Evaluation of the alpha2C-adrenoceptor as a neuropsychiatric drug target studies in transgenic mouse models.
The functional characterization of the three distinct alpha2-adrenoceptor (Q2-AR) subtypes was for long hampered by the inavailability of subtype-selective pharmacological probes. Recent studies with gene-targeted mice have revealed that the alpha2A-AR has a major role in the mediation of many prominent effects of subtype non-selective alpha2-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 alpha2C-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 alpha2C-AR gene (alpha2C-KO) or over-expressing the alpha2C-AR (alpha2C-OE). Lack of alpha2C-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 alpha2C-OE mice. The results suggest that the alpha2C-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 alpha2C-AR-selective drugs may have therapeutic value in the treatment of various neuropsychiatric disorders.
Scheinin
M
M
Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland. mika.scheinin@utu.fi
Sallinen
J
J
Haapalinna
A
A
D000161:Acoustic Stimulation; D000374:Aggression / Q000187:drug effects; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D020927:Dexmedetomidine / Q000494:pharmacology*; D018390:Gene Targeting; D017781:Genes, Immediate-Early / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D013550:Swimming / Q000502:physiology
D015306:Biogenic Monoamines; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018341:Receptors, Adrenergic, alpha-2; D020927:Dexmedetomidine; D000661:Amphetamine; D003345:Corticosterone