title: Selective depletion of cortical noradrenaline by anti-dopamine beta-hydroxylase-saporin impairs attentional function and enhances the effects of guanfacine in the rat.
abstract: BACKGROUND
  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 (DbetaH)-saporin, to make relatively selective lesions of the noradrenergic projections to the prefrontal cortex (PFC) in rats trained to perform the 5CSRT.
  
  
  OBJECTIVE
  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 alpha-2 adrenoceptor agonist on attentional performance in sham and NA-depleted rats.
  
  
  METHODS
  Animals received either intramedial prefrontal anti-DbetaH-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-DbetaH-saporin infused into the PFC produced a substantial loss of DbetaH-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Experimental Psychology, University of Cambridge Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
authors.forename: Jean A
authors.initials: JA
authors.lastname: Milstein
authors.forename: Olivia
authors.initials: O
authors.lastname: Lehmann
authors.forename: David E H
authors.initials: DE
authors.lastname: Theobald
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Dalley
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity*; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D001288:Attention / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000502:physiology; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016316:Guanfacine / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000187:drug effects / Q000502:physiology; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D012691:Serial Learning / Q000187:drug effects / Q000502:physiology; D013268:Stimulation, Chemical
chemical_list: D000316:Adrenergic alpha-Agonists; D000911:Antibodies, Monoclonal; D054789:Ribosome Inactivating Proteins, Type 1; C101397:anti-dopamine beta-hydroxylase immunotoxin; D016316:Guanfacine; D000076985:Saporins; D009638:Norepinephrine