Acute pharmacological blockade of alpha1 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 beta-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 alpha1AR 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 alpha1AR signaling contributes to, but is not required for sensitization in Dbh+/- control animals. We conclude that in contrast to acute alpha1AR blockade, chronic NE deficiency induces changes similar to sensitization, perhaps by altering DA-signaling pathways.