The anti-dyskinetic and the anti-parkinsonian effects of sub-anesthetic ketamine are also present in female preclinical models

Biological sex is an important determinant of neuropharmacological response, yet females remain underrepresented in preclinical studies of Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). We previously demonstrated that sub-anesthetic ketamine reduces established LID, attenuates dyskinesia development, and produces anti-parkinsonian effects in male unilateral 6-hydroxydopamine (6-OHDA) rat models. However, whether these therapeutic effects extend to females remained unknown. Here, we evaluated the anti-dyskinetic and anti-parkinsonian effects of sub-anesthetic ketamine in female Sprague-Dawley rats using the attenuation and established models of LID. In the attenuation paradigm, unilateral 6-OHDA-lesioned females received repeated L-DOPA administration with either ketamine (20 mg/kg, i.p.; 10-h dosing paradigm) or vehicle. Ketamine significantly attenuated the progressive development of dyskinesia, indicating that early intervention modified the trajectory of LID expression. In the established LID paradigm, ketamine produced robust significant acute reductions in abnormal involuntary movements (AIMs) after dyskinesia had fully developed, and these significant effects persisted for up to 49 days following treatment, demonstrating sustained suppression of dyskinesia severity. To determine whether ketamine altered therapeutic motor function, forelimb adjusting steps testing was performed in female unilateral 6-OHDA rats. Ketamine did not impair L-DOPA-mediated motor improvement suggesting compatibility with the gold standard medication. Ketamine was also by itself associated with significantly improved stepping performance during ketamine treatment conditions, indicating acute anti-parkinsonian motor benefit. Together, these findings demonstrate that the anti-dyskinetic and anti-parkinsonian effects of ketamine extend to female preclinical models and strengthen the translational rationale for repurposing sub-anesthetic ketamine as a potential therapeutic strategy for individuals with LID.