Remediation of attentional dysfunction in rats with lesions of the medial prefrontal cortex by intra-accumbens administration of the dopamine D2/3 receptor antagonist sulpiride
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Anti-psychotic drugs are widely recognised to produce beneficial effects on impaired cognition in schizophrenia but their mechanism of action is poorly understood. The prefrontal cortex (PFC) and nucleus accumbens (NAC) are key brain loci considered to mediate many of the cognitive deficits associated with schizophrenia and related disorders.
To investigate (1) the effects of selective damage to the PFC on visuo-spatial attention and cognition in the rat and (2) the ability of the anti-psychotic drug sulpiride after its intra-NAC administration to ameliorate cognitive and behavioural deficits produced by lesions of the PFC.
Selective lesions of the medial PFC were made using quinolinic acid in rats previously trained on a five-choice serial reaction time task of sustained visual attention (n = 7). Sham rats received phosphate-buffered saline infusions (n = 7). Following a period of recovery, low doses of sulpiride (0.5ng or 1ng) were infused into the core sub-region of the NAC of sham and lesioned rats immediately prior to testing on the five-choice task.
Lesions of the medial PFC produced a range of impairments on the five-choice task, including decreased attentional accuracy, slower latencies to respond correctly and increased omissions and premature responses, the latter an operational measure of impulsivity. Intra-NAC sulpiride dose-dependently ameliorated the increased impulsivity and attentional impairment present in PFC-lesioned rats.
These findings suggest that attentional and cognitive impairment in schizophrenia may be determined in part by a dysregulation of the subcortical dopamine systems occurring as a consequence of damage to the PFC.
KeywordsSulpiride Nucleus accumbens Prefrontal cortex Cognition Impulsivity Dopamine Neuroleptic
This study was conducted within the Cambridge University Behavioural and Clinical Neuroscience Institute and was funded by a Wellcome Trust Programme grant (076274/z/04/z) and a consortium joint award from the MRC and Wellcome Trust (G0001354). MAP was supported by a Marie Curie Fellowship and is currently supported by a Medical Research Scotland Jean-Baxter Fellowship.
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