Dysregulation of the mesolimbic dopamine system and reward in MCH-/- mice.
BACKGROUND
The hypothalamic neuropeptide melanin-concentrating hormone (MCH) plays a critical role in energy homeostasis. Abundant expression of the MCH receptor is observed outside the hypothalamus, especially in the dorsal and the ventral striatum, raising the possibility that MCH modulates the function of the midbrain dopamine neurons and associated circuitry.


METHODS
The MCH receptor 1 (MCHR1) expression was assessed by in situ hybridization. Expression of dopamine transporter (DAT) and the dopamine D1 and D2 receptor (D1R and D2R) subtypes in the caudate-putamen (CPu) and the nucleus accumbens (Acb) was evaluated by immunoblotting. Amperometry in ex vivo slices of the Acb was used to measure evoked-dopamine release in MCH-/ - mice. Catalepsy in MCH+/+ and MCH-/- mice was assessed by the bar test after haloperidol injection. Locomotor activity was measured after acute and chronic treatment with amphetamine and after dopamine reuptake inhibitor GBR 12909 administration.


RESULTS
The psychostimulant amphetamine caused enhanced behavioral sensitization in MCH-/- mice. We found significantly elevated expression of the DAT in the Acb of MCH-/- mice. The DAT-mediated uptake of dopamine was also enhanced in MCH-/- mice consistent with increased expression of DAT. We also found that evoked dopamine release is significantly increased in the Acb shell of MCH-/- mice. The GBR 12909 administration increased the locomotor activity of MCH-/- mice significantly above that of MCH+/+ mice.


CONCLUSIONS
These results demonstrate that MCH, in addition to its known role in feeding and weight regulation, plays a critical role in regulating Acb dopamine signaling and related behavioral responses.
Pissios
Pavlos
P
Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. ppissios@bidmc.harvard.edu
Frank
Lauren
L
Kennedy
Adam R
AR
Porter
Douglas R
DR
Marino
Francis E
FE
Liu
Fen-Fen
FF
Pothos
Emmanuel N
EN
Maratos-Flier
Eleftheria
E
D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002375:Catalepsy / Q000139:chemically induced / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology; D066298:In Vitro Techniques; D008032:Limbic System / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D011863:Radioimmunoassay / Q000379:methods; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000172:deficiency*; D012201:Reward
D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; C491209:Mchr1 protein, mouse; D010879:Piperazines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D017481:Receptors, Somatostatin; C043425:vanoxerine; D000661:Amphetamine; D006220:Haloperidol; D004298:Dopamine