (LH) can induce antinociception. It has been indicated that hypothalamic orexinergic neurons send projections throughout the dopamine mesolimbic pathway. Functional interaction between the LH and the main area of the mesolimbic pathway such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc) implicates in pain modulation. Thus, in this study, we investigated the role of D2-like dopamine receptors within the VTA and NAc in the LH stimulation-induced antinociception. Male Wistar rats weighing 230-280 g were unilaterally implanted with two separate cannulae into the LH and VTA or NAc. Animals received intra-VTA (0.25, 1 and 4 μg/0.3 μl DMSO) and intra-accumbal (0.125, 0.25, 1 and 4 μg/0.5 μl DMSO) infusions of sulpiride as a selective D2-like receptor antagonist, prior to intra-LH carbachol (125 nM/rat) administration. In the tail-flick test, the antinociceptive effects were measured using a tail-flick algesiometer and represented as maximal possible effect (%MPE) within 5, 15, 30, 45 and 60 min after injections. Our results showed that intra-VTA and intra-accumbal sulpiride dose-dependently attenuated the LH stimulation-induced antinociception. However, the blockade of D2-like receptors within the NAc was more significant than that of the VTA. These findings show that D2-like dopamine receptors in these regions play an important role in the LH-mediated modulation of nociceptive information in the acute model of pain in the rats. It seems that this pain modulating system is more relevant to D2-like receptors in the nucleus accumbens.

Evidence from animal models suggests a role for orexinergic system in reward processing and drug addiction. The lateral hypothalamus (LH) orexin neurons send projections to the dorsal hippocampus (CA1 region) which plays a pivotal role in reward processes. Moreover, it has been shown that orexin containing terminals and orexin receptors are distributed in the hippocampal formation. In this study, we assessed the role of orexin 1 (OX1r) and orexin2 (OX2r) receptors in the CA1 on the development of LH stimulation-induced conditioned place preference (CPP). Animals weighing 230-280 g were unilaterally implanted by two separate cannulae into the LH and CA1. The CPP paradigm was done; SB334867 and TCSOX229, as selective OX1r and OX2r antagonists (1, 3, 10 and 30 nM/0.5 μl DMSO) administrated into the CA1 prior to intra-LH carbachol microinjection (250 nM; the most effective dose) during the 3-days conditioning phase, respectively. Conditioning scores and locomotor activities were recorded by Ethovision software on the test day. The results showed that the administration of OX1r and OX2r antagonists into the CA1 attenuated the development of CPP induced by chemical stimulation of the LH. However, this decrease in OX1r antagonist treated groups was more significant than that in OX2r antagonist treated animals. Our findings suggest that OX1 and OX2 receptors in the CA1 region of the hippocampus were involved in the development of CPP induced by chemical stimulation of the LH and the efficiency of OX1 receptors in this phenomenon was more considerable than OX2 receptors in rats.

Background: The present study assessed the therapeutic effects of dalteparin in patients who had recent onset central retinal vein occlusion (CRVO) as compared with those of acetylsalicylic acid (ASA). Methods: Patients with recent onset of CRVO were randomly assigned to receive dalteparin subcutaneously every day for 20 days or ASA daily for the same period. Complete ophthalmic examinations were conducted at baseline and at each follow-up interval: 1 week and 1, 2, 3, 4, and 6 months later. Best-corrected visual acuity was assessed by an investigator blind to the treatment group. Results: The mean 6-month change in logMAR visual acuity for dalteparin-treated patients was an increase of 5.5 letters (Early Treatment Diabetic Retinopathy Study chart) (−0.11 [SD 0.71] logMAR) and for ASA-treated patients was a decrease of 14 letters (+0.28 [SD 0.79] logMAR), representing a significant difference between the 2 groups ( p = 0.016). One patient in the dalteparin group and 14 in the ASA group showed iris neovascularization (NVI) (2.1% vs. 30.4%, p=0.0001). Interpretation: Dalteparin was found to be superior to ASA in terms of improving visual acuity and preventing NVI over the first 6 months of treatment. Similar studies are recommended of other newer types of anticoagulants, especially those that could be used orally.