Decreased corticolimbic allopregnanolone expression during social isolation enhances contextual fear: A model relevant for posttraumatic stress disorder.
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 5alpha-reductase type I (5alpha-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 mumol/kg) that increase brain Allo levels but fail to inhibit serotonin 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 social isolation alters emotional responses by reducing the positive allosteric modulation of Allo 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 Allo 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 neurosteroidogenesis may be useful in PTSD therapy.
Pibiri
Fabio
F
Psychiatric Institute, Department of Psychiatry, University of Illinois, 1601 West Taylor Street, Chicago, IL 60612, USA.
Nelson
Marianela
M
Guidotti
Alessandro
A
Costa
Erminio
E
Pinna
Graziano
G
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D000818:Animals; D001923:Brain Chemistry; D002540:Cerebral Cortex / Q000503:physiopathology; D005239:Fear; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation; D008032:Limbic System / Q000503:physiopathology*; D051379:Mice; D023421:Models, Animal; D011280:Pregnanolone / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012934:Social Isolation / Q000523:psychology*; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D005473:Fluoxetine; D011280:Pregnanolone; D012333:RNA, Messenger; D017367:Selective Serotonin Reuptake Inhibitors; C036139:norfluoxetine