Neurosteroids reduce social isolation-induced behavioral deficits: a proposed link with neurosteroid-mediated upregulation of BDNF expression

Abstract

The pharmacological action of selective serotonin reuptake inhibitor antidepressants may include a normalization of the decreased brain levels of the brain-derived neurotrophic factor (BDNF) and of neurosteroids such as the progesterone metabolite allopregnanolone, which are decreased in patients with depression and posttraumatic stress disorders (PTSD). The allopregnanolone and BDNF level decrease in PTSD and depressed patients is associated with behavioral symptom severity. Antidepressant treatment upregulates both allopregnanolone levels and the expression of BDNF in a manner that significantly correlates with improved symptomatology, which suggests that neurosteroid biosynthesis and BDNF expression may be interrelated. Preclinical studies using the socially isolated mouse as an animal model of behavioral deficits, which resemble some of the symptoms observed in PTSD patients, have shown that fluoxetine and derivatives improve anxiety-like behavior, fear responses and aggressive behavior by elevating the corticolimbic levels of allopregnanolone and BDNF mRNA expression. These actions appeared to be independent and more selective than the action of these drugs on serotonin reuptake inhibition. Hence, this review addresses the hypothesis that in PTSD or depressed patients, brain allopregnanolone levels, and BDNF expression upregulation may be mechanisms at least partially involved in the beneficial actions of antidepressants or other selective brain steroidogenic stimulant molecules.

Keywords: 5α-reductase type I; BDNF; GABAA receptors; PTSD; aggressive behavior; allopregnanolone; anxiety; selective brain steroidogenic stimulants.

Figure 1

In the brain, allopregnanolone is synthesized from progesterone by the sequential action of: (i) 5α-reductase type I (5α-RI), which reduces progesterone into 5α-dihydroprogesterone (5α-DHP) and functions as the rate-limiting step enzyme in allopregnanolone biosynthesis; and (ii) 3α-hydroxysteroid dehydrogenase (3α-HSD), which either converts 5α-DHP into allopregnanolone (reductive reaction) or allopregnanolone into 5α-DHP (oxidative reaction). 17β-(N,N-diisopropylcarbamoyl)-androstan-3,5-diene-3-carboxylic acid (SKF 105,111) is a potent competitive 5α-RI inhibitor (Cheney et al., 1995). S-norfluoxetine stimulates the accumulation of allopregnanolone likely by targeting 3α-HSD (Griffin and Mellon, 1999). P450 scc, P450 cholesterol side-chain cleavage; 3β-HSD, 3β-hydroxysteroid dehydrogenase.

Figure 2

Allopregnanolone biosynthesis and action on GABA_A receptors located on synaptic membranes of cortical pyramidal neurons. GABA, after been released from GABAergic interneurons, binds to and activates post-synaptic and extra-synaptic GABA_A receptors. Allopregnanolone facilitates the synaptic inhibitory action of GABA at post-synaptic and extra-synaptic GABA_A receptors by a paracrine (arrow 1) or autocrine (arrow 2) mechanism or may access GABA_A receptors by acting at the intracellular sites (arrow 3) of the GABA_A receptors. Finally, allopregnanolone may affect the expression of target genes, including BDNF, directly (arrow 4) or indirectly (arrow 5) by acting at GABA_A receptors. BDNF may be released and induce rapid effects at synapses via altering ion channels, or may exert intracellular genomic actions. Modified from Pinna et al. (2008).