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The Journal of Neuroscience, April 15, 1998, 18(8):3035-3042

Adrenergic _2C-Receptors Modulate the Acoustic Startle Reflex, Prepulse Inhibition, and Aggression in Mice

Jukka Sallinen¹, Antti Haapalinna², Timo Viitamaa², Brian K. Kobilka³, and Mika Scheinin¹

¹ Department of Pharmacology and Clinical Pharmacology, University of Turku, FIN-20520 Turku, Finland, ² Orion Corporation, Orion Pharma, FIN-20101 Turku, Finland, and ³ Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, and Division of Cardiovascular Medicine, Stanford University, Stanford, California 94305

Studies on animal models of stress, anxiety, aggression, and sensorimotor gating have linked specific monoamine neurotransmitter abnormalities to the cognitive and behavioral disturbances associated with many affective neuropsychiatric disorders. Although ₂-adrenoceptors (₂-ARs) have been suggested to have a modulatory role in these disorders, the specific roles of each ₂-AR subtype (_2A, _2B, and _2C) are largely unknown. The restricted availability of relevant animal models and the lack of subtype-selective ₂-AR drugs have precluded detailed studies in this area. Therefore, transgenic mice were used to study the possible role of the _2C-AR subtype in two well established behavioral paradigms: prepulse inhibition (PPI) of the startle reflex and isolation-induced aggression. The _2C-AR-altered mice appear grossly normal, but subtle changes have been observed in their brain dopamine (DA) and serotonin (5-HT) metabolism. In this study, the mice with targeted inactivation of the gene encoding _2C-ARs (_2C-KO) had enhanced startle responses, diminished PPI, and shortened attack latency in the isolation-aggression test, whereas tissue-specific overexpression of _2C-ARs (_2C-OE) was associated with opposite effects. Correlation analyses suggested that both the magnitude of the startle response and its relative PPI (PPI%) were modulated by the mutations. In addition, the differences in PPI, observed between drug-naive _2C-OE mice and their wild-type controls, were abolished by treatment with a subtype nonselective ₂-agonist and antagonist. Thus, drugs acting via _2C-ARs might have therapeutic value in disorders associated with enhanced startle responses and sensorimotor gating deficits, such as schizophrenia, attention deficit disorder, post-traumatic stress disorder, and drug withdrawal.

Key words: _2C-adrenoceptor; gene-targeting; isolation-induced aggression; schizophrenia; sensorimotor gating; startle; transgenic mice

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1883035-08$05.00/0

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