Positive Allosteric Modulation of α5-GABAA Receptors Reverses Stress-Induced Alterations in Dopamine System Function and Prepulse Inhibition of Startle

• Published in: The international journal of neuropsychopharmacology 2022-08, Vol.25 (8), p.688-698
• Main Authors: McCoy, Alexandra M, Prevot, Thomas D, Mian, Md Yenus, Cook, James M, Frazer, Alan, Sibille, Etienne L, Carreno, Flavia R, Lodge, Daniel J
• Format: Article
• Language: English
• Subjects: Allosteric Regulation - genetics; Allosteric Regulation - physiology; Animals; Dopamine - genetics; Dopamine - metabolism; Hippocampus; Male; Prepulse Inhibition - genetics; Prepulse Inhibition - physiology; Rats; Rats, Sprague-Dawley; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; Regular s; Stress, Psychological - genetics; Stress, Psychological - metabolism
• ISSN: 1461-1457; 1469-5111; 1469-5111
• DOI: 10.1093/ijnp/pyac035

Abstract Background Up to 64% of patients diagnosed with posttraumatic stress disorder (PTSD) experience psychosis, likely attributable to aberrant dopamine neuron activity. We have previously demonstrated that positive allosteric modulators of α5-GABAARs 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 2-day inescapable foot shock (IS) procedure to induce stress-related pathophysiology in male Sprague-Dawley rats. We evaluated the effects of intra-ventral hippocampus (vHipp) administration GL-II-73, an α5-GABAAR, 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 dopamine neuron population activity, or the number of dopamine neurons firing spontaneously (n = 6; P = .016), 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 = .039). Interestingly, intra-vHipp administration of GL-II-73 completely reversed IS-induced increases in dopamine neuron population activity (n = 6; P = .024) and deficits in prepulse inhibition (n = 8; P = .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.