Evaluation of the alpha(2C)-adrenoceptor as a neuropsychiatric drug target- Studies in transgenic mouse models

The functional characterization of the three distinct alpha (2)-adrenocepto r (alpha (2)-AR) subtypes was for long hampered by the inavailability of su btype-selective pharmacological probes. Recent studies with gene targeted m ice have revealed that the alpha (2A)-AR has a major role in the mediation of many prominent effects of subtype non-selective alpha (2)-AR agonists, i .e. sedation, analgesia, hypothermia, sympatho-inhibition, and reduction of blood pressure. We have now employed several neuropsychopharmacological te st models to investigate the effects mediated by the alpha (2C)-AR subtype and this receptor's potential as a CNS drug target. The studies employed tw o genetically engineered mouse strains, having either a targeted inactivati on of the alpha (2C)-AR gene (alpha (2C)-KO) or over-expressing the alpha ( 2C)-AR (alpha (2C)-OE). Lack of alpha (2C)-AR expression was associated wit h increased amphetamine-induced locomotor activity, startle reactivity, agg ression, and activity in the forced swimming test; prepulse inhibition of t he startle reflex was attenuated. Opposite changes were observed in the alp ha (2C)-OE mice. The results suggest that the alpha (2C)-AR subtype has a d istinct inhibitory role in the processing of sensory information and in the control of motor and emotion-related activities in the CNS. It is therefor e possible that alpha (2C)-AR-selective drugs may have therapeutic value in the treatment of various neuropsychiatric disorders. (C) 2001 Elsevier Sci ence Inc. All rights reserved.