Role of α2C-adrenoceptor subtype in spatial working memory as revealed by mice with targeted disruption of the α2C-adrenoceptor gene

The role of the alpha(2C)-adrenoceptor subtype in mediating the beneficial effect of alpha(2)-adrenoceptor agonists on spatial working memory was studied in adult mice with targeted inactivation of the alpha(2C)-receptor gene (KO) and their wild-type controls (WT). A delayed alternation task was run in a T-maze with mixed delays varying from 20 s to 120 s. Dexmedetomidine, a specific but subtype nonselective alpha(2)-adrenoceptor agonist, dose-dependently decreased the total number of errors. The effect was strongest at the dose of 5 mu g/kg (s.c.), and was observed similarly in KO and WT mice. KO mice performed inferior to WT mice due to a higher number of perseverative errors. Dexmedetomidine slowed initiation of the motor response in the start phase at lower doses in WT mice than in KO mice but no such difference was observed in the return phase of the task, suggesting involvement of alpha(2C)-adrenoceptors in the cognitive aspect of response preparation or in response sequence initiation. According to these findings, enhancement of spatial working memory is best achieved with alpha(2)-adrenoceptor agonists which have neither agonistic nor antagonistic effects at the alpha(2C)-adrenoceptor subtype.