No abstract

Background Up to 64% of patients diagnosed with PTSD experience psychosis, likely attributable to aberrant dopamine neuron activity. We have previously demonstrated that positive allosteric modulators of α5-GABAARs (α5-PAMs) can selectively decrease hippocampal activity and reverse psychosis-like physiological and behavioral alterations in a rodent model used to study schizophrenia; however, whether this approach translates to a PTSD model remains to be elucidated. Methods We utilized a two-day inescapable foot shock (IS) procedure to induce stress-related pathophysiology in male Sprague-Dawley rats. We evaluated the effects of intra-vHipp administration GL-II-73, an α5-PAM, or viral overexpression of the α5 subunit, using in vivo electrophysiology and behavioral measures in control and IS-treated rats. Results IS significantly increased ventral tegmental area (VTA) dopamine neuron population activity (n=6; p = 0.016), the number of dopamine neurons firing spontaneously, consistent with observation in multiple rodent models used to study psychosis. IS also induced deficits in sensorimotor gating, as measured by reduced prepulse-inhibition of startle (n=12; p = 0.039). Interestingly, intra-vHipp administration of GL-II-73 completely reversed IS-induced increases in dopamine neuron population activity (n=6; p=0.024), and deficits in PPI (n=8; p=0.025) whereas viral overexpression of the α5 subunit in the vHipp was not effective. Conclusions Our results demonstrate that pharmacological intervention augmenting α5-GABAAR function, but not α5 overexpression in itself, can reverse stress-induced deficits related to PTSD in a rodent model, providing a potential site of therapeutic intervention to treat comorbid psychosis in PTSD.