Psychopharmacology

, Volume 190, Issue 1, pp 51–63 | Cite as

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

  • Jean A. Milstein
  • Olivia Lehmann
  • David E. H. Theobald
  • Jeffrey W. Dalley
  • Trevor W. Robbins
Original Investigation

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.

Keywords

Noradrenaline Prefrontal cortex Anti-DβH–saporin Attention Guanfacine 

Notes

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.

References

  1. Arnsten AF (2004) Adrenergic targets for the treatment of cognitive deficits in schizophrenia. Psychopharmacology (Berl) 174:25–31CrossRefGoogle Scholar
  2. Arnsten AF, Contant TA (1992) Alpha-2 adrenergic agonists decrease distractibility in aged monkeys performing the delayed response task. Psychopharmacology (Berl) 108:159–169CrossRefGoogle Scholar
  3. Arnsten AF, Cai JX, Goldman-Rakic PS (1988) The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci 8:4287–4298PubMedGoogle Scholar
  4. Aston-Jones G, Shipley M, Grzanna R (1995) The locus coeruleus A5 and A7 groups. In: Paxinos G (ed) The Rat nervous system. Academic, London, pp 183–214Google Scholar
  5. Aston-Jones G, Rajkowski J, Cohen J (1999) Role of locus coeruleus in attention and behavioural flexibility. Biol Psychiatry 46:1309–1320PubMedCrossRefGoogle Scholar
  6. Beane M, Marrocco R (2004) Cholinergic and noradrenergic inputs to the posterior parietal cortex modulate the components of exogenous attention. In: Posner M (ed) The cognitive neuroscience of attention. Guilford, New York, pp 313–325Google Scholar
  7. Berridge CW, Waterhouse BD (2003) The locus coeruleus–noradrenergic system: modulation of behavioural state and state-dependent cognitive processes. Brain Res Brain Res Rev 42:33–84PubMedCrossRefGoogle Scholar
  8. Callado LF, Stamford JA (1999) Alpha2A- but not alpha2B/C-adrenoceptors modulate noradrenaline release in rat locus coeruleus: voltammetric data. Eur J Pharmacol 366:35–39PubMedCrossRefGoogle Scholar
  9. 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
  10. Carlson S, Tanila H, Rama P, Mecke E, Pertovaara A (1992) Effects of medetomidine, an alpha-2 adrenoceptor agonist, and atipamezole, an alpha-2 antagonist on spatial working memory performance in adult and aged rats. Behav Neural Biol 58:113–119PubMedCrossRefGoogle Scholar
  11. Chudasama Y, Robbins TW (2004) Dopaminergic modulation of visual attention and working memory in the rodent prefrontal cortex. Neuropsychopharmacology 29:1628–1636PubMedCrossRefGoogle Scholar
  12. Chudasama Y, Passetti F, Desai A, Rhodes S, Lopian D, 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
  13. Chudasama Y, Dalley JW, Nathwani F, Bouger P, Robbins TW (2004) Cholinergic modulation of visual attention and working memory: dissociable effects of basal forebrain 192–IgG–saporin lesions and intra-prefrontal infusions of scopolamine. Learn Mem 11:78–86PubMedCrossRefGoogle Scholar
  14. Cole BJ, Robbins TW (1987) Amphetamine impairs the discriminative performance of rats with dorsal noradrenergic bundle lesions on a 5-choice serial reaction time task: new evidence for central dopaminergic–noradrenergic interactions. Psychopharmacology (Berl) 91:458–466CrossRefGoogle Scholar
  15. Cole BJ, Robbins TW (1992) Forebrain norepinephrine: role in controlled information processing in the rat. Neuropsychopharmacology 7:129–142PubMedGoogle Scholar
  16. Coull JT, Middleton HC, Robbins TW, Sahakian BJ (1995) Clonidine and diazepam have differential effects on tests of attention and learning. Psychopharmacology (Berl) 120:322–332CrossRefGoogle Scholar
  17. Coull JT, Frith CD, Dolan RJ, Frackowiak RS, Grasby PM (1997) The neural correlates of the noradrenergic modulation of human attention, arousal and learning. Eur J Neurosci 9:589–598PubMedCrossRefGoogle Scholar
  18. Coull JT, Jones ME, Egan TD, Frith CD, Maze M (2004) Attentional effects of noradrenaline vary with arousal level: selective activation of thalamic pulvinar in humans. Neuroimage 22:315–322PubMedCrossRefGoogle Scholar
  19. Curet O, Dennis T, Scatton B (1987) Evidence for the involvement of presynaptic alpha-2 adrenoceptors in the regulation of norepinephrine metabolism in the rat brain. J Pharmacol Exp Ther 240:327–336PubMedGoogle Scholar
  20. Dalley JW, McGaughy J, O’Connell MT, Cardinal RN, Levita L, Robbins TW (2001) Distinct changes in cortical acetylcholine and noradrenaline efflux during contingent and noncontingent performance of a visual attentional task. J Neurosci 21:4908–4914PubMedGoogle Scholar
  21. Dalley JW, Theobald DE, Bouger P, Chudasama Y, Cardinal RN, Robbins TW (2004) Cholinergic function and deficits in visual attentional performance in rats following 192 IgG–saporininduced lesions of the medial prefrontal cortex. Cereb Cortex 14:922–932PubMedCrossRefGoogle Scholar
  22. Eichenbaum HB, Ross R, Raji A, McGaughy JA (2003) Noradrenergic, but not cholinergic, deafferentation of the infralimbic/prelimbic cortex impairs attentional set-shifting. Society for Neuroscience Abstracts, pp 940–947Google Scholar
  23. Everitt BJ, Robbins TW, Selden NRW (1990) Functions of the locus coeruleus noradrenergic system: a neurobiological and behavioural synthesis. In: Marsden CA, Heal DJ (eds) Pharmacology of Noradrenaline, Oxford University Press, Oxford, pp 349–378Google Scholar
  24. Fernandez-Pastor B, Meana JJ (2002) In vivo tonic modulation of the noradrenaline release in the rat cortex by locus coeruleus somatodendritic alpha (2)-adrenoceptors. Eur J Pharmacol 442:225–229PubMedCrossRefGoogle Scholar
  25. Fernandez-Pastor B, Mateo Y, Gomez-Urquijo S, Javier MJ (2005) Characterization of noradrenaline release in the locus coeruleus of freely moving awake rats by in vivo microdialysis. Psychopharmacology (Berl) 180:570–579CrossRefGoogle Scholar
  26. Franowicz JS, Arnsten AF (1999) Treatment with the noradrenergic alpha-2 agonist clonidine, but not diazepam, improves spatial working memory in normal young rhesus monkeys. Neuropsychopharmacology 21:611–621PubMedCrossRefGoogle Scholar
  27. Granon S, Passetti F, Thomas KL, Dalley JW, Everitt BJ, Robbins TW (2000) Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex. J Neurosci 20:1208–1215PubMedGoogle Scholar
  28. Howell DC (1997) Statistical methods for psychology, 4th edn. Wadsworth, LondonGoogle Scholar
  29. Hughes ZA, Stanford SC (1998) A partial noradrenergic lesion induced by DSP-4 increases extracellular noradrenaline concentration in rat frontal cortex: a microdialysis study in vivo. Psychopharmacology (Berl) 136:299–303CrossRefGoogle Scholar
  30. Jakala P, Riekkinen M, Sirvio J, Koivisto J, Kejonen K, Vanhanen M, Riekkinen PJ (1999) Gunafacine, but not clonidine, improves planning and working memory performance in humans. Neuropsychopharmacology 20:460–470PubMedCrossRefGoogle Scholar
  31. Lapiz MD, Morilak DA (2005) Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability. Neuroscience 137:1039–1049PubMedCrossRefGoogle Scholar
  32. Mair RD, Zhang Y, Bailey KR, Toupin MM, Mair RG (2005) Effects of clonidine in the locus coeruleus on prefrontal- and hippocampal-dependent measures of attention and memory in the rat. Psychopharmacology (Berl) 181:280–288CrossRefGoogle Scholar
  33. Marrs W, Kuperman J, Avedian T, Roth RH, Jentsch JD (2005) Alpha-2 adrenoceptor activation inhibits phencyclidine-induced deficits of spatial working memory in rats. Neuropsychopharmacology 30:1500–1510PubMedCrossRefGoogle Scholar
  34. Mateo Y, Meana JJ (1999) Determination of the somatodendritic alpha2-adrenoceptor subtype located in rat locus coeruleus that modulates cortical noradrenaline release in vivo. Eur J Pharmacol 379:53–57PubMedCrossRefGoogle Scholar
  35. Muir JL, Everitt BJ, Robbins TW (1996) The cerebral cortex of the rat and visual attentional function: dissociable effects of mediofrontal, cingulate, anterior dorsolateral, and parietal cortex lesions on a five-choice serial reaction time task. Cereb Cortex 6:470–481PubMedCrossRefGoogle Scholar
  36. Muller U, Clark L, Lam ML, Moore RM, Murphy CL, Richmond NK, Sandhu RS, Wilkins IA, Menon DK, Sahakian BJ, Robbins TW (2005) Lack of effects of guanfacine on executive and memory functions in healthy male volunteers. Psychopharmacology (Berl) 182:205–213CrossRefGoogle Scholar
  37. Olpe HR, Glatt A, Laszlo J, Schellenberg A (1980) Some electrophysiological and pharmacological properties of the cortical, noradrenergic projection of the locus coeruleus in the rat. Brain Res 186:9–19PubMedCrossRefGoogle Scholar
  38. Passetti F, Chudasama Y, Robbins TW (2002) The frontal cortex of the rat and visual attentional performance: Dissociable functions of distinct medial prefrontal subregions. Cereb Cortex 12:1254–1268PubMedCrossRefGoogle Scholar
  39. Paxinos G, Watson C (1998) The rat brain in stereotaxic co-ordinates, 2nd edn. Academic, SydneyGoogle Scholar
  40. Robbins TW (2000) Chemical neuromodulation of frontal-executive function in humans and other animals. Exp Brain Res 133:130–138PubMedCrossRefGoogle Scholar
  41. Robbins TW (2002) The five-choice serial reaction time task: Behavioural pharmacology and functional neurochemistry. Psychopharmacology (Berl) 163:362–380CrossRefGoogle Scholar
  42. Stirpe F, Barbieri L (1986) Ribosome-inactivating proteins up to date. FEBS Lett 195:1–8PubMedCrossRefGoogle Scholar
  43. Wrenn CC, Picklo MJ, Lappi DA, Robertson D, Wiley RG (1996) Central noradrenergic lesioning using anti-DβH–saporin: anatomical findings. Brain Res 740:175–184PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Jean A. Milstein
    • 1
  • Olivia Lehmann
    • 1
  • David E. H. Theobald
    • 1
  • Jeffrey W. Dalley
    • 1
  • Trevor W. Robbins
    • 1
  1. 1.Department of Experimental Psychology, University of Cambridge Behavioural and Clinical Neuroscience InstituteUniversity of CambridgeCambridgeUK

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