sch-23390 and Morphine-Dependence

Reinstatement to drug abuse is the most challenging issue in the treatment of addiction. Thus, knowledge of the involved neurobiological mechanisms of reinstatement is a fundamental necessity. There is substantial and crucial evidence that dopamine is implicated in motivational processes such as relapse. Our behavioral results reported that the administration of dopamine receptor antagonists inhibited reinstatement of morphine in food-deprived rats. Previous studies have indicated that the ERK pathway plays a critical role in the cellular responses to stress and reward. Therefore, the purpose of the current study was to evaluate the effect of intra-dentate gyrus administration of dopamine receptor antagonists on the phosphorylation of hippocampal ERK in the reinstatement phase of morphine reward in food-deprived rats. All groups of animals passed conditioned place preference and were bilaterally given different doses of D1- or D2-like dopamine compounds (0.25, 1 and 4 μg/0.5 μl) into the dentate gyrus. Immediately after the reinstatement phase, each animal was euthanized, and the hippocampi were immediately dissected. Then, the p-ERK/ERK ratio was evaluated using Western blot analysis. The principal findings in this study demonstrated that intra-dentate gyrus administration of the highest dose of the D1-like receptor antagonist could enhance the hippocampal p-ERK/ERK ratio in food-deprived rats while the D2-Like receptor antagonist failed to change this ratio.

Topics: Analgesics, Opioid; Animals; Benzazepines; Dentate Gyrus; Disease Models, Animal; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Extinction, Psychological; Extracellular Signal-Regulated MAP Kinases; Food Deprivation; MAP Kinase Signaling System; Morphine; Morphine Dependence; Phosphorylation; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Recurrence; Sulpiride

Previous researches demonstrated that genetics and environment are two essential factors to prone individuals to drug abuse. Our previous data showed that dopaminergic system changed in the offspring of morphine-abstinent rats. In the present study, we evaluated whether blocking the D1-like dopamine receptors (DR) in the nucleus accumbens (NAC) affect the rewarding effect of morphine in the offspring of morphine-abstinent rats.. In the study, male and female Wistar rats received morphine orally for 21 days. Ten days after last morphine administration, animals prepared to mate either with a morphine abstinent or a drug-naive rat. Adult male offspring were chosen for further evaluation. SCH23390 (0.01 μg/rat) was administrated intra-NAC during the conditioning phase in the CPP paradigm (morphine 7.5 mg/kg).. Obtained data showed that morphine administration (7.5 mg/kg) did not induce conditioning in the offspring of the morphine-abstinent parent(s) (p < 0.001) compared with the control group. However, when SCH23390 injected in the NAC during the induction phase, the offspring of morphine-abstinent rats were conditioned with the same dose of morphine.. Previous studies showed that the offspring of morphine-abstinent rats are more prone to opioid consumption, and also developed tolerance to the rewarding effect of morphine. Current data indicated that blockade of D1-like DR in the NAC could prevent morphine-induced tolerance in these offspring. Therefore, inhibition of D1-like DR in the NAC might be a new candidate against morphine-reinforcing effect in the offspring of morphine-abstinent parent(s).

Topics: Animals; Behavior, Animal; Benzazepines; Conditioning, Classical; Conditioning, Operant; Dopamine Antagonists; Female; Male; Morphine; Morphine Dependence; Nucleus Accumbens; Rats; Rats, Wistar; Receptors, Dopamine D1; Substance Withdrawal Syndrome

Dopaminergic pathways from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) play a critical role in reward-related phenomena as well as in the reinstatement of drug-seeking behavior. Stress is a major trigger for inducing reinstatement, however, the interaction between stress and the dopaminergic system is not well known. The present study was undertaken to investigate the effect of D1- and D2-like dopamine receptors within the NAc in forced swim stress (FSS)- and priming-induced reinstatement of morphine-seeking behaviors. The conditioned place preference (CPP) was induced by injecting morphine (5 mg/kg, SC for 3 days) and lasted for eight days after cessation of the morphine treatment. The FSS (6 min) and effective priming dose of morphine (1 mg/kg, sc) reinstated the extinguished morphine-induced CPP. In order to investigate the effect of intra-accumbal injection of SCH23390 as a D1-like receptor antagonist, or Sulpiride as a D2-like receptor antagonist on the FSS-induced reinstatement of morphine extinguished rats, animals received bilaterally intra-NAc injection of SCH23390 or Sulpiride (0.25, 1 and 4 μg/side) before application of FSS, and then, they were tested in the reinstatement day. Our results showed that the intra-accumbal administration of D1- and D2-like receptors antagonists dose-dependently blocked the effect of FSS on the reinstatement and significantly modulated morphine priming-induced reinstatement as well. These findings suggested that the D1- and D2-like dopamine receptors in the NAc involve in morphine-seeking behaviors and antagonism of these receptors can reduce the effect of stress on rewarding properties of morphine.

Topics: Animals; Benzazepines; Conditioning, Psychological; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug-Seeking Behavior; Male; Morphine; Morphine Dependence; Narcotics; Nucleus Accumbens; Phosphoproteins; Random Allocation; Rats, Wistar; Receptors, Dopamine D2; Spatial Behavior; Stress, Psychological; Sulpiride; Transcription Factors

In the current study, we investigated the role of intra-dentate gyrus (DG) administration of D1 and/or D2 receptor antagonists on the expression, acquisition, and extinction of morphine-CPP. Cannulae were implanted bilaterally into the DG region in male Wistar rats and CPP was induced by the subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. Three experimental designs were separately employed in the CPP paradigm during the acquisition, expression and extinction phases, and different doses (0.25, 1, or 4 μg/0.5 μl saline) of SCH23390, as a selective D1-like receptor antagonist, and sulpiride (0.25, 1, or 4 μg/0.5 μl DMSO), as a selective D2-like receptor antagonist, were bilaterally microinjected into the DG region. Conditioning scores and locomotor activities were recorded during the test. Results showed that the injection of the antagonists into the DG region dose-dependently attenuated the acquisition and expression of the morphine-induced CPP and sulpiride revealed prominent behavioral results compared to SCH23390 in both mentioned phases. Moreover, the blockade of D1- and D2-like receptors shortened the extinction phase of the morphine-induced CPP but had no effect on the locomotor activity. We found that the dopamine receptors within the DG region are involved in the acquisition and expression of morphine-CPP and have a critical role in the association between a morphine-paired context and the rewarding proprieties of morphine.

Topics: Animals; Benzazepines; Conditioning, Psychological; Dentate Gyrus; Dopamine Antagonists; Dose-Response Relationship, Drug; Extinction, Psychological; Male; Morphine; Morphine Dependence; Motor Activity; Narcotics; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Reward; Spatial Behavior; Sulpiride

Nucleus accumbens (NAc) plays an essential role in morphine sensitization and suppression of pain. Repeated exposure to stress and morphine increases dopamine release in the NAc and may lead to morphine sensitization. This study was carried out in order to investigate the effect of forced swim stress (FSS), as a predominantly physical stressor and morphine on the development of morphine sensitization; focusing on the function of D1/D2-like dopamine receptors in the NAc in morphine sensitization. Eighty-five adult male Wistar rats were bilaterally implanted with cannulae in the NAc and various doses of SCH-23390 (0.125, 0.25, 1 and 4μg/0.5μl/NAc) as a D1 receptor antagonist and sulpiride (0.25, 1 and 4μg/0.5μl/NAc) as a D2 receptor antagonist were microinjected into the NAc, during a sensitization period of 3days, 5min before the induction of FSS. After 10min, animals received subcutaneous morphine injection (1mg/kg). The procedure was followed by 5days free of antagonist, morphine and stress; thereafter on the 9th day, the nociceptive response was evaluated by tail-flick test. The results revealed that the microinjection of sulpiride (at 1 and 4μg/0.5μl/NAc) or SCH-23390 (at 0.25, 1 and 4μg/0.5μl/NAc) prior to FSS and morphine disrupts the antinociceptive effects of morphine and morphine sensitization. Our findings suggest that FSS can potentiate the effect of morphine and causes morphine sensitization which induces antinociception.

Topics: Animals; Benzazepines; Disease Models, Animal; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Male; Morphine; Morphine Dependence; Narcotics; Nociception; Nucleus Accumbens; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Stress, Psychological; Sulpiride; Swimming