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 alpha2-adrenoceptors (alpha2-ARs) have been suggested to have a modulatory role in these disorders, the specific roles of each alpha2-AR subtype (alpha2A, alpha2B, and alpha2C) are largely unknown. The restricted availability of relevant animal models and the lack of subtype-selective alpha2-AR drugs have precluded detailed studies in this area. Therefore, transgenic mice were used to study the possible role of the alpha2C-AR subtype in two well established behavioral paradigms: prepulse inhibition (PPI) of the startle reflex and isolation-induced aggression. The alpha2C-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 alpha2C-ARs (alpha2C-KO) had enhanced startle responses, diminished PPI, and shortened attack latency in the isolation-aggression test, whereas tissue-specific overexpression of alpha2C-ARs (alpha2C-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 alpha2C-OE mice and their wild-type controls, were abolished by treatment with a subtype nonselective alpha2-agonist and antagonist. Thus, drugs acting via alpha2C-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.