DSP-4-induced depletion of brain norepinephrine produces opposite effects on exploratory behavior 3 and 14 days after treatment.

Exploratory behavior of a complex novel environment was examined 3 and 14 days following treatment with the noradrenergic-selective neurotoxin, DSP-4. This toxin significantly decreased norepinephrine concentrations in neocortex and hippocampus but not hypothalamus. DSP-4 significantly increased exploratory behavior in animals tested 3 days after treatment. In contrast, exploratory behavior was decreased in animals tested 14 days after treatment. The effect of DSP-4 at 3 days is similar to treatments that act to inhibit noradrenergic function such as administration of the alpha 1-antagonist, prazosin, or the alpha 2-agonist, clonidine. The effect of DSP-4 at 14 days resembles that observed following treatment with the alpha 1-agonist, phenylephrine, or the alpha 2-antagonist, idazoxan. These data provide additional support for a role of noradrenergic systems in exploratory behavior. The simplest explanation for the time dependent effects of DSP-4 on exploratory behavior is the occurrence of the slow development of a supersensitivity of cerebral systems affected by norepinephrine.