Prodepressant- and anxiogenic-like effects of serotonin-selective, but not noradrenaline-selective, antidepressant agents in mice lacking α2-containing GABAA receptors

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 8 mg/kg fluoxetine or 53 mg/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.

Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions

“…In this same study, subchronic treatment with desipramine had no effect ( Shen et al, 2010 ), suggesting that this drug acts over time to balance GABAergic inhibition deficits. In another study, chronic fluoxetine treatment induced pro-depressive and anxiogenic-like effects in γ2+/- mice ( Benham et al, 2017 ), pointing to a requirement of GABA A -containing γ2 subunit in the antidepressant effect of SSRIs. Interestingly, studies reported that fluoxetine can act directly as an allosteric modulator of GABA A receptors ( Robinson et al, 2003 ).…”

An Emerging Circuit Pharmacology of GABAA Receptors

“…Global heterozygous knockdown of the γ2 subunit leads to impaired GABAergic signaling [11 ], as well as anxiety- and despair-like behavior that is reversed with chronic desipramine (but not fluoxetine) [127] and acute ketamine [126] treatment. More recently it was demonstrated that global knockdown of the α2 subunit also leads to anxiety- and despair-like behavior [9], and that in these mice sensitivity to anxiogenic-and prodepressant-like effects with chronic fluoxetine treatment is increased [128]. Studies in post-partum female mice demonstrated that decreases in the δ subunit lead to increased anxious- and depressive-like behavior as well as maternal neglect, while the δ subunit preferring agonist gaboxadol improved maternal care [129].…”

Early-life adversity selectively impairs α2-GABAA receptor expression in the mouse nucleus accumbens and influences the behavioral effects of cocaine

“…Consequently, such mice may provide an insight into how genetic variations and the environment interact to perturb brain circuitry, thereby predisposing to substance abuse, but also to influence other psychological disorders such as anxiety and depression. ( Low et al, 2000 , Dixon et al, 2008 , Benham et al, 2017 ).…”