Study on social isolation-induced functional changes in noradrenergic system in the brain

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Long-term social isolation enhances spontaneous motor activity, and induces aggressive behavior in mice and rats. However, underlying mechanisms of such behavioral changes remain unclear. We preliminary reported that an antidepressant drug desipramine (DMI) enhanced aggressive behavior in isolated mice (Matsumoto et al., Pharmacol.Biochem.Behav., 39, 167, 1991). In this study, we investigated functional changes in central noradrenergic system caused by social isolation. Male ddY mice were isolated for 6-7 weeks before experiments. When testing aggressive, two isolated mice were placed in a neutral cage. The total duration of biting attacks and/or wrestling observed during a 20-min period was measured. Antidepressants with ability to block noradrenaline (NA) uptake in the brain enhanced aggressive behavior at lower doses. The effects of these drugs were blockd by an a2 adrenoceptor antagonist yohimbine, but not alpha1 adrenoceptor antagonist prazosin, suggesting an involvement of alpha2 adrenoceptors in antidepressant enhancement of aggressive behavior. Moreover, a beta-adrenoceptor atntagonist propranolol and a beta2-adrenoceptor antagonist ICIII8551 dose-dependently blockd the effect of DMI without affecting the basal aggressive behavior, while a beta1-adrenoceptor antagonist metprolol failed to affect the effect of desipramine. Clenbuterol, a selective beta2-agonist, enhanced aggressive behavior in isolated mice. Taken together, these results indicated that alpha2- and beta2-adrenoceptor stimulation by NA plays important roles in enhancement of aggressive behavior. Then, we tested effect of a neurotoxin DSP-4 on the aggressive behavior in isolated mice. This toxin is known to selectively degnerate noradrenergic terminals originating from locus coeruleus. DSP-4 treatment did not affect the basal aggressive behavior, but it attenuated the DMI enhancement of aggressive behavior. Thus, these results show the possibility that the activity of locus coeruleus noradrener