Mice with chronic norepinephrine deficiency resemble amphetamine-sensitized animals.
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.
Weinshenker
David
D
Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. dweinshenker@genetics.emory.edu
Miller
Nicole S
NS
Blizinsky
Katherine
K
Laughlin
Marc L
ML
Palmiter
Richard D
RD
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency / Q000235:genetics; D004351:Drug Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000172:deficiency*; D011224:Prazosin / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000378:metabolism; D019257:Quinpirole / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000819:agonists; D017448:Receptors, Dopamine D2 / Q000819:agonists; D015398:Signal Transduction; D013239:Stereotyped Behavior / Q000187:drug effects
D001552:Benzazepines; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D018340:Receptors, Adrenergic, alpha-1; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D019257:Quinpirole; C067113:SK&F 81297; D000661:Amphetamine; D004299:Dopamine beta-Hydroxylase; D009638:Norepinephrine; D011224:Prazosin