Orexins are hypothalamic peptides involved in the modulation of the feeding, arousal, reward function, learning, and memory; nevertheless, the role of orexins in stress and relapse are largely unclear. Therefore, in the present study, the reinstatement model were used to examine the effects of intradentate gyrus (DG) administration of SB334867 as an orexin-1 receptor antagonist and TCS OX2 29, as an orexin-2 receptor antagonist on drug priming- and forced swim stress (FSS)-induced reinstatement of morphine. One-hundred and 44 adult male albino Wistar rats weighing 200 g-280 g were bilaterally implanted by cannulas into the DG. For induction of conditioned place preference (CPP), subcutaneous (sc) injection of morphine (5 mg/kg) was used daily during a 3-day conditioning phase. Then, the conditioning score (conditional stimulus [CS]) was calculated. After a 24 hr "off" period following achievement of extinction criterion, rats were tested for drug priming-induced reinstatement by priming dose of morphine (1 mg/kg, sc) and for FSS-induced reinstatement 10 min after FSS. In the next experiments, animals received different doses of intra-DG administration of SB334867 and TCS OX2 29 (3, 10, and 30 μg/0.5 μl 12% DMSO per side), bilaterally and were subsequently tested for morphine priming- and FSS-induced reinstatement. Our findings indicated that the FSS-induced the reinstatement of seeking behaviors. Furthermore, intra-DG administration of orexin-1 and orexin-2 receptor antagonists attenuated drug priming-induced reinstatement dose-dependently. However, they have trivial role in FSS-induced reinstatement. It is concluded that drug priming-induced reinstatement may be mediated, at least in part, by stimulation of orexin receptors in the DG.

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The high rate of relapse to drug use is one of the main problems in the treatment of addiction. Stress plays the essential role in drug abuse and relapse; nevertheless, little is known about the mechanisms underlying stress and relapse. Accordingly, the effects of intra-accumbal administration of Sulpiride, as a dopamine D2-like receptor antagonist, on an ineffective morphine dose + food deprivation(FD)- and morphine priming-induced reinstatement of conditioned place preference (CPP). About 104 adult male albino Wistar rats weighing 200-280 g were bilaterally implanted by cannula into the nucleus accumbens (NAc). Subcutaneous (sc) injection of morphine (5 mg kg ) was used daily during a 3-day conditioning phase. After a 24-hr "off" period following achievement of extinction criterion, rats were tested for FD- and priming-induced reinstatement of morphine CPP by an ineffective (0.5 mg kg , sc) and priming (1 mg kg , sc) dose of morphine, respectively. In the next experiments, animals received different doses of intra-accumbal Sulpiride (0.25, 1, and 4 µg/0.5 µL saline) bilaterally and were subsequently tested for morphine reinstatement. Our findings indicated that the 24-hr FD facilitated reinstatement of morphine CPP. Furthermore, the D2-like receptor antagonist attenuated the ineffective morphine dose+ FD- and priming-induced reinstatement of morphine CPP dose-dependently. Also, contribution of D2-like receptors in mediation of the ineffective morphine dose+ FD-induced reinstatement of CPP was greater than morphine priming-induced reinstatement of CPP. The role of dopaminergic system in morphine reinstatement through a neural pathway in the NAc provides the evidence that D2-like receptor antagonist can be useful therapeutic targets for reinstatement of morphine CPP.

Previous studies on drug abuse have shown that response to drug-associated cues exist during prolonged abstinence. In succession to previous investigations in our laboratory on morphine dependence and our research on acquisition and expression phases of morphine–conditioned place preference (CPP), in this study we attempt to determine the effects of intraaccumbal administration of SCH-23390, as a D1-like receptor antagonist, and sulpiride, as a D2-like receptor antagonist, in the maintenance of morphine-induced CPP in rats. Seventy-nine adult male Wistar rats weighing 200–280 g were bilaterally implanted with cannulas into the nucleus accumbens. During the 3-day conditioning phase, the animals received daily subcutaneous administration of morphine (5 mg/kg). CPP score and locomotor activity of animals were recorded by Ethovision software. Different doses (0.25, 1, 4 μg per 0.5 μL vehicle) of D1- and D2-like antagonists were bilateral injected daily after the expression phase and during the extinction phase. Our findings revealed that intraaccumbal administration of D1-like and D2-like antagonists after the CPP test shortened the extinction phase in the rats. The results suggested that the existence of the dopamine receptors in the nucleus accumbens was important for the maintenance of morphine-rewarding properties during the extinction phase. Therefore, dopamine receptors may be considered as a promising therapeutic agent in preventing the maintenance of morphine-rewarding effects in dependent individuals.