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.
- Carli M, Robbins TW, Evenden JL, Everitt BJ (1983) Effects of lesions to ascending noradrenergic neurones on performance of a 5-choice serial reaction task in rats; implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal. Behav Brain Res 9:361–380PubMedCrossRefGoogle Scholar
- Chudasama Y, Passetti F, Rhodes SE, Lopian D, Desai A, Robbins TW (2003) Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity. Behav Brain Res 146:105–119PubMedCrossRefGoogle Scholar
- Dalley JW, Thomas KL, Howes SR, Tsai TH, Aparicio-Legarza MI, Reynolds GP, Everitt BJ, Robbins TW (1999) Effects of excitotoxic lesions of the rat prefrontal cortex on CREB regulation and presynaptic markers of dopamine and amino acid function in the nucleus accumbens. Eur J Neurosci 11:1265–1274PubMedCrossRefGoogle Scholar
- Dalley JW, Fryer TD, Brichard L, Robinson ES, Theobald DE, Laane K, Pena Y, Murphy ER, Shah Y, Probst K, Abakumova I, Aigbirhio FI, Richards HK, Hong Y, Baron JC, Everitt BJ, Robbins TW (2007) Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science 315:1267–1270PubMedCrossRefGoogle Scholar
- Paxinos G, Watson C (1996) The rat brain in stereotaxic co-ordinates. 3rd edition. Academic Press, San DiegoGoogle Scholar
- Roberts AC, De Salvia MA, Wilkinson LS, Collins P, Muir JL, Everitt BJ, Robbins TW (1994) 6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: possible interactions with subcortical dopamine. J Neurosci 14:2531–2544PubMedGoogle Scholar
- Wilkinson LS, Dias R, Thomas KL, Augood SJ, Everitt BJ, Robbins TW, Roberts AC (1997) Contrasting effects of excitotoxic lesions of the prefrontal cortex on the behavioural response to D-amphetamine and presynaptic and postsynaptic measures of striatal dopamine function in monkeys. Neuroscience 80:717–730PubMedCrossRefGoogle Scholar