Genetic Inactivation of Melanin-Concentrating Hormone Receptor Subtype 1 (MCHR1) in Mice Exerts Anxiolytic-Like Behavioral Effects

Abstract

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.