Quinolinic acid (QA)-induced neurotoxicity involves a cascade of events such as increased calcium concentration in cytoplasm, exhaustive ATP depletion, oxidative stress, as well as selective GABAergic, dopaminergic, and cholinergic neuronal death. Clinical data hint towards the connection between signalling of dopaminergic system and efficient amelioration of chorea following a tetrabenazine administration in Huntington's disease patients. Therefore, the present study has been designed to explore the neuroprotective potential of paliperidone, an active metabolite of risperidone (a dopaminergic antagonist) against QA-induced neurotoxicity and related complications in rats. QA (200nmol) was administered bilaterally to the striatum over a period of 2min by means of a 28-gauge stainless steel needle attached to a Hamilton syringe. The study protocol involves seven treatment groups (n=12): naïve, sham, control (QA), paliperidone (0.5, 1 and 2mg/kg) and paliperidone (2) per se. Single bilateral intrastriatal injection of QA (200nmol/2μl saline) significantly caused motor incordination, memory impairment, oxidative damage, decrease in biogenic amines levels, cellular alterations (TNF-α, IL-6, PGE2, PGF2α, caspase-3, BDNF, mitochondrial function) and damage of striatal neurons compared to the sham treatment. Treatment with paliperidone (0.5, 1 and 2mg/kg) for 21days significantly attenuated the QA-induced behavioural (motor and memory function), neurochemical (antioxidant enzymes and biogenic amines) and cellular alterations, as well as striatal neurodegeneration. The study indicated that modulation of dopaminergic pathway by paliperidone treatment could be a useful approach in the management of motor and memory abnormality in HD patients.