Prodepressant- and anxiogenic-like effects of serotonin-selective, but not noradrenaline-selective, antidepressant agents in mice lacking α2-containing GABA
Publication/Presentation Date
8-14-2017
Abstract
Deficits in neuronal inhibition via gamma-aminobutyric acid (GABA) type A receptors (GABAA-Rs) are implicated in the pathophysiology of major depressive disorder and the therapeutic effects of current antidepressant treatments, however, the relevant GABAA-R subtype as defined by its alpha subunit is still unknown. We previously reported anxiety- and depressive-like behavior in alpha2+/- and alpha2-/- mice, respectively (Vollenweider, 2011). We sought to determine whether this phenotype could be reversed by chronic antidepressant treatment. Adult male mice received 4 or 8mg/kg fluoxetine or 53mg/kg desipramine in their drinking water for four weeks before undergoing behavioral testing. In the novelty suppressed feeding test, desipramine had anxiolytic-like effects reducing the latencies to bite and to eat the pellet in both wild-type and alpha2+/- mice. Surprisingly, 4mg/kg fluoxetine had anxiogenic-like effects in alpha2+/- mice increasing latency to bite and to eat while 8mg/kg fluoxetine increased the latency to eat in both wild-type and alpha2+/- mice. In the forced swim and tail suspension tests, chronic desipramine treatment increased latency to immobility in wild-type and alpha2-/- mice. In contrast, chronic fluoxetine treatment increased immobility in alpha2-/- mice in both tasks while generally having no effect in wild-type mice. These findings suggest that in preclinical paradigms of anxiety and behavioral despair the antidepressant-like effects of desipramine are independent of alpha2-containing GABAA-Rs, while a reduction in alpha2 expression leads to an increased sensitivity to anxiogenic- and prodepressant-like effects with chronic fluoxetine treatment, pointing to a potential role of alpha2-containing GABAA-Rs in the response to serotonin-selective antidepressants.
Volume
332
First Page
172
Last Page
179
ISSN
1872-7549
Published In/Presented At
Benham, R. S., Hewage, N. B., Suckow, R. F., Engin, E., & Rudolph, U. (2017). Prodepressant- and anxiogenic-like effects of serotonin-selective, but not noradrenaline-selective, antidepressant agents in mice lacking α2-containing GABAA receptors. Behavioural brain research, 332, 172–179. https://doi.org/10.1016/j.bbr.2017.05.063
Disciplines
Medicine and Health Sciences
PubMedID
28587819
Department(s)
Fellows and Residents
Document Type
Article