Brain-derived neurotrophic factor signalling mediates antidepressant effects of lamotrigine

Abstract

The anticonvulsant drug lamotrigine has been shown to produce antidepressant effects in patients with bipolar disorder. To date, only a few preclinical studies have been conducted using lamotrigine treatment in the forced swim test (FST), an animal model of depression with low face validity. The underlying mechanisms by which lamotrigine works have not been well characterized either. This study extends earlier work on the role of brain-derived neurotrophic factor (BDNF) in regulating the antidepressant actions of lamotrigine. We showed that in rats subjected to chronic unpredictable stress, chronic administration of 30 mg/kg lamotrigine ameliorates behavioural deficits of stressed rats in both sucrose preference test (SPT) and novelty-suppressed feeding test (NSFT). In parallel, chronic lamotrigine treatment up-regulates frontal and hippocampal BDNF protein expression in both naive and stressed animals, and restores the stress-induced down-regulation of BDNF levels. In addition, inhibition of BDNF signalling by infusion of K252a, an inhibitor of the BDNF receptor TrkB, blocks the antidepressant effects of lamotrigine in SPT, NSFT and FST. Taken together, this study provides further evidence that BDNF is an essential mediator for the antidepressant effects of lamotrigine.

Orcinol glucoside produces antidepressant effects by blocking the behavioural and neuronal deficits caused by chronic stress

“…Chronic stress and glucocorticoid administration may induce depressive effects in rats by lowering hippocampal BDNF levels (Smith et al, 1995;Hansson et al, 2003), whereas some antidepressants are reported to achieve their efficacy by increasing BDNF in the hippocampus (Li et al, 2011;Takano et al, 2012;Zhang et al, 2012). Although the underlying mechanisms remain unidentified, it has been reported that glucocorticoids can prevent synaptic function maturation through suppression of the BDNF-stimulated MAPK/ERK pathway (Kumamaru et al, 2011(Kumamaru et al, , 2008.…”

Decreased cerebrospinal fluid secretogranin II concentrations in severe forms of bipolar disorder

“…In line with this observation, previous studies have reported an upregulation of BDNF expression and secretion in response to lamotrigine treatment. 52,53 It should be noted, however, that in this crosssectional case-control study, we were not able to rule out the possibility that higher CSF concentration of SgII is associated with a subset of patients with bipolar disorder treated with lamotrigine as opposed to other medication. 54 …”

Anti-Stress Effects of Mood Stabilizers and Relevance to Their Therapeutic Actions

“…Chronic stress-induced spatial memory impairment is attenuated by chronic lithium treatment (Vasconcellos et al, 2003). Chronic or subchronic treatment with lamotrigine ameliorates behavioral parameters in stress-induced animal models of depression with concomitant restoration of stress-induced downregulation of neuroprotective proteins (N. Li et al, 2010;N. Li et al, 2011).…”