AB-300, A NOVEL 5-HT2A/2C AGONIST, REVERSES MOTIVATIONAL DEFICITS IN A TETRABENAZINE MODEL OF PARKINSON’S DISEASE APATHY

Background

Apathy is one of the most prevalent and debilitating nonmotor symptoms (NMS) of Parkinson’s Disease (PD), affecting up to 70% of patients. It is characterized by reduced initiative and goal-directed behavior, significantly increasing caregiver burden and predicting cognitive decline. Despite its impact, there are no FDAapproved therapies for PD apathy. While dopaminergic replacement therapies effectively treat motor symptoms, they often fail to improve apathy, and standard treatments like SSRIs can exacerbate it. Emerging neuroimaging evidence suggests that serotonergic degeneration—specifically the loss of 5-HT2A receptor availability—plays a critical role in the pathophysiology of NMS in PD. We investigated the therapeutic potential of AB-300, a novel, non-hallucinogenic 5-HT2A/2C receptor agonist, to reverse motivational deficits in a translational rodent model.

Methods

The efficacy of AB-300 was evaluated in a tetrabenazine (TBZ)-induced model of reduced motivation. Male Long-Evans rats (N=27) were trained on a Progressive Ratio (PR) schedule of reinforcement, where the effort required to obtain a food reward increases exponentially. Once stable performance was achieved, apathy was induced via the administration of the VMAT2 inhibitor TBZ (2.5 mg/kg IP), which depletes monoamines and reliably induces a low-effort bias. In a randomized, counterbalanced, repeated-measures design, animals received AB-300 (5 mg/kg or 10 mg/kg SC) or vehicle 15 minutes prior to testing. Bupropion (20 mg/kg IP) served as a positive control. Primary endpoints included the total number of lever presses and rewards earned (breakpoint).

Results

Administration of TBZ significantly reduced motivational behavior compared to vehicle control, lowering both total lever presses and rewards earned (p < 0.001). Treatment with AB-300 significantly attenuated these TBZ-induced deficits. At the 5 mg/kg dose, AB300 significantly increased the number of rewards earned compared to the TBZ/Vehicle condition (p < 0.001). This restorative effect was comparable to that of the positive control, Bupropion (p < 0.001). Subgroup analysis revealed that the efficacy of AB-300 was most pronounced in animals with lower baseline motivation (“low performers”), effectively normalizing their effort-based decision-making. The 10 mg/kg dose also improved performance but did not show increased efficacy over the 5 mg/kg dose.

Conclusions

AB-300 demonstrated robust efficacy in reversing experimentally induced motivational deficits driven by monoamine depletion. These data support the hypothesis that 5-HT2A/2C agonism can restore goal-directed behavior in the absence of intact dopaminergic tone. Given the specific serotonergic pathology associated with apathy in human PD, AB-300 represents a promising, novel therapeutic candidate for the treatment of non-motor symptoms in Parkinson’s Disease, addressing a significant unmet need where current standard-of-care options are insufficient.

References

1. Maillet A, Krack P, Lhommée E, et al. The prominent role of serotonergic degeneration in apathy, anxiety and depression in de novo Parkinson’s disease. Brain. 2016;139(9):2486-2502. 2) Maher S, Yilmaz Z, O’Keane V, et al. Treatment of Apathy in Parkinson’s Disease and Implications for Underlying Pathophysiology. J Clin Med. 2024;13(8):2216.