Role of gamma-aminobutyric acid ergic activation in pathology of −dopamine-2 receptors model of Parkinsonism in mice

Abstract

BACKGROUND: Blocking of dopamine-2 receptors (D2R) in the brain showed motor symptoms seen in Parkinsonism. Since D2R is excitatory in the brain and blocking it is like inhibition. This work is designed to show if activating gamma aminobutyric acid (GABA) system in the brain contributes to the pathogenesis of Parkinsonism seen in–D2R model of Parkinsonism. MATERIALS AND METHODS: Twenty male adult albino mice were randomly divided into four groups (Veh, −D2R, +GABA, and −D2R + GABA). Veh. animals were given 0.04 mL of normal saline, −D2R were given 10 mg/kg body weight (BW) of haloperidol for 14 days, +GABA were given 10 mg/kg BW of diazepam for 7 days and −D2R + GABA were given 10 mg/kg BW of haloperidol for 14 days with subsequent 10 mg/kg BW of diazepam for 7 days. Each group contains 5 animals and all treatment was done intraperitoneally. Motor activity of the animals was assessed using rotarod, Y-maze for spatial memory and elevated plus maze for anxiety and locomotion. At the end of treatment, the animals were anesthetized using ketamine and perfused transcardially with formal saline. Brains were then excised and fixed in formal saline. The prefrontal cortex (PFC) and hippocampus were processed for histological study using hematoxylin and eosin stain and immunohistochemistry for Lewy bodies. Data were expressed as mean ± standard error of mean and analyzed using analysis of variance with Tukey post hoc test significant level was set at P < 0.05. RESULTS: Motor activity was significantly reduced in all treated groups (−D2R, +GABA and −D2R/+GABA) compared to the control (Veh) as they all have lower latency of fall and arm entries. Y-maze result shows that spatial memory was significantly reduced in –D2R and −D2R/+GABA groups but not + GABA. Anxiety-related behavior was high in all treated groups compared to control. Cellular distortion was observed in the PFC and hippocampus of all treated groups with −D2R/+GABA group having a high level of distortion. Lewy bodies accumulation was absent in the brain regions observed from all the groups. CONCLUSIONS: GABAergic activation aids motor and memory deficit and marked brain pathology in −D2R model of Parkinsonism.