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

作者：Pibiri Fabio; Nelson Marianela; Guidotti Alessandro; Costa Erminio; Pinna Graziano^*

来源：Proceedings of the National Academy of Sciences, 2008, 105(14): 5567-5572.

DOI：10.1073/pnas.0801853105

• fear conditioning
• selective brain steroiclogenic stimulants

Mice subjected to social isolation (3-4 weeks) exhibit enhanced contextual fear responses and impaired fear extinction. These responses are time-related to a decrease of 5 alpha-reductase type I (5 alpha-RI) mRNA expression 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 mu mol/kg) that increase brain Allo levels but fail to inhibit serotonin reuptake, greatly attenuates enhanced contextual fear response. SKF 105,111 (a potent 5a-RI inhibitor) decreases corticolimbic Alto levels and enhances the contextual fear response in group housed mice, which suggests that social isolation alters emotional responses by reducing the positive allosteric modulation of Alto at GABA(A) receptors in corticolimbic circuits. Thus, these procedures model emotional hyperreactivity, including enhanced contextual fear and impaired contextual fear extinction, which also is observed in posttraumatic stress disorder (PTSD) patients. A recent clinical study reported that cerebrospinal fluid Alto levels also are down-regulated in PTSD patients and correlate negatively with PTSD symptoms and negative mood. Thus, protracted social isolation of mice combined with tests of fear conditioning 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 neurosteroido-genesis may be useful in PTSD therapy.

• 出版日期2008-4-8