Antidepressant- Like Actions of Inhibitors of Poly(ADP-Ribose) Polymerase in Rodent Models

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The DNA base excision repair enzyme, poly(ADP-ribose) polymerase-1 (PARP1), is a multi-functional enzyme and a member of a subfamily of three PARPs that covalently build PAR polymers onto proteins to regulate their function. Drug inhibitors of PARPs have anti-cancer, anti-inflammatory, and neuroprotective effects. Recently, we reported elevated gene expression levels of PARP1 in postmortem brain tissues from donors who had an active major depressive disorder at the time of death. Since PARP1 gene expression is positively correlated with PARP1 activity, these findings indicate that elevated PARP1 activity may contribute to brain pathology associated with depressive behavior. Therefore, we speculated that drug inhibitors of PARP1 may have antidepressant properties. To determine whether a rodent model could be used to evaluate the role of PARP1 in depressive-like behaviors, rats were exposed to repeated psychological stressors (social defeat and chronic unpredictable stress) for 10 days. Anhedonia (estimated by sucrose preference) and brain PARP1 gene expression levels were measured. After stress exposure, rats exhibited significantly reduced sucrose preference and significantly higher levels of brain PARP1 gene expression. To examine potential antidepressant activity of PARP inhibitors, rats were administered PARP inhibitors or saline vehicle and were exposed to the Porsolt swim test or repeated social defeat and chronic unpredictable stress. Two PARP inhibitors were investigated, 3-aminobenzamide (3-AB) and 5-aminoisoquinolinone (5-AIQ). PARP inhibitors produced antidepressant-like effects in the Porsolt swim test similar to the common antidepressant fluoxetine by significantly decreasing immobility time and increasing latency to immobility. PARP1 inhibitors did not significantly affect locomotor activity or swim speeds, suggesting that antidepressant-like actions of these drugs were not secondary to a stimulant effect. Treatment of rats with a combination of 3-AB and fluoxetine, at low doses of these drugs that individually did not have antidepressant-like effects, significantly decreased immobility time and increased latency to immobility in the swim test. Finally, treatment of rats with 3-AB significantly increased sucrose preference and social interaction times relative to vehicle-treated control rats following repeated exposure to combined social defeat and unpredictable stress, exhibiting effects similar to fluoxetine treatment. These findings uncover PARP1 as a unique molecular target for the development of a novel class of antidepressants that could be used alone or in combination with existing antidepressants.

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