A study of the involvement of melanin-concentrating hormone receptor 1 (MCHR1) in murine models of depression.

BACKGROUND: Most antidepressant medications target central monoamine systems and are often characterized by limited efficacies and unwanted side effects. Thus, significant efforts are ongoing to identify novel targets for the treatment of depression. Growing evidence suggests that neuropeptides play a role in the pathophysiology of depression. The melanin-concentrating hormone (MCH) is one such neuropeptide, implicated in the modulation of many physiological responses. METHODS: We utilized an array of techniques including chronic mild stress (CMS) as a depression paradigm, neurobehavior, gene expression analysis, and knockout genetics to investigate the role of MCH receptor subtype 1 (MCHR1) in murine models of depression. RESULTS: We report here that following a 5-week exposure to repeated chronic mild stress (an ethologically relevant animal model of depression), C57Bl/6J mice have increased hippocampal gene expression of MCH receptor subtype 1 (MCHR1), the cognate melanin concentrating hormone receptor in mice. This increased gene expression is reversed by chronic fluoxetine hydrochloride (Prozac) treatment. Additionally, while female and male mice carrying a null mutation of the MCHR1 gene show comparable anxiolytic-like behavior on the open field, only female knockout mice exhibit antidepressant-like behavior, when tested on the forced swim and tail suspension tests. CONCLUSION: Taken together, we suggest that antagonism of the MCHR1 receptor may provide a novel approach for the treatment of affective disorders, including depression, with a potentially increased efficacy in women.

Genetic inactivation of melanin-concentrating hormone receptor subtype 1 (MCHR1) in mice exerts anxiolytic-like behavioral effects.

The biological effects of the melanin-concentrating hormone (MCH) are mediated by the melanin concentrating hormone receptor 1 (MCHR1) in mice. This receptor is enriched in brain areas that are involved in the modulation of mood and affect, suggesting that MCH-dependent signaling may influence neurobiological mechanisms underlying fear and anxiety processes. To test this, we have generated mice lacking functional MCHR1 and characterized phenotypic traits using a number of behavioral tests. Mice carrying a null mutation of the MCHR1 gene display anxiolytic-like behavior across a battery different behavioral paradigms commonly used to assess fear and anxiety responses in rodents: open field, elevated plus maze, social interaction, and stress-induced hyperthermia. The brain serotonin (5-HT) system is central to the control of mood- and anxiety-related processes. To examine the impact of MCHR1 receptor deletion on 5-HT neurotransmission, we used in vivo microdialysis in freely moving knockout and wild-type mice. Baseline dialysate 5-HT levels were significantly lower in MCHR1 knockout mice as compared with wild-type controls (9.53+/-0.24 fmol for wild types vs 6.91+/-0.36 fmol for knockouts) in the prefrontal cortex (PFC), one of the main target structures of the serotonergic system and one that is highly associated with the control of emotional processes. Moreover, forced swim increased 5-HT efflux in the PFC of wild-type but not MCHR1 knockout mice. In summary, we show that MCHR1 can modulate stress- and anxiety-like behaviors and suggest that this may be due to changes in serotonergic transmission in forebrain regions.

Reactivation of latent bovine herpesvirus type 5 in cattle with polioencephalomalacia induced by ammonium sulphate

In the state Mato Grosso do Sul, Brazil, outbreaks of meningoencephalitis by BoHV-5 and polioencephalomalacia (PEM) display similar epidemiological features, suggesting that meningoencephalitis may be associated with reactivation of a latent BoHV-5 infection, during the development of PEM. To test this hypothesis, four 7-8 months old steers negative for BoHV-5 antibodies were inoculated intranasally with BoHV-5 and received amprolium from day 35 to day 105 after inoculation. Because PEM was not produced during this period, ammonium sulphate was given from day 114 to day 180 after inoculation. Two uninfected control steers received amprolium and ammonium sulphate for the same periods. All inoculated cattle developed antibodies against BoHV-5 after inoculation and the virus was isolated from nasal swabs, indicating that they were infected. Two inoculated steers had clinical signs of PEM after 118 and 146 days after virus inoculation. One was euthanized after a clinical manifestation period of seven days and had severe lesions of PEM and meningoencephalitis. BoHV-5 was isolated from the central nervous system of this animal. The other animal recovered but continued to manifest chronic signs of PEM and was euthanatized. On histological examination, the cerebral cortex, caudate nucleus and thalamus had multifocal areas of malacia and mild meningoencephalitis of the cortex. BoHV-5 was not isolated from the brain. One uninfected control steer had signs of neurological disease on day 158 and had lesions of PEM without meningoencephalitis at necropsy. The simultaneous production of PEM and diffuse meningoencephalitis, with isolation of BoHV-5, in one steer treated with ammonium sulphate, 118 days after BoHV-5 inoculation, suggests that latent BoHV-5 was reactivated in this animal submitted to experimental induction of PEM.

No Mato Grosso do Sul surtos de meningoencefalite por herpesvírus bovino-5 (BoHV-5) e polioencefalomalacia (PEM) apresentam características epidemiológicas semelhantes, o que sugere que a meningoencefalite pode estar associada com a reativação de uma infecção latente por BoHV-5 em animais com PEM. Para testar esta hipótese, 4 garrotes de 7-8 meses de idade, sem anticorpos séricos para BoHV-5 foram inoculados intranasal com BoHV-5 e receberam amprólio desde o dia 35 até o dia 105 após inoculação. Como não foi reproduzida PEM durante este período, os animais receberam sulfato de amônia desde o dia 114 até o dia 180 após inoculação. Dois bovinos controles, não inoculados, receberam amprólio e sulfato de amônia durante os mesmos períodos. Todos os bovinos inoculados apresentaram anti-corpos contra BoHV-5 após a inoculação e o vírus foi isolado de suabes nasais, indicando que foram infectados. Dois bovinos inoculados tiveram sinais clínicos de PEM após 118 e 146 dias da inoculação de vírus. Um que foi eutanasiado após um curso clínico de 7 dias apresentou lesões severas de PEM e meningoencefalite. BoHV-5 foi isolado do sistema nervoso central. O outro se recuperou, mas continuou a apresentar sinais crônicos de PEM. No exame histológico o córtex cerebral, núcleo caudato e tálamo apresentavam áreas multifocais de malacia e no córtex havia moderada meningoencefalite. BoHV-5 não foi isolado do encéfalo. Um garrote controle, não inoculado, apresentou sinais nervosos aos 158 dias após inoculação e na necropsia apresentava lesões de PEM, mas sem meningoencefalite. A reprodução simultânea de PEM e encefalite difusa em um animal tratado com sulfato de amônia, 118 dias após a inoculação de BoHV-5 e o re-isolamento do vírus do animal infectado sugere que a infecção latente por BoHV-5 foi reativada no animal submetido a indução experimental de PEM.