The metabotropic glutamate receptor type 5 (mGlu5) and adenosine A(2A) receptor form a mutually inhibitory heteromer with the dopamine D2 receptor, where the activation of either mGlu5 or A(2A) leads to reduced D2 signaling. This study investigated whether a mGlu5-positive allosteric modulator (PAM) or an A(2A) agonist treatment could mitigate sensorimotor gating deficits and alter cyclic AMP response element-binding protein (CREB) levels in a rodent neonatal quinpirole (NQ) model of psychosis. F0 Sprague–Dawley rats were treated with neonatal saline or quinpirole (1 mg/kg) from postnatal day 1 to 21 and bred to produce an F1 generation. F1 offspring underwent prepulse inhibition (PPI) testing from postnatal day 44 to 48 to assess sensorimotor gating. The rats were treated with mGlu5 PAM 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) or A(2A) agonist CGS21680. Rats with at least one NQ-treated parent showed PPI deficits, which were alleviated by both CDPPB and CGS21680. Sex differences were noted across groups, with CGS21680 showing greater efficacy than CDPPB. Additionally, CREB levels were elevated in the nucleus accumbens (NAc), and both CDPPB and CGS21680 reduced CREB expression to control levels. These findings suggest that targeting the adenosinergic and glutamatergic systems alleviates sensorimotor gating deficits and abnormal CREB signaling, both of which are associated with psychosis.

Background: Major depressive disorder (MDD) affects approximately 20% of the population, with over 30% of cases demonstrating treatment resistance. Postmortem analyses have revealed increased poly (ADP-ribose) polymerase 1 (PARP-1) expression in prefrontal cortical white matter of individuals with MDD, suggesting PARP-1 as a potential therapeutic target. Chronic stress, a major risk factor for depression, affects multiple physiological domains including behavior, cardiovascular function, neuroinflammation, and gut-brain axis signaling. Methods: We conducted a comprehensive multi-system investigation of PARP inhibition effects on stress-induced pathophysiology using the social defeat stress/chronic unpredictable stress (SDS+CUS) rodent model. In the primary study, male Sprague-Dawley rats (N=32) underwent 10 days of SDS+CUS while receiving daily treatment with the PARP inhibitor 3-aminobenzamide (3-AB; 40mg/kg), selective serotonin reuptake inhibitor fluoxetine (FLX; 10mg/kg), or saline (0.9% NaCl), with non-stressed controls included. Behavioral outcomes were assessed via sucrose preference and social interaction tests. Neurobiological analyses examined PARP-1 expression, microglial morphology, and proinflammatory cytokine levels (IL-1β, TNF-α, IL-6) in relevant brain regions. In a parallel cardiovascular study, a separate cohort of stressed rats (N=8) received either saline or 3-AB treatment while hemodynamic parameters were monitored via telemetry before, during, and after stress exposure. Exploratory gut microbiome analyses were also conducted (see Supplemental Materials). Results: Saline-treated stressed rats demonstrated significantly elevated anhedonia and social avoidance compared to all other groups, while 3-AB treatment prevented these behavioral deficits. Cardiovascular monitoring revealed that stressed saline-treated rats developed significant elevations in systolic and mean blood pressure with decreased heart rate compared to baseline, whereas 3-AB treatment prevented these hemodynamic changes. Neurobiological analyses showed that FLX-treated stressed rats unexpectedly exhibited elevated PARP-1 expression in prefrontal cortical gray matter. Microglial morphological analysis revealed significantly more prolate (activated) microglia in the saline-treated stressed rats compared to all other treatment groups. Saline-treated stressed rats exhibited significantly increased hippocampal proinflammatory cytokines, with 3-AB treatment specifically normalizing TNF-α levels. Conclusion: PARP inhibition with 3-AB provides multi-system protection against chronic stress effects, preventing behavioral deficits, cardiovascular dysfunction, and neuroinflammation. These findings establish PARP-1 as a key mediator in the systemic pathophysiology of chronic stress and highlight PARP inhibition as a promising therapeutic approach for stress-related disorders with treatment-resistant features. Significant Outcomes: PARP inhibition with 3-aminobenzamide (3-AB) prevented stress-induced behavioral deficits (anhedonia and social avoidance) in a validated rodent model combining social defeat and chronic unpredictable stress. 3-AB treatment prevented stress-induced increases in arterial blood pressure. PARP inhibition prevented microglial activation and reduced proinflammatory cytokine expression (IL-1β and TNF-α) in stress-sensitive brain regions, supporting an anti-neuroinflammatory mechanism of action. FLX-treated stressed rats unexpectedly showed elevated PARP-1 expression in prefrontal cortical gray matter, suggesting a previously unrecognized interaction between serotonergic antidepressants and PARP-1 signaling that warrants further investigation. The multi-system protective effects of PARP inhibition, spanning behavioral, cardiovascular, and neuroinflammatory domains, suggest therapeutic potential for treatment-resistant depression. Limitations: This study examined only male rats, limiting generalizability to female subjects despite the higher prevalence of MDD in women. Behavioral assessments were limited to anhedonia and social interaction; additional tests of other depression-relevant behaviors would provide a more comprehensive phenotypic profile. Long-term effects of 3-AB treatment beyond the 10-day stress paradigm remain unexplored.