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Selective depletion of cortical noradrenaline by anti-dopamine beta-hydroxylase–saporin impairs attentional function and enhances the effects of guanfacine in the rat

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Abstract

Rationale

Previous data indicate that depletion of cortical noradrenaline (NA) impairs performance of an attentional five-choice serial reaction time task (5CSRT) under certain conditions. This study employed a novel immunotoxin, anti-dopamine-beta hydroylase (DβH)–saporin, to make relatively selective lesions of the noradrenergic projections to the prefrontal cortex (PFC) in rats trained to perform the 5CSRT.

Objectives

The aim of this work is to examine (1) the effect of cortical noradrenaline depletion on sustained attentional performance in the 5CSRT under a variety of test conditions and (2) the effects of guanfacine, a selective α-2 adrenoceptor agonist on attentional performance in sham and NA-depleted rats.

Materials and methods

Animals received either intramedial prefrontal anti-DβH–saporin or vehicle and were tested on the baseline task with a variety of additional manipulations including (1) decreasing target duration, (2) increasing rate and (3) temporal unpredictability of target presentation and (4) systemic guanfacine.

Results

Anti-DβH-saporin infused into the PFC produced a substantial loss of DβH-positive fibers in that region and in other adjacent cortical areas. There was no significant depletion of DA or 5-HT. NA-depleted animals were not impaired on the baseline task, but were slower to respond correctly under high event rate conditions, and their discriminative accuracy was reduced when stimulus predictability decreased. Guanfacine significantly reduced discriminative accuracy in NA-depleted animals only.

Conclusion

Selective cortical NA depletion produced deficits on the 5CSRT test of sustained attention, especially when the attentional load was increased and in response to systemic guanfacine. These results are consistent with a role of coeruleo-cortical NA in the regulation of effortful attentional processes.

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Acknowledgement

This work was supported by a Programme Grant from the Wellcome Trust, and the work was completed within the University of Cambridge Behavioral and Clinical Neuroscience Institute funded by a joint consortium award from the MRC and the Wellcome Trust. J. Milstein is an NIMH-Cambridge University Scholar. O. Lehmann was a Marie Curie Fellow. We thank Dr. Mercedes Arroyo for assistance with immunocytochemistry.

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Authors and Affiliations

  1. Department of Experimental Psychology, University of Cambridge Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing St., Cambridge, CB2 3EB, UK

    Jean A. Milstein, Olivia Lehmann, David E. H. Theobald, Jeffrey W. Dalley & Trevor W. Robbins

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  1. Jean A. Milstein
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  2. Olivia Lehmann
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  3. David E. H. Theobald
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  4. Jeffrey W. Dalley
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  5. Trevor W. Robbins
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Correspondence to Trevor W. Robbins.

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Milstein, J.A., Lehmann, O., Theobald, D.E.H. et al. Selective depletion of cortical noradrenaline by anti-dopamine beta-hydroxylase–saporin impairs attentional function and enhances the effects of guanfacine in the rat. Psychopharmacology 190, 51–63 (2007). https://doi.org/10.1007/s00213-006-0594-x

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  • DOI: https://doi.org/10.1007/s00213-006-0594-x

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