Abstract
RationaleSpatial 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.ObjectivesThe 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.MethodsYoung 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.ResultsInfusion 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.ConclusionsSpatial 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.
Highlights
Among the many cognitive functions for which it is important, the medial prefrontal cortex is perhaps most closely associated with working memory, defined as the ability to transiently maintain and manipulate task-relevant information in a temporary buffer to guide performance (Arnsten et al 1998; De Luca et al 2003; Arnsten 2006)
This study investigated the prefrontal adrenergic contribution to delay-dependent spatial working memory performance in the touchscreen continuous trial-unique non-matching to location (cTUNL) task (Oomen et al 2015) in young, healthy rats
High concentrations of muscimol and baclofen (0.033 and 0.33 nmol, respectively) led to sedative effects resulting in a lack of trial completion
Summary
Among the many cognitive functions for which it is important, the medial prefrontal cortex (mPFC) is perhaps most closely associated with working memory, defined as the ability to transiently maintain and manipulate task-relevant information in a temporary buffer to guide performance (Arnsten et al 1998; De Luca et al 2003; Arnsten 2006). The α1 and α2 noradrenergic receptors (R) have been postulated to have opposing roles within the PFC (Arnsten 1997; Arnsten et al 1998), with high affinity α2-R activation improving and low-affinity α1-R stimulation impairing PFC function (Arnsten 2000; Robbins and Arnsten 2009). One interpretation of these findings (Arnsten 2000) is that higher levels of NA release, that activate α1-receptors, are associated with stress that impairs spatial working memory according to an inverted U-shaped function
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