| Summary: | In GWAS studies, the neural adhesion molecule encoding the neuronal growth regulator 1 (<i>NEGR1</i>) gene has been consistently linked with both depression and obesity. Although the linkage between <i>NEGR1</i> and depression is the strongest, evidence also suggests the involvement of <i>NEGR1</i> in a wide spectrum of psychiatric conditions. Here we show the expression of NEGR1 both in tyrosine- and tryptophan hydroxylase-positive cells. <i>Negr1</i><sup>−/−</sup> mice show a time-dependent increase in behavioral sensitization to amphetamine associated with increased dopamine release in both the dorsal and ventral striatum. Upregulation of transcripts encoding dopamine and serotonin transporters and higher levels of several monoamines and their metabolites was evident in distinct brain areas of <i>Negr1</i><sup>−/−</sup> mice. Chronic (23 days) escitalopram-induced reduction of serotonin and dopamine turnover is enhanced in <i>Negr1</i><sup>−/−</sup> mice, and escitalopram rescued reduced weight of hippocampi in <i>Negr1</i><sup>−/−</sup> mice. The current study is the first to show alterations in the brain monoaminergic systems in <i>Negr1</i>-deficient mice, suggesting that monoaminergic neural circuits contribute to both depressive and obesity-related phenotypes linked to the human <i>NEGR1</i> gene.
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