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Behavioral and biochemical responses to d‐ amphetamine in MCH 1 receptor knockout mice
Author(s) -
Smith Daniel G.,
Qi Hongshi,
Svenningsson Per,
Wade Mark,
Davis Richard J.,
Gehlert Donald R.,
Nomikos George G.
Publication year - 2008
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20473
Subject(s) - amphetamine , striatum , dopaminergic , creb , medicine , endocrinology , dopamine , sensitization , chemistry , conditioned place preference , ventral tegmental area , receptor , mapk/erk pathway , pharmacology , phosphorylation , biology , neuroscience , biochemistry , transcription factor , gene
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. Synapse 62:128–136, 2008. © 2007 Wiley‐Liss, Inc.