Hippocampal α5-GABAA Receptors Modulate Dopamine Neuron Activity in the Rat Ventral Tegmental Area

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

“…Further, intra-vHipp administration of GL-II-73, a selective α5-GABA A R PAM, reversed the effects of IS on dopamine neuron population activity and PPI, suggesting that α5-GABA A Rs may be a novel target for treating PTSD and comorbid psychosis. Although administration of GL-II-73 did produce a statistically significant change in the burst firing activity of VTA dopamine neurons, we do not believe this to be physiologically relevant because our previous work demonstrates that multiple α5-GABA A R PAMs ( Perez et al, 2022 ), or other hippocampal manipulations ( Perez et al, 2013 ; Perez and Lodge, 2013 , 2018 ), do not consistently alter burst firing. Indeed, previous studies have established that burst firing is largely independent of hippocampal activity and mediated by other regions, such as the laterodorsal tegmental nucleus and pedunculopontine tegmental nucleus ( Floresco et al, 2003 ; Lodge and Grace, 2006a ; Grace and Gomes, 2019 ).…”

“…Even if overexpression produced functional receptors, it has been shown that α5-GABA A R localization (extrasynaptic vs synaptic) is highly dynamic ( Loebrich et al, 2006 ; Hausrat et al, 2015 ; Davenport et al, 2021 ), and overexpression may shunt α5-GABA A R receptors, the majority of which are found extrasynaptically, into the synapse. This relocation is relevant to the work done here because we previously published data that suggest that targeting extrasynaptic, but not synaptic, GABA A Rs in the vHipp can restore aberrant dopamine system function ( Donegan et al, 2019 ; Perez et al, 2022 ). Although we did not measure inhibitory currents in the vHipp in this study, we previously observed an increase in tonic inhibition following transfection with the same vector and protocol utilized here, suggesting that this overexpression approach yields functional, extrasynaptic α5-GABA A Rs ( Donegan et al, 2019 ).…”

“…This is particularly exciting for the treatment of PTSD because comorbid depression and anxiety as well as cognitive deficits are commonly present in this disorder ( Brady et al, 2000 ; Quinones et al, 2020 ). In combination with its robust effects on dopamine neuron activity and PPI, it appears that GL-II-73 may be beneficial for treating multiple comorbidities associated with PTSD as well as other psychiatric disorders ( Prevot et al, 2019 , 2020 ; Perez et al, 2022 ).…”

“…GL-II-73 or vehicle (85% H 2 0, 14% propylene glycol, 1% Tween80) was administered directly into the vHipp (100 ng/uL; 0.75 µL; AP −5.3, ML ± 5.0, DV −6.0 mm from bregma) 20 minutes prior to electrophysiology or behavior. This dose and timing was selected based on previous characterization ( Prevot et al, 2019 ) as well as our own data ( Perez et al, 2022 ). Although systemic administration would be a more therapeutically relevant approach, we chose intra-vHipp administration because rats seem to rapidly metabolize this compound (Prevot et al, unpublished observations).…”

“…Deficits in α5 expression have been noted in animal models of psychosis ( Kiemes et al, 2021 ), and knockdown of α5-GABA A Rs in otherwise healthy animals has been shown to induce psychosis-like deficits in sensorimotor gating, as measured by prepulse inhibition (PPI) ( Hauser et al, 2005 ). Furthermore, overexpression of the α5 subunit in the vHipp ( Donegan et al, 2019 ) or administration of an α5-GABA A R PAM ( Gill et al, 2011 ; Perez et al, 2022 ) can reverse dopamine system dysfunction and behavioral deficits associated with psychosis in a model used to study schizophrenia. These studies provide preclinical evidence that targeting α5-GABA A Rs may represent an effective treatment for psychosis.…”