Lamotrigine inhibits basal and Na+-stimulated, but not Ca2+-stimulated, release of corticotropin-releasing hormone from the rat hypothalamus

Abstract

Corticotropin-releasing hormone (CRH) is a peptide neurotransmitter involved in the pathogenesis of anxiety and depressive disorders; CRH receptor antagonists are currently developed as anxiolytic and antidepressive agents, and several antidepressants negatively modulate CRH in the central nervous system. Originally marketed as an antiepileptic drug, lamotrigine (LTG) was subsequently shown to be effective as a mood stabilizer and an antidepressant. In this study, we used acute rat hypothalamic explants to investigate the effects of LTG on the gene expression and secretion of CRH from the hypothalamus in short-term incubation experiments. We found that LTG reduces basal CRH release in a time- and concentration-dependent manner. LTG also inhibits veratridine-stimulated, but not K+-stimulated, CRH release in 1-h experiments. Moreover, LTG tended to reduce CRH mRNA expression in 1-h experiments, regardless of whether the drug was given alone or in combination with veratridine or high K+ concentrations; such reduction achieved statistical significance after 3 h of incubation. In 1-h experiments, LTG reduces CRH release from CRH-containing neurons in the rat hypothalamus by interfering with Na+-driven secretion mechanisms. After 3-h incubations, the reduction in CRH release is also accounted for by LTG-induced decrease in CRH gene expression.