VU0155041, a positive allosteric modulator of mGluR4, in the nucleus accumbens facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats.

Nucleus accumbens (NAc) neurons appear to be at the hub of the reward circuit. New evidence suggests that the behavioural effects of morphine substances may be significantly regulated by glutamate-mediated transmission, notably by metabotropic glutamate (mGlu) receptors. Here, we examined the hypothesis that the mGlu4 receptor within that NAc has a role in the extinction and reinstatement of morphine-induced conditioned place preference (CPP). The animals received bilaterally microinjections of VU0155041, a positive allosteric modulator (PAM) and partial agonist of mGlu4 receptor, into the NAc. In Experiment 1, the rats received VU0155041 (10, 30 and 50 µg/0.5 µL) during the extinction period. In Experiment 2, the CPP extinguished rats received VU0155041 (10, 30 and 50 µg/0.5 µL) five minutes prior to the administration of morphine (1 mg/kg) in order to reinstate the extinguished CPP. The results showed that the intra-accumbal administration of VU0155041 reduced the extinction period of CPP. Furthermore, the administration of VU0155041 into the NAc dose-dependently inhibited the reinstatement of CPP. The findings suggested that the mGluR4 in the NAc facilitates the extinction and inhibits the reinstatement of the morphine-induced CPP, which could be mediated by an increase in the release of extracellular glutamate.

Effect of ramosetron, a 5-HT3 receptor antagonist on the severity of seizures and memory impairment in electrical amygdala kindled rats.

The entorhinal cortex (EC) plays a pivotal role in epileptogenesis and seizures. EC expresses high density of serotonergic receptors, especially 5-HT3 receptors. Cognitive impairment is common among people with epilepsy. The present study investigated the role of 5-HT3 receptor on the severity of seizures and learning and memory impairment by electrical kindling of amygdala in rats. The amygdala kindling was conducted in a chronic kindling manner in male Wistar rats. In fully kindled animals, ramosetron (as a potent and selective 5-HT3 receptor antagonist) was microinjected unilaterally (ad doses of 1, 10 or 100 µg/0.5 µl) into the EC 5 min before the novel object recognition (NOR) and Y-maze tests or kindling stimulations. Applying ramosetron at the concentration of 100 µg/0.5 µl (but not at 1 and 10 µg/0.5 µl) reduced afterdischarge (AD) duration and increased stage 4 latency in the kindled rats. Moreover, the obtained data from the NOR test showed that treatment by ramosetron (10 and 100 µg/0.5 µl) increased the discrimination index in the fully kindled animals. Microinjection of ramosetron (10 and 100 µg/0.5 µl) in fully kindled animals reversed the kindling induced changes in the percentage of spontaneous alternation in Y-maze task. The findings demonstrated an anticonvulsant role for a selective 5-HT3 receptor antagonist microinjected into the EC, therefore, suggesting an excitatory role for the EC 5-HT3 receptors in the amygdala kindling model of epilepsy. This anticonvulsive effect was accompanied with a restoring effect on cognitive behavior in NOR and Y-maze tests.

The role of mGlu4 receptors within the nucleus accumbens in acquisition and expression of morphine-induced conditioned place preference in male rats.

BACKGROUND: Several studies have shown that glutamate neurotransmission in the nucleus accumbens (NAc) is required for the development of morphine-induced conditional place preference (CPP). In addition, metabotropic glutamate receptors (mGluRs) in NAc play important roles in the reward pathways. However, the precise role of mGluR4 in different steps of the morphine-induced CPP is less well known. In the present study the effect of bilateral intra-accumbal infusion of VU0155041, as a specific mGluR4 agonist on the acquisition and expression of morphine induced CPP in male Wistar rats was investigated. The animals were bilaterally implanted with guide cannulae above the NAc. In the first step of the study, the VU0155041 was administered at doses of 10, 30 and 50 µg/0.5 µL saline per side into the NAc during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase of morphine-induced CPP. In the second step of the study, the rats bilaterally received VU0155041 at the dose of 50 µg/0.5 µL, 5 min before the post-conditioning test in order to check the effect of VU0155041 on the expression of morphine-induced CPP. RESULTS: The results showed that the intra-accumbal injection of VU0155041 inhibits the acquisition of morphine-induced CPP in a dose dependent manner, but had no effect on expression. CONCLUSIONS: The data indicated that intra-NAc administration of VU0155041 dose dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine. These effects may be related to changes in glutamate activity in the NAC and/or learning dependent mechanism of glutamate neurotransmission in reward pathway(s).

The effect of the mGlu8 receptor agonist, (S)-3,4-DCPG on acquisition and expression of morphine-induced conditioned place preference in male rats.

BACKGROUND: The nucleus accumbens (NAc) plays a principal role in drug reward. It has been reported that metabotropic glutamate receptors (mGlu receptors) play a key role in the rewarding pathway(s). Previous studies have shown the vast allocation of the different types of mGlu receptors, including mGlu8 receptors, in regions that are associated with opioid rewards, such as the NAc. The aim of the present study was to evaluate the role of mGlu8 receptors within the NAc in the acquisition and expression phases of morphine induced conditioned place preference (CPP). Adult male Wistar rats were bilaterally implanted by two cannulas' in the NAc and were evaluated in a CPP paradigm. Selective mGlu8 receptor allosteric agonist (S-3,4-DCPG) was administered at doses of 0.03, 0.3, and 3 µg/0.5 µL saline per side into the NAc on both sides during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase, or before place preference test, or post-conditioning (expression) phase of morphine-induced CPP. RESULTS: The results revealed that intra-accumbal administration of S-3,4-DCPG (0.3 and 3 µg) markedly decreased the acquisition in a dose-dependent manner but had no effect on expression of morphine-induced CPP. CONCLUSIONS: The findings suggest that activation of mGlu8 receptors in the NAc dose-dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine which may be related to the glutamate activity into the NAc and in reward pathway(s). These data suggest that mGlu8 receptor may be involved in conditioned morphine reward.