SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake

Abstract

Brain principal glutamatergic neurons synthesize 3alpha-hydroxy-5alpha-pregnan-20-one (Allo), a neurosteroid that potently, positively, and allosterically modulates GABA action at GABA(A) receptors. Cerebrospinal fluid (CSF) Allo levels are decreased in patients with posttraumatic stress disorder (PTSD) and major depression. This decrease is corrected by fluoxetine in doses that improve depressive symptoms. Emotional-like behavioral dysfunctions (aggression, fear, and anxiety) associated with a decrease of cortico-limbic Allo content can be induced in mice by social isolation. In socially isolated mice, fluoxetine and analogs stereospecifically normalize the decrease of Allo biosynthesis and improve behavioral dysfunctions by a mechanism independent from 5-HT reuptake inhibition. Thus, fluoxetine and related congeners facilitate GABA(A) receptor neurotransmission and effectively ameliorate emotional and anxiety disorders and depression by acting as selective brain steroidogenic stimulants (SBSSs).

Fig. 1

Simplified cortical circuitry that depicts the action of Allo on GABA_A receptors (GR) expressed on the cell body, dendrites, or axon hillocks of a pyramidal neuron. Allo is synthesized in pyramidal neurons by the action of 5α-R-type I and 3α-HSD. Allo diffuses (indicated by ) to cell membranes and facilitates the action of GABA at synaptic and extrasynaptic GABA_A receptors. , denotes Allo biosynthesis downregulation in pyramidal neurons of socially isolated mice. , denotes a decrease of Allo levels reaching synaptic or extrasynaptic GABA_A receptors located on pyramidal neurons in socially isolated mice. GRα_xβ_x, extrasynaptic GABA_A receptors that express δ subunits.

Fig. 2

Schematic representation of the main intrinsic connections of the basolateral (BLA) and central (CeA) nuclei of the amygdala and extrinsic projections from the medial frontal cortex (mFC) (layer V/VI) and hippocampus (CA1) pyramidal neurons to the BLA. In socially isolated mice, the decrease in Allo biosynthesis in layer V/VI pyramidal glutamatergic neurons of the mFC and in pyramidal-like glutamatergic neurons of the BLA (indicated by ) downregulates the inhibitory potency of GABAergic interneurons (indicated by ) impinging on these pyramidal neurons. This Allo content decrease results in an increased excitatory output from BLA to the intercalated (ITC) neurons or to neurons of the CeA nucleus, which project to the hypothalamus (Hyp) and brain stem, enhancing fear and aggression (indicated by ). Pyramidal-like glutamatergic neurons expressing Allo Pyramidal glutamatergic neurons expressing Allo Inhibitory GABAergic interneurons Intercalated (ITC) GABAergic neuron Decreased Allo biosynthesis in mFC pyramidal and BLA pyramidal-like glutamatergic neurons Modified from Sah and Westbrook [45].

Fig. 3

The stereospecific potency of S-norfluoxetine required to stimulate Allo biosynthesis is 55 times higher than 5-HT reuptake inhibition. Data on the x-axis (potency index) represent the ratios between the EC₅₀ doses that inhibit 5-HT reuptake and the EC₅₀ doses that stimulate Allo biosynthesis. Each value is the mean of four to six socially isolated mice (data from Table 1).