Behavioral and biochemical responses to d-amphetamine in MCH1 receptor knockout mice.

The melanin-concentrating hormone (MCH) system is anatomically and functionally interlaced with the mesocorticolimbic dopamine system. Therefore, we investigated whether MCH(1) receptor knockout (KO) mice are more susceptible than wild-type (WT) mice to psychostimulant-induced locomotor stimulation and sensitization, dopamine receptor-mediated phosphorylation events and c-fos expression within the frontal cortex and ventral striatum. MCH(1) receptor KO mice have 20% higher basal locomotor activity, are hypersensitive to the locomotor activating effects of d-amphetamine (1 mg/kg), and develop behavioral sensitization to a regimen of repeated d-amphetamine administration that does not induce sensitization in WT mice. In addition, d-amphetamine-mediated regulation of p44-mitogen activated protein kinase (MAPK) phosphorylation within the frontal cortex was significantly enhanced in MCH(1) receptor KO mice, when compared with WT mice. No significant genotype difference in the effects of d-amphetamine on MAPK phosphorylation events within the ventral striatum, phosphorylation at Ser(897) of the NR1 subunit of the NMDA receptor or Ca(2+) and cyclic AMP response-element binding-protein (CREB) at Ser(133) in the frontal cortex was detected. d-Amphetamine (3 mg/kg) increased c-fos expression within the frontal cortex in MCH(1) receptor KO mice, but not WT mice. There were no d-amphetamine-induced changes in c-fos expression within the ventromedial striatum in KO or WT mice. Overall, MCH(1) receptor KO mice are hypersensitive to the behavioral and molecular effects of the dopaminergic psychostimulant d-amphetamine. Increased frontal cortical MAPK phosphorylation and c-fos expression in MCH(1) receptor KO mice indicates that the MCH(1) receptor may be an important target for treating neuropsychiatric disorders characterized by frontal cortex dysfunction, including depression, attention deficit hyperactivity disorder (ADHD) and schizophrenia.