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

• Published in: Psychopharmacologia Vol. 190; no. 1; pp. 51 - 63
• Main Authors: MILSTEIN, Jean A, LEHMANN, Olivia, THEOBALD, David E. H, DALLEY, Jeffrey W, ROBBINS, Trevor W
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.01.2007; Springer Nature B.V
• Subjects: Adrenergic alpha-Agonists - pharmacology; Animals; Antibodies, Monoclonal - toxicity; Arousal - drug effects; Arousal - physiology; Attention - drug effects; Attention - physiology; Biological and medical sciences; Brain; Brain - drug effects; Brain - physiology; Brain Mapping; Cerebral Cortex - drug effects; Cerebral Cortex - physiology; Choice Behavior - drug effects; Choice Behavior - physiology; Discrimination Learning - drug effects; Discrimination Learning - physiology; Dose-Response Relationship, Drug; Drug therapy; Enzymes; Guanfacine - pharmacology; Locus Coeruleus - drug effects; Locus Coeruleus - physiology; Male; Medical sciences; Memory, Short-Term - drug effects; Memory, Short-Term - physiology; Nerve Fibers - drug effects; Nerve Fibers - physiology; Nerve Net - drug effects; Nerve Net - physiology; Norepinephrine - metabolism; Original Investigation; Prefrontal Cortex - drug effects; Prefrontal Cortex - physiology; Rats; Rats, Inbred Strains; Reaction Time - drug effects; Reaction Time - physiology; Ribosome Inactivating Proteins, Type 1; Rodents; Saporins; Serial Learning - drug effects; Serial Learning - physiology; Stimulation, Chemical; Toxicity; α2-Adrenergic receptor; Dopamine β-monooxygenase; Agonist; Rat; Enzyme; Rodentia; Central nervous system; Attention; Guanidines; Prefrontal cortex; Guanfacine; Catecholamine; Encephalon; Vertebrata; Mammalia; Depletion; Animal; Neurotransmitter; α-Adrenergic receptor agonist; Norepinephrine; Oxidoreductases; Anti-DβH-saporin; Noradrenaline
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-006-0594-x

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. 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. 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. 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. 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.