Abstract

Drugs acting via α₂-adrenoceptors modulate cognitive functions mediated via frontostriatothalamic feedback loops. The α_2C-adrenoceptor subtype is expressed in the basal ganglia, hippocampus, and neocortex, areas that are involved in memory and other cognitive functions. α_2C-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, α_2C-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 α_2C-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 α_2C-adrenoceptors. Therefore, α₂-agonists lacking α_2C-AR affinity or α_2C-AR subtype-selective α₂ antagonists could modulate functioning of frontostriatothalamic feedback loops more effectively than the current subtype-nonselective drugs.