GABA(A) receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress: Possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders

Protracted social isolation in laboratory animals causes stress, which induces a variety of behavioral abnormalities including increased aggressiveness, anxiety-related behaviors, cognitive deficits and hyper locomotion. Many of these disorders are similar to the symptoms found in psychiatric disorders, such as depression, anxiety, premenstrual dysphoria and posttraumatic stress disorders ( PTSD). Recent studies have demonstrated that male mice that have been socially isolated for more than 4 weeks show: (a) reduced responsiveness of GABA(A) receptors (GABA(A)- R) to the administrations of GABA mimetic drugs at GABA(A)-R; (b) downregulated biosynthesis of 3 alpha,5 alpha-tetrahydroprogesterone (3 alpha,5 alpha-THP) (allopregnanolone: ALLO), a neurosteroid with a potent positive allosteric modulatory effect on the action of GABA on GABA(A)-R; and(c) alterations in the expression of GABA(A)-R subunits (i.e. a decrease of alpha 1/alpha 2 and gamma 2 subunits and an increase of alpha 4 and alpha 5 subunits). The selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) and its congener norfluoxetine (Nor-FLX), when administered systemically at nmol/kg doses, normalize the reduced content of brain ALLO and the reduced responsiveness of GABA(A)-R to GABA mimetic drugs (i.e. pentobarbital) and also attenuate aggressive behavior in socially isolated mice in a stereospecific manner. Although these compounds inhibit ex vivo serotonin reuptake into brain tissue, their SSRI activities require high mu mol/kg dose ranges and are not stereospecific. These studies suggest that in socially isolated mice, abnormalities of GABA(A)-R signal transduction are attributable to the downregulation of ALLO production and to a switch in heteropentamericGABA(A)-R subunit assembly composition. Hence, the normalization of ALLO biosynthesis may be a new target for the development of drugs effective for psychiatric disorders related to neurosteroid biosynthesis downregulation.