Background GPR88 is an orphan G protein coupled receptor (GPCR) highly enriched in the striatum, and previous studies have focused on GPR88 function in striatal physiology. The receptor is also expressed in other brain areas and here we examined whether GPR88 function extends beyond striatal-mediated responses. Methods We created Gpr88 knockout mice and examined both striatal and extra-striatal regions at molecular and cellular levels. We also tested striatum, hippocampus- and amygdala-dependent behaviors in Gpr88−/− mice using extensive behavioral testing. Results We found increased G protein coupling for delta (DOR) and mu opioid, but not other Gi/o coupled receptors, in the striatum of Gpr88 knockout mice. We also found modifications in gene transcription, dopamine and serotonin contents, and dendritic morphology inside and outside the striatum. Behavioral testing confirmed striatal deficits (hyperactivity, stereotypies, motor impairment in rotarod). In addition, mutant mice performed better in spatial tasks dependent on hippocampus (Y-maze, novel object recognition, dual solution cross-maze) and also showed markedly reduced levels of anxiety (elevated plus maze, marble burying, novelty suppressed feeding). Strikingly, chronic blockade of DOR using naltrindole partially improved motor coordination, and normalized spatial navigation and anxiety of Gpr88−/− mice. Conclusion We demonstrate that GPR88 is implicated in a large repertoire of behavioral responses that engage motor activity, spatial learning and emotional processing. Our data also reveal functional antagonism between GPR88 and DOR activities in vivo. The therapeutic potential of GPR88 therefore extends to cognitive and anxiety disorders, possibly in interaction with other receptor systems.

The etiology of Autism Spectrum Disorders (ASDs) remains largely unknown. Identifying vulnerability genes for autism represents a major challenge in the field and allows the development of animal models for translational research. Mice lacking the mu opioid receptor gene (Oprm1 À / À ) were recently proposed as a monogenic mouse model of autism, based on severe deficits in social behavior and communication skills. We confirm this hypothesis by showing that adult Oprm1 À / À animals recapitulate core and multiple comorbid behavioral symptoms of autism and also display anatomical, neurochemical, and genetic landmarks of the disease. Chronic facilitation of mGluR4 signaling, which we identified as a novel pharmacological target in ASDs in these mice, was more efficient in alleviating behavioral deficits than the reference molecule risperidone. Altogether, our data provide first evidence that disrupted mu opioid receptor signaling is sufficient to trigger a comprehensive autistic syndrome, maybe through blunted social reward processes, and this mouse model opens promising avenues for therapeutic innovation.

Background-Opiate abuse is a chronic relapsing disorder and maintaining prolonged abstinence remains a major challenge. Protracted abstinence is characterized by lowered mood and clinical studies show elevated co-morbidity between addiction and depressive disorders. At present, their relationship remains unclear and has been little studied in animal models. Here we investigated emotional alterations during protracted abstinence, in mice with a history of chronic morphine exposure.

Melatonin, an important marker of the endogenous rhythmicity in mammals, also plays a role in the body defence against pathogens and injuries. In vitro experiments have shown that either pro- or anti-inflammatory agents, acting directly in the organ, are able to change noradrenaline-induced pineal indoleamine production. Whereas corticosterone potentiates melatonin production, incubation of the gland with tumour necrosis factor-alpha decreases pineal hormonal production. In the present study, we show that nocturnal melatonin production measured by intra-pineal microdialysis is enhanced in pineals perfused with corticosterone at concentrations similar to those measured in inflamed animals. In vitro experiments suggest that this enhancement may be due to an increase in the activity of the two enzymes that convert serotonin to N-acetylserotonin (NAS) and NAS to melatonin. The present results support the hypothesis that the pineal gland is a sensor of inflammation mediators and that it plays a central role in the control of the inflammatory response.

No abstract

The main mammalian circadian clock, localized in the suprachiasmatic nuclei can be synchronized not only with light, but also with serotonergic activation. Serotonergic agonists and serotonin reuptake inhibitors (e.g., fluoxetine) have a nonphotic influence (shifting effects during daytime and attenuation of photic resetting during nighttime) on hamsters' and mice' main clock. Surprisingly, in rats serotonergic modulation of the clock shows essentially photic-like features in vivo (shifting effects during nighttime). To delineate this apparent paradox, we analyzed the effects of fluoxetine and serotonin agonists on rats' clock. First, fluoxetine induced behavioral phase-advances associated with down-regulated expression of the clock genes Per1 and Rorb and up-regulated expression of Rev-erba during daytime. Moreover, fluoxetine produced an attenuation of light-induced phase-advances in association with altered expression of Per1, Per2 and Rorb during nighttime. Second, we showed that 5-HT 1A receptors -maybe with co-activation of 5-HT 7 receptors-were implicated in non-photic effects on the main clock. By contrast, 5-HT 3 and 5-HT 2C receptors were involved in photic-like effects and, for 5-HT 2C subtype only, in potentiation of photic resetting. Thus this study demonstrates that as for other nocturnal rodents, a global activation of the serotonergic system induces non-photic effects in the rats' clock during daytime and nighttime.

No abstract

Under special restricted feeding conditions the mammalian circadian clock, contained in the hypothalamic suprachiasmatic nucleus (SCN), can be entrained by food. During food restriction, hungry animals are very motivated to obtain food. This motivational state could be a key component in altering the SCN timing by feeding. In order to comprehend how hedonic signals of food affect the SCN clock, we evaluated the effects of a daily palatable snack on the behavioural rhythm of mice fed ad libitum with regular food, and housed under constant darkness conditions. As light synchronization of the SCN is modulated by feeding/metabolic cues, the effects of a palatable meal coupled to a light pulse were tested on behavioural and molecular rhythms. A daily palatable snack entrained behavioural rhythms of mice in constant darkness conditions. Furthermore, palatable meal access at the activity onset reduced light-induced behavioural phase-delays and Period genes expression in the SCN. In addition, an increase in the dopamine content and Period genes expression in the forebrain of mice was observed, concomitant with a c-FOS activation in dopaminergic and orexinergic neurons, suggesting that the effects of a palatable snack on the SCN clock are mediated by the reward/arousal central systems. In conclusion, this study establishes an underlying sensitivity of the master circadian clock to changes in motivational states related to palatable food intake.