Amphetamine reward in food restricted mice lacking the melanin-concentrating hormone receptor-1.

Chronic food restriction (FR) and maintenance of low body weight have long been known to increase the rewarding and motor-activating effects of addictive drugs. However, the neurobiological mechanisms through which FR potentiates drug reward remain largely unknown. Melanin-concentrating hormone (MCH) signaling could be one of these mechanisms since this peptide is involved in energy homeostasis and modulates mesolimbic dopaminergic transmission. The purpose of the present study was to test this hypothesis by investigating the impact of FR on amphetamine reward in wild-type (WT) and knockout mice lacking the melanin-concentrating hormone receptor-1 (MCHR1-KO). The rewarding effects of amphetamine (0.75-2.25 mg/kg, i.p.) were measured with the conditioned place preference (CPP) technique. The food of the mice was restricted to maintain their body weight at 80-85% of their free-feeding (FF) weight throughout the entire CPP experiment. Locomotor activity of the animals was recorded during the conditioning sessions. Our results show that locomotion of all the food-restricted mice treated with saline or amphetamine increased over the sessions whatever the genotype. On the place preference test, the amplitude of CPP induced by 0.75 mg/kg amphetamine was higher in food restricted WT mice than in free-fed WT mice and food restricted MCHR1-KO mice. However, FR did not affect amphetamine reward in MCHR1-KO mice. The present results indicate that MCH signaling could be involved in the ability of FR to increase amphetamine-induced CPP.

Amphetamine- and cocaine-induced conditioned place preference and concomitant psychomotor sensitization in mice with genetically inactivated melanin-concentrating hormone MCH(1) receptor.

The melanin-concentrating hormone MCH(1) receptor has been proposed to exert an inhibitory control on monoaminergic (especially dopaminergic) activity within the mesolimbic system, which underpins drug seeking and reward. That hypothesis predicts that an inactivation of these receptors should enhance the sensitivity to drug rewarding effects. To test that prediction, we examined the propensity of mice lacking the melanin-concentrating receptor (MCH(1) KO) and their intact counterparts (WT) to form cocaine- and amphetamine-induced conditioned place preference. The conditioned rewarding effects induced by 0.375, 0.75, 1.5 and 3 mg/kg amphetamine were assessed in two sub-experiments and those induced by 1, 2, 4 and 8 mg/kg cocaine in two other sub-experiments. All mice were tested under saline for place preference 24 h following four every-other-day conditioning trials and an initial pre-conditioning session under saline. Most of the cocaine and amphetamine doses induced place preference, but without any genotype difference being revealed. Also, none of the cocaine doses induced psychomotor sensitization during conditioning, whereas amphetamine generated clear-cut dose-dependent sensitization in both genotypes. Albeit MCH(1) KO mice exhibited higher levels of psychomotor activation, the rates of sensitization were comparable across genotypes at 1.5 and 3 mg/kg amphetamine. Moreover, 0.375 and especially 0.75 mg/kg amphetamine produced a slight but yet significant sensitization in MCH(1) KO but not in their WT counterparts. Despite such an effect, the results cannot be considered as unambiguously supportive of the tested prediction.

Deletion of Melanin-Concentrating Hormone Receptor-1 gene accentuates D-amphetamine-induced psychomotor activation but neither the subsequent development of sensitization nor the expression of conditioned activity in mice.

The present study aimed to test the hypothesis that mice lacking the MCHR1 receptor (Melanin-Concentrating Hormone Receptor-1) present an elevated vulnerability towards the neurobehavioural effects of D-amphetamine, presumably due to previously established up-regulations of dopamine D1 receptors in these mice. We examined the psychomotor effects of five once-daily injections of 1.5 and 3 mg/kg D-amphetamine (i.p.) or ten once-daily injections of 2.25 mg/kg D-amphetamine in knockout (KO) mice lacking the MCHR1 receptor. The first injection of D-amphetamine induced a greater psychomotor response amongst the KO mice at 2.25 and 3.0 mg/kg. On all subsequent d-amphetamine injections, KO mice still showed greater levels of psychomotor activity than the WT mice, but with no between-genotype difference in the rate of development of sensitization (similar slopes of the curves). Furthermore, 24 h after the last injection of 2.25 mg/kg D-amphetamine both genotypes exhibited a significant post-sensitization conditioned activity. Thus, MCHR1 receptors are likely not deeply involved in the mechanisms of induction of sensitization and related conditioned activity induced by D-amphetamine, albeit our results confirm a contribution of these receptors to the mechanisms of the acute effects of that drug, possibly via an inhibitory action on the dopaminergic mesolimbic system. Our results do not support the hypothesis of a functional contribution of MCHR1 receptors to the addictive effects of D-amphetamine.

Mice lacking the melanin-concentrating hormone receptor-1 exhibit an atypical psychomotor susceptibility to cocaine and no conditioned cocaine response.

The present study aimed at characterizing the acute and intermittent psychomotor responsiveness to cocaine in mice lacking the MCHR1 receptor, which is thought to modulate the mesocorticolimbic sytem functioning [Smith DG, Tzavara ET, Shaw J, Luecke S, Wade M, Davis R, et al. Mesolimbic dopamine super-sensitivity in melanin-concentrating hormone-1 receptor deficient mice. J Neurosci 2005;25:914-22]. On a first free-drug session, MCHR1-deficient mice exhibited significantly higher levels of locomotor activity elicited by the novelty of the test chambers than their wild-type counterparts. On the following day session, a first injection of 6 or 12 mg/kg cocaine induced comparable dose-related psychomotor activations in both genotypes, without significant difference in the relative increase in locomotion. Over the following eight once-daily test sessions, the slight psychomotor increase induced by 6 mg/kg was equivalent in both genotypes and constant over the sessions. At 12 mg/kg, cocaine induced a clear-cut incremental responsiveness to cocaine in both genotypes on the three first sessions; on the following sessions, only the wild-types displayed an incremental responsiveness until the last session, a sensitized effect that was confirmed for the wild-types but not for the knockouts on a subsequent sensitization test (cocaine challenge). Finally, the knockouts did not exhibit any sign of cocaine-conditioning (saline challenge), contrarily to the wild-types. It is speculated that MCHR1 may contribute to the neurobiological mechanisms of conditioned cocaine-induced psychomotor effects, possibly to those underpinning sensitization, and to a lesser extent to those sub-serving acute pharmacological cocaine action.

Disrupting the melanin-concentrating hormone receptor 1 in mice leads to cognitive deficits and alterations of NMDA receptor function.

In order to investigate the physiological properties of the melanin-concentrating hormone (MCH) we have generated and used mice from which the MCH receptor 1 gene was deleted (MCHR1(Neo/Neo) mice). Complementary experimental approaches were used to investigate alterations in the learning and memory processes of our transgenic model. The ability of the knockout strain to carry out the inhibitory passive avoidance test was found to be considerably impaired although no significant differences were observed in anxiety levels. This impaired cognitive property prompted us to explore modifications in N-methyl D-aspartate (NMDA) responses in the hippocampus. Intracellular recordings of CA1 pyramidal neurons in hippocampal slices from the MCHR1(Neo/Neo) mice revealed significantly decreased NMDA responses. Finally, using in situ hybridization we found a 15% reduction in NMDAR1 subunit in the CA1 region. These results show for the first time a possible role for MCH in the control of the function of the NMDA receptor.