Elsevier

Life Sciences

Volume 68, Issues 19–20, 6 April 2001, Pages 2277-2285
Life Sciences

Cloning and regulation g-protein coupled receptor
Evaluation of the α2C-adrenoceptor as a neuropsychiatric drug target: Studies in transgenic mouse models

https://doi.org/10.1016/S0024-3205(01)01016-5Get rights and content

Abstract

The functional characterization of the three distinct α2-adrenoceptor (α2-AR) subtypes was for long hampered by the inavailability of subtype-selective pharmacological probes. Recent studies with gene-targeted mice have revealed that the α2A-AR has a major role in the mediation of many prominent effects of subtype non-selective α2-AR agonists, i.e. sedation, analgesia, hypothermia, sympatho-inhibition, and reduction of blood pressure. We have now employed several neuropsychopharmacological test models to investigate the effects mediated by the α2C-AR subtype and this receptor's potential as a CNS drug target. The studies employed two genetically engineered mouse strains, having either a targeted inactivation of the α2C-AR gene (α2C-KO) or over-expressing the α2C-AR (α2C-OE). Lack of α2C-AR expression was associated with increased amphetamine-induced locomotor activity, startle reactivity, aggression, and activity in the forced swimming test; prepulse inhibition of the startle reflex was attenuated. Opposite changes were observed in the α2C-OE mice. The results suggest that the α2C-AR subtype has a distinct inhibitory role in the processing of sensory information and in the control of motor and emotion-related activities in the CNS. It is therefore possible that α2C-AR-selective drugs may have therapeutic value in the treatment of various neuropsychiatric disorders.

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