α2C-Adrenoceptor-Overexpressing Mice Are Impaired in Executing Nonspatial and Spatial Escape Strategies

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Abstract
Drugs acting via α2-adrenoceptors modulate cognitive functions mediated via frontostriatothalamic feedback loops. The α2C-adrenoceptor subtype is expressed in the basal ganglia, hippocampus, and neocortex, areas that are involved in memory and other cognitive functions. α2C-Overexpressing (OE) mice were impaired in spatial or nonspatial water maze (WM) tests, and α2 antagonist treatment fully reversed the WM escape defect in OE mice. However, α2C-overexpression did not influence open field and passive avoidance behaviors or cortical EEG arousal or the actions of α2 agonist or antagonist drugs on these functions. Our results suggest that α2C-adrenoceptors can modulate navigation to a hidden or visible escape platform, whereas many other actions of α2-adrenergic agents, such as sedation, are not mediated via α2C-adrenoceptors. Therefore, α2-agonists lacking α2C-AR affinity or α2C-AR subtype-selective α2 antagonists could modulate functioning of frontostriatothalamic feedback loops more effectively than the current subtype-nonselective drugs.