Decreased corticolimbic allopregnanolone expression during social isolation enhances contextual fear: A model relevant for posttraumatic stress disorder (2008)

Pibiri, F., Nelson, M., Guidotti, A. et al.

Abstract

Mice subjected to (3-4 weeks) exhibit enhanced contextual fear responses and impaired fear extinction. These responses are time-related to a decrease of 5alpha-reductase type I (5alpha-RI) and allopregnanolone (Allo) levels in selected neurons of the medial prefrontal cortex, hippocampus, and basolateral amygdala. Of note, the cued fear response was not different between group housed and socially isolated mice. In socially isolated mice, S-norfluoxetine, a selective brain steroidogenic stimulant (SBSS), in doses (0.45-1.8 mumol/kg) that increase brain Allo levels but fail to inhibit reuptake, greatly attenuates enhanced contextual fear response. SKF 105,111 (a potent 5alpha-RI inhibitor) decreases corticolimbic Allo levels and enhances the contextual fear response in group housed mice, which suggests that alters emotional responses by reducing the positive allosteric modulation of Allo at GABAA receptors in corticolimbic circuits. Thus, these procedures model emotional hyperreactivity, including enhanced contextual fear and impaired contextual fear extinction, which also is observed in (PTSD) patients. A recent reported that Allo levels also are down-regulated in PTSD patients and correlate negatively with PTSD symptoms and negative mood. Thus, protracted of mice combined with tests of may be a suitable model to study emotional behavioral components associated with neurochemical alterations relating to PTSD. Importantly, drugs like SBSSs, which rapidly increase corticolimbic Allo levels, normalize the exaggerated contextual fear responses resulting from social isolation, suggesting that selective activation of neurosteroidogenesis may be useful in PTSD therapy.