Mice with chronic norepinephrine deficiency resemble amphetamine-sensitized animals

Acute pharmacological blockade of α1 adrenoreceptors (ARs) attenuates the locomotor response to amphetamine (LRA). We took a genetic approach to study how norepinephrine (NE) signaling modulates psychostimulant responses by testing LRA in dopamine β-hydroxylase knockout (Dbh−/−) mice that lack NE. Surprisingly, Dbh−/− animals were hypersensitive to the behavioral effects of amphetamine. Amphetamine (2 mg/kg) elicited greater locomotor activity in Dbh−/− mice compared to controls, whereas 5 mg/kg caused stereotypy in Dbh−/− mice, which is only observed in control mice at higher doses. Prazosin, an α1AR antagonist, attenuated LRA in Dbh+/− mice but had no effect in Dbh−/− mice. Changes in the sensitivity of dopamine (DA)-signaling pathways may contribute to the altered amphetamine responses of Dbh−/− mice because they were relatively insensitive to a D1 agonist and hypersensitive to a D2 agonist. Daily amphetamine administration resulted in behavioral sensitization in both Dbh+/− and Dbh−/− mice, demonstrating that NE is not required for the development or expression of behavioral sensitization. Daily prazosin administration blunted but did not completely block locomotor sensitization in Dbh+/− mice, suggesting that α1AR signaling contributes to, but is not required for sensitization in Dbh+/− control animals. We conclude that in contrast to acute α1AR blockade, chronic NE deficiency induces changes similar to sensitization, perhaps by altering DA-signaling pathways.