ADRENERGIC ALPHA(2C)-RECEPTORS MODULATE THE ACOUSTIC STARTLE REFLEX, PREPULSE INHIBITION, AND AGGRESSION IN MICE

Studies on animal models of stress, anxiety, aggression, and sensorimo tor gating have linked specific monoamine neuro-transmitter abnormalit ies to the cognitive and behavioral disturbances associated with many affective neuropsychiatric disorders. Although alpha(2)-adrenoceptors (alpha(2)-ARs) have been suggested to have a modulatory role in these disorders, the specific roles of each alpha(2)-AR subtype (alpha(2A), alpha(2B), and alpha(2C)) are largely unknown. The restricted availabi lity of relevant animal models and the lack of subtype-selective alpha (2)-AR drugs have precluded detailed studies in this area. Therefore, transgenic mice were used to study the possible role of the alpha(2C)- AR subtype in two well established behavioral paradigms: prepulse inhi bition (PPI) of the startle reflex and isolation-induced aggression. T he alpha(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 alpha(2C)-ARs (alpha(2C)-KO) had enhanced startle respon ses, diminished PPI, and shortened attack latency in the isolation-agg ression test, whereas tissue-specific overexpression of alpha(2C)-ARs (alpha(2C)-OE) was associated with opposite effects. Correlation analy ses 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 alpha(2C)-OE mice and their wild-type controls, were abolished by treatment with a subtype n onselective alpha(2)-agonist and antagonist. Thus, drugs acting via al pha(2C)-ARs might have therapeutic value in disorders associated with enhanced startle responses and sensorimotor gating deficits, such as s chizophrenia, attention deficit disorder, post-traumatic stress disord er, and drug withdrawal.