Development Of Morphine-induced Place Preference Research Articles

The orexin receptors in the ventral tegmental area are involved in the development of sensitization to expression of morphine-induced preference in rats.

Recent studies have shown that orexin neurons in the lateral hypothalamus send a compelling project to the ventral tegmental area (VTA). Besides, orexin-1 (OX1) and orexin-2 (OX2) in the VTA are necessary for the development of morphine-induced place preference. Also, sensitivity to morphine can reinforce the rewarding effects of morphine. The current study aims to determine the role of VTAs orexin receptors in morphine sensitization in rats. In 84 adult male albino Wistar rats, two separate cannulae bilaterally implanted into the VTA. They received intra-VTA infusions of SB334867 (0.1, 1 and 10 nM) and TCS OX2 29 (1, 7 and 20 nM) as OX1 and OX2 receptor antagonists, respectively, 10 min before subcutaneous administration of morphine (5 mg/kg) during 3-day sensitization period. After a 5-day drug-free period, the conditioned place preference (CPP) paradigm induced by subthreshold doses of morphine (0.5 mg/kg), and CPP scores were measured by EthoVision software. The results revealed that the blockade of both OX1 and OX2 receptors within the VTA reduced the expression of morphine-induced CPP in the sensitized rats. It is plausible that VTAs orexin receptors are involved in the development/acquisition of sensitization to morphine-induced CPP in the rats.

Up-regulation of Cav1.2 subunit via facilitating trafficking induced by Vps34 on morphine-induced place preference in mice

In the present study, we investigated the role of Vps34, a kinase classified into PI 3-kinase class III, in the brain of mouse after repeated in vivo treatment with morphine. The intracerebroventricular (i.c.v.) administration of nifedipine caused a dose-dependent inhibition of morphine-induced place preference. The protein levels of Vps34 in the frontal cortex including the cingulate cortex and the limbic forebrain including the nucleus accumbens significantly increased in morphine-induced place preference. I.c.v. administration of PI 3-kinase inhibitors such as wortmannin and LY294002 inhibited morphine-induced place preference in a dose-dependent manner. Cav1.2 protein level of L-type voltage-dependent calcium channels significantly increased in the frontal cortex and the limbic forebrain of the morphine psychologically dependent mice, which was significantly inhibited by PI 3-kinase inhibitors. Similar changes in the expression of Cav1.2 and Vps34 proteins are found in the primary culture of cerebral cortical neurons during short-term exposure to morphine. Under such conditions, facilitated translocation of Cav1.2 to the plasma membrane remarkably increased by the treatment of the cultured neurons with morphine when measuring protein level of Cav1.2, and such changes in Cav1.2 were also suppressed by PI 3-kinase inhibitors. These findings indicate a critical role of Vps34 in the up-regulation of Cav1.2 in the neuronal plasma membrane and the development of morphine-induced place preference.

Suppression of morphine-induced conditioned place preference by l-12-chloroscoulerine, a novel dopamine receptor ligand

The effect of l-12-chloroscoulerine ( l-CSL), a novel ligand with dual dopamine D 1 receptor agonistic and D 2 receptor antagonistic actions, on the development of morphine-induced conditioned place preference (CPP) was investigated in mice. Morphine (10 mg/kg)-induced place preference was dose dependently suppressed by coadministration of l-CSL (5, 10 and 20 mg/kg), which induced neither place preference nor place aversion when administered alone at a dose of 20 mg/kg. The D 1 receptor antagonist SCH23390 (0.1 mg/kg) suppressed, whereas the D 2 receptor agonist (±)-2-( N-phenylethyl- N-propyl)-amino-5-hydroxytetralin (PPHT) (0.5 mg/kg) had no influence on the development of morphine-induced place preference. However, SCH23390 (0.1 mg/kg) did not affect, whereas PPHT (0.5 mg/kg) reversed the suppressive effect of l-CSL on the development of morphine-induced place preference. These results indicate that l-CSL suppresses the development of place preference of morphine by blocking D 2 receptors.

Molecular evidence for the involvement of NR2B subunit containing N-methyl- d-aspartate receptors in the development of morphine-induced place preference

The present study was designed to clarify the role of the NR1, NR2A and NR2B subunits of N-methyl- d-aspartate receptors in the development of morphine-induced place preference using specific antibodies to N-methyl- d-aspartate receptor subunits in the mouse. An i.c.v. injection with specific antibodies against the carboxyl-terminal region of either NR1, NR2A or NR2B subunits caused the attenuation of seizures induced by i.v. infusion of N-methyl- d-aspartate in the mouse. Using western blotting, NR1, NR2A and NR2B subunits were found to be highly expressed in the cerebral cortex and hippocampus of the mouse brain, which are key areas in producing seizures regulated by N-methyl- d-aspartate receptors. These findings indicate that all three subunits of the N-methyl- d-aspartate receptor in these areas are likely to be critical for the seizure induced by i.v. infusion of N-methyl- d-aspartate. Furthermore, present data provide evidence that these antibodies when given into the brain specifically act on the target sites, resulting in the blockade of the respective N-methyl- d-aspartate receptor subunit. Under these conditions, i.c.v. treatment with the antibody against NR2B subunits abolished the morphine-induced place preference, whereas antibodies against NR1 and NR2A subunits did not affect the rewarding effect of morphine. Furthermore, the NR2B subunit protein was specifically up-regulated in the limbic forebrain of morphine-conditioned mice, whereas the protein levels of either NR1 or NR2A subunits were not altered. From these results, we suggest that the stimulation of the carboxyl-terminal region of NR2B subunits in the limbic forebrain may contribute to the development of morphine-induced rewarding effect.