Facilitation of spatial working memory performance following intra-prefrontal cortical administration of the adrenergic alpha1 agonist phenylephrine.
BACKGROUND
Spatial working memory is dependent on the appropriate functioning of the prefrontal cortex (PFC). PFC activity can be modulated by noradrenaline (NA) released by afferent projections from the locus coeruleus. The coreuleo-cortical NA system could therefore be a target for cognitive enhancers of spatial working memory. Of the three classes of NA receptor potentially involved, the α2 and α1 classes seem most significant, though agents targeting these receptors have yielded mixed results. This may be partially due to the use of behavioural assays that do not translate effectively from the laboratory to the clinical setting. Use of a paradigm with improved translational potential may be essential to resolve these discrepancies.


OBJECTIVE
The objective of this study was to assess the effects of PFC-infused α2 and α1 adrenergic receptor agonists on spatial working memory performance in the touchscreen continuous trial-unique non-matching to location (cTUNL) task in rats.


METHODS
Young male rats were trained in the cTUNL paradigm. Cannulation of the mPFC allowed direct administration of GABA agonists for task validation, and phenylephrine and guanfacine to determine the effects of adrenergic agonists on task performance.


RESULTS
Infusion of muscimol and baclofen resulted in a delay-dependent impairment. Administration of the α2 agonist guanfacine had no effect, whilst infusion of the α1 agonist phenylephrine significantly improved working memory performance.


CONCLUSIONS
Spatial working memory as measured in the rat cTUNL task is dependent on the mPFC. Enhancement of noradrenergic signalling enhanced performance in this paradigm, suggesting a significant role for the α1 receptor in this facilitation.
Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK. mh473@cam.ac.uk.|MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK. mh473@cam.ac.uk.
Martha
M
Hvoslef-Eide
Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.|MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.|Current address: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Geert Grooteplein Noord 21, 6525 EZ, Nijmegen, The Netherlands.
C A
CA
Oomen
Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.|MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.
B M
BM
Fisher
Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.|MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.
C J
CJ
Heath
Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.|MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.
T W
TW
Robbins
Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.|MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.
L M
LM
Saksida
Department of Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.|MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.
T J
TJ
Bussey
D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology*; D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D016316:Guanfacine / Q000494:pharmacology; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects*; D009118:Muscimol / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D065852:Spatial Memory / Q000187:drug effects*
D058646:Adrenergic alpha-1 Receptor Agonists; D058647:Adrenergic alpha-2 Receptor Agonists; D018755:GABA Agonists; D010656:Phenylephrine; D009118:Muscimol; D016316:Guanfacine; D001418:Baclofen; D009638:Norepinephrine
Baclofen; Guanfacine; Muscimol; Noradrenaline; Phenylephrine; Prefrontal cortex; Rat; Touchscreen; Working memory