Expression Of Morphine-induced Conditioned Place Preference Research Articles

Effects of CB1 receptor antagonist within the nucleus accumbens on the acquisition and expression of morphine-induced conditioned place preference in morphine-sensitized rats

It has been shown that cannabinoids interact with the opiate system in reward-related behaviors and in animal models of addiction. In the present study, the effects of bilateral intra-accumbal administration of AM251, a CB1 receptor antagonist, on the acquisition and expression of ineffective dose of morphine-induced conditioned place preference (CPP) in morphine-sensitized rats were investigated. 158 adult male albino Wistar rats were used in these experiments. Subcutaneous (s.c.) administration of morphine (0.25, 0.5, 0.75, 1, 2.5 and 5 mg/kg) induced CPP only at the dose of 5 mg/kg. In addition, repeated administration of morphine (5 mg/kg; s.c.), once daily for 3 days followed by 5 days free of the opioid (sensitization period), increased conditioning response induced by ineffective doses of morphine (0.25, 0.5 and 0.75 mg/kg). Bilateral intra-accumbal administration of AM251 (5, 25 and 125 ng/0.5 μl per side) dose-dependently reduced the acquisition and expression of morphine-induced CPP in morphine-sensitized rats, while bilateral intra-accumbal administration of neither saline nor DMSO (0.5 μl/side) had effects on the acquisition and expression of morphine-induced CPP in sensitized rats. The results indicated that CB1 receptors within the nucleus accumbens are involved in the acquisition and expression of morphine-induced CPP in sensitized rats. Our findings also suggest the existence of cross-talk between cannabinoids and opiates on the sensitization to morphine and the implication of endocannabinoid system in the process of sensitization to opiates.

Mirtazapine, a Noradrenergic and Specific Serotonergic Antidepressant, Attenuates Morphine Dependence and Withdrawal in Sprague-Dawley Rats

The effects of mirtazapine, a noradrenergic and specific serotonergic antidepressant, on morphine withdrawal and morphine conditioned place preference (CPP) were investigated in rats. Our results showed that some morphine withdrawal signs, including teeth chattering, grooming, chewing, and escape attendance, were attenuated by single pretreatments with 3, 10, or 30 mg/kg mirtazapine. Wet-dog shakes, rearing, and grooming were inhibited by daily pretreatment with 1, 3, or 10 mg/kg mirtazapine. The expression of morphine-induced CPP was significantly blocked by mirtazapine (10 or 30 mg/kg, i.p.), while chronic treatment with mirtazapine (1 or 10 mg/kg, i.p. once, daily, for six consecutive days) significantly attenuated the acquisition of morphine CPP. Our results demonstrated that mirtazapine attenuates morphine withdrawal and morphine-induced CPP in rats and suggest that mirtazapine may have therapeutic potential in the treatment of opiate dependence.

Effect of glycine site/NMDA receptor antagonist MRZ2/576 on the conditioned place preference and locomotor activity induced by morphine in mice

To study the effect of glycine site/NMDA (N-methyl-D-aspartate) receptor antagonist MRZ2/576 on the conditioned place preference (CPP) and locomotor activity induced by morphine in mice. Different doses (1.25, 2.5 and 5 mg/kg, i.p.) of MRZ2/576 were used to evaluate the effect of MRZ2/576 on the acquisition and expression of CPP induced by morphine (5 mg/kg) in mice. In addition, we examined the locomotor activity of mice in conditioning and testing phase of CPP paradigm. MRZ2/576 alone could not establish place preference, but a 5 mg/kg dose of MRZ2/576 could block both acquisition and expression of morphine-induced CPP. In testing phase of CPP, there was no statistical difference for locomotor activity between the groups; injection of MRZ2/576 showed a dose-dependent decrease of locomotor activity on both control and morphine-treated mice, especially 5 mg/kg of MRZ2/576 significantly suppressed the locomotor activity of mice. Based on the present results, we assume that MRZ2/576 can antagonize the rewarding effect of morphine, suggesting that this glycine site/NMDA receptor antagonist could be used to treat addictions due to its light side effect profile.

Repeated peripheral electrical stimulations suppress both morphine-induced CPP and reinstatement of extinguished CPP in rats: accelerated expression of PPE and PPD mRNA in NAc implicated

Previous studies have shown that peripheral electrical stimulation (PES) can suppress morphine-induced conditioned place preference (CPP) and the reinstatement of extinguished CPP in the rat. The present study was performed to elucidate if preproenkephalin (PPE) and preprodynorphin (PPD) mRNAs in the nucleus accumbens (NAc) play a role in this event. Rats were trained with morphine for 4 days to establish CPP paradigm. They were then given 15-min test once a day for eight consecutive days for extinction trial. Twenty-four hours after the 8th session of extinction trials, rats were given peripheral electrical stimulation (PES) at 2 or 100 Hz once a day for 3 days, then a morphine-priming injection at a dose of 1, 2, or 4 mg/kg to reinstate the extinguished CPP. At the end of the experiment, PPE and PPD mRNA levels in the nucleus acccumbens (NAc) were determined by the semiquantitative RT-PCR technique. The results showed that PES at 2- and 100-Hz administered 30 min a day for 3 days suppressed both the expression of morphine-induced CPP and the reinstatement of extinguished CPP. PES at 2 Hz increased preproenkephalin (PPE) mRNA levels, whereas PES of 100 Hz that of preprodynorphin (PPD) mRNA levels in the NAc. These findings suggest that enkephalin and dynorphin in NAc may play important roles in the mechanisms underlying the inhibitory effect of PES on the expression and reinstatement of morphine-induced CPP in rats.

The role of alpha-adrenoceptor mechanism(s) in morphine-induced conditioned place preference in female mice

It has been shown that the alpha-adrenergic system is involved in some effects of opioids, including analgesia and reward. Gender differences also exist between males and females in response to alpha-adrenergic agents. This study was designed to determine the effects of alpha-adrenoceptor agonists and antagonists on the acquisition or expression of morphine-induced conditioned place preference (CPP) in female mice. The experiments showed that subcutaneous injections of morphine (0.5–8 mg/kg) induced CPP in a dose-dependent manner in mice. Intrapritoneal administration of the alpha-1-adrenoceptor agonist, phenylephrine (0.03, 0.1 and 0.3 mg/kg), and alpha-2 adrenoceptor agonist, clonidine (0.0001, 0.0005 and 0.001 mg/kg), as well as alpha-1-adrenoceptor antagonist, prazosin (0.01, 0.05 and 0.1 mg/kg) or alpha-2 adrenoceptor antagonist, yohimbine (0.005, 0.01 and 0.05 mg/kg) did not induce motivational effects and also did not alter locomotor activity in the animals. In the second set of experiments, the drugs were used before testing on Day 5, to test their effects on the expression of morphine-induced CPP. Intrapritoneal administration of phenylephrine and clonidine decreased the expression of morphine-induced CPP. In contrast, after application of prazosin or yohimbine, the expression of morphine-induced CPP was increased. Administration of lower (0.03 mg/kg) and higher doses of phenylephrine (0.1 and 0.3 mg/kg) during acquisition of morphine CPP decreased and increased the morphine CPP, respectively. Similarly, the administration of prazosin and clonidine decreased while yohimbine increased the morphine CPP. It may be concluded that alpha-adrenoceptor mechanism(s) influence morphine-induced CPP in female mice.

Brain opioid-receptors are involved in mediating peripheral electric stimulation-induced inhibition of morphine conditioned place preference in rats

Conditioned place preference (CPP) paradigm has been suggested as one of the animal models for drug craving. The present study was performed to examine the effect of 100 Hz peripheral electric stimulation (PES) on the expression of morphine-induced CPP. Rats were trained with morphine for 4 days to establish the CPP paradigm in a three-chamber ‘unbiased’ apparatus. Morphine-induced CPP was maintained up to 4 weeks when tests were given once a week. PES of 100 Hz administered 30 min a day for 3 days significantly attenuated morphine-induced CPP ( P<0.01). I.c.v. injection of the δ-opioid receptor antagonist naltrindole (NTI) or the κ-antagonist norbinaltorphimine (nor-BNI) but not the μ-antagonist cyclic d-Phe–Cys–Tyr– d-Trp–Arg–Thr–Pen–Thr–NH 2 (CTAP), completely blocked the inhibitory effect of 100 Hz PES on the expression of morphine-induced CPP ( P<0.05–0.01). These results indicate that the anti-craving effects induced by repeated PES of 100 Hz is mediated by the activation of supra-segmental δ- and κ-opioid receptors in the central nervous system.

Morphine conditioned reward is inhibited by MPEP, the mGluR5 antagonist

In the present study we examined the effect of MPEP [2-methyl-6-(phenylethynyl)-pyridine] a potent, selective and systemically active metabotropic glutamate receptor (mGluR) type I (subtype mGluR5) antagonist on conditioned morphine reward in mice. In an unbiased version of conditioned place preference (CPP) paradigm, single conditioning with 10 mg/kg of morphine produced reliable place preference. MPEP at 30, but not 10 mg/kg significantly inhibited the acquisition as well as expression of morphine-induced CPP, but it neither produced place preference or aversion, nor affected locomotor activity of mice. Effects of MPEP on learning and memory were studied in the elevated plus maze model of spatial learning. In contrast to 0.1 mg/kg of MK-801, which inhibited the acquisition of this task, 30 mg/kg of MPEP affected neither learning nor memory retrieval. These data suggest that mGluR5 may be involved in conditioned morphine reward.

Effect of imipramine on the expression and acquisition of morphine-induced conditioned place preference in mice

The effect of imipramine and α-adrenoceptor agonists and antagonists on the acquisition or expression of morphine-induced conditioned place preference (CPP) was studied in mice. An unbiased CPP paradigm was used to study the effect of the agents. In the first set of experiments, the drugs were used during the development of CPP by morphine or they were used alone in order to see if they induce CPP or conditioned place aversion (CPA). Our data showed that intraperitoneal injection of morphine sulphate (2.5–10 mg/kg) induced CPP in mice. Imipramine (0.5–2.5 mg/kg), phenylephrine (0.5–2 mg/kg), yohimbine (0.5–2 mg/kg) or prazosin (0.1–1 mg/kg) did not influence CPP, but clonidine (0.002–0.05 mg/kg) induced CPA. Yohimbine increased, while clonidine and prazosin reversed, morphine-induced CPP. Phenylephrine did not influence the CPP induced by morphine. In the second set of experiments, when the drugs were used before testing on Day 6, in order to test their effects on the expression of morphine-induced CPP, imipramine (0.5–5 mg/kg) reversed morphine-induced CPP and this reversal was blocked by naloxone (2 mg/kg). Clonidine and prazosin reversed, while yohimbine decreased morphine-induced CPP. Phenylephrine did not alter the morphine response. Furthermore, yohimbine and prazosin reversed the imipramine effect. None of the drugs influenced locomotion. However, prazosin or yohimbine in combination with morphine altered locomotor activity during the acquisition of CPP. Yohimbine by itself increased locomotion. It is concluded that imipramine can induce CPA through an opioid receptor mechanism and α-adrenoceptor agents may influence morphine CPP.