The blockade of serotonin (5-HT) and norepinephrine (NE) transporters in vitro and in vivo by the dual 5-HT

Amongst the SSRIs examined, only fluoxetine acutely increases extracellular concentrations of norepinephrine and dopamine as well as serotonin in prefrontal cortex, suggesting that fluoxetine is an atypical SSRI.

Melanin-concentrating hormone (MCH) neurons and MCH-1 receptors (MCH1r) densely populate mesolimbic dopaminergic brain regions such as the nucleus accumbens (NAc). The regulation of dopamine by MCH1r was suggested to be an important mechanism underlying the hyperactive phenotype of MCH1r knock-out (ko) mice. However, MCH1r modulation of monoamine neurotransmission has yet to be examined. We tested whether dopamine, norepinephrine, and serotonin function is dysregulated in MCH1r ko and wild-type

No abstract

The mammalian neuropeptide, melanin-concentrating hormone, interacts with two G protein-coupled receptors, melanin-concentrating hormone receptor (MCHR) 1 and MCHR2; however, only MCHR1 is expressed in rats and mice. In the present study, we evaluated MCHR1 antagonism in preclinical models believed to be predictive of antiobesity and antidepressant activity. Central activity of the selective MCHR1 antagonist, GW803430 [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one], was evaluated using ex vivo binding with autoradiography. Effective doses of GW803430 (1 and 3 mg/kg p.o.) were correlated with antiobesity activity in a 14-day study of diet-induced obese rats. GW803430 was evaluated subsequently for antidepressant-like effects in mice and rats. Acute and subchronic administration reduced immobility time in the mouse forced-swim test at doses of 3 (acute) and 3 and 10 (chronic) mg/kg p.o., an effect that was absent in MCHR1(-/-) mice. Combined subeffective doses of GW803430 (0.3 and 1 mg/kg p.o.) and imipramine (5 mg/kg) produced a robust antidepressant-like response. The compound was also active in the tail suspension test at a dose of 10 mg/kg p.o. GW803430 (30 mg/kg p.o.) significantly reduced submissive behaviors at weeks 2 and 3, a model of submissive behavior that may predict antidepressant onset. GW803430 decreased marble burying in mice at doses of 3, 10, and 30 mg/kg p.o., an assay that detects anxiolytic-like effects. Thus, GW803430 produces robust antiobesity and antidepressant-like effects in rats and mice at doses that compete for central MCHR1 in vivo. As such, MCHR1 should be considered as a promising target for future drug discovery efforts.