Blockade of dopamine D3 but not D2 receptors reverses the novel object discrimination impairment produced by post-weaning social isolation: implications for schizophrenia and its treatment

Abstract

Dopamine D₃ receptors are densely expressed in mesolimbic projection areas, and selective antagonists enhance cognition, consistent with their potential therapeutic use in the treatment of schizophrenia. This study examines the effect of dopamine D₃ vs. D₂ receptor antagonists on the cognitive impairment and hyperactivity produced by social isolation of rat pups, in a neurodevelopmental model of certain deficits of schizophrenia. Three separate groups of male Lister hooded rats were group-housed or isolation-reared from weaning. Six weeks later rats received either vehicle or the dopamine D₃ selective antagonist, S33084 (0.04 and 0.16 mg/kg), the preferential D₃ antagonist, S33138 (0.16 and 0.63 mg/kg) or the preferential D₂ antagonist, L-741,626 (0.63 mg/kg) s.c. 30 min prior to recording; horizontal locomotor activity in a novel arena for 60 min and, the following day, novel object discrimination using a 2-h inter-trial interval. Isolation rearing induced locomotor hyperactivity in a novel arena and impaired novel object discrimination compared to that in group-housed littermates. Both S33084 and S33138 restored novel object discrimination deficits in isolation-reared rats without affecting discrimination in group-housed controls. By contrast, L-741,626 impaired novel object discrimination in group-housed rats, without affecting impairment in isolates. S33084 (0.16 mg/kg), S33138 and, less markedly, L741,626 reduced the locomotor hyperactivity in isolates without attenuating activity in group-housed controls. Selective blockade of dopamine D₃ receptors reverses the visual recognition memory deficit and hyperactivity produced by isolation rearing. These data support further investigation of the potential use of dopamine D₃ receptor antagonists to treat schizophrenia.