1. ¹Department of Human Genetics, Emory University, Atlanta, GA, USA
2. ²Dipartimento di Psicologia, Università 'La Sapienza', Rome, Italy
3. ³Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, Rome, Italy
4. ⁴Center for Behavioral Neuroscience, Emory University, Atlanta, GA, USA
5. ⁵Department of Pharmacology, University of Toronto, Toronto, ON, Canada

Correspondence: Dr D Weinshenker, Department of Human Genetics, Emory University School of Medicine, Whitehead 301, 615 Michael Street, Atlanta, GA 30322, USA. Tel: +1 404 727 3106; Fax: +1 404 727 3949; E-mail: dweinshenker@genetics.emory.edu

⁶These two authors contributed equally to this work.

Received 29 April 2005; Revised 7 September 2005; Accepted 13 September 2005; Published online 14 December 2005.

Abstract

Multiple lines of evidence demonstrate that the noradrenergic system provides both direct and indirect excitatory drive onto midbrain dopamine (DA) neurons. We used DA -hydroxylase (DBH) knockout (Dbh-/-) mice that lack norepinephrine (NE) to determine the consequences of chronic NE deficiency on midbrain DA neuron function in vivo. Basal extracellular DA levels were significantly attenuated in the nucleus accumbens (NAc) and caudate putamen (CP), but not prefrontal cortex (PFC), of Dbh-/- mice, while amphetamine-induced DA release was absent in the NAc and attenuated in the CP and PFC. The decrease in dopaminergic tone was associated with a profound increase in the density of high-affinity state D₁ and D₂ DA receptors in the NAc and CP, while DA receptors in the PFC were relatively unaffected. As a behavioral consequence of these neurochemical changes, Dbh-/- mice were hypersensitive to the psychomotor, rewarding, and aversive effects of cocaine, as measured by locomotor activity and conditioned place preference. Antagonists of DA, but not 5-HT, receptors attenuated the locomotor hypersensitivity to cocaine in Dbh-/- mice. As DBH activity in humans is genetically controlled and the DBH inhibitor disulfiram has shown promise as a pharmacotherapy for cocaine dependence, these results have implications for the influence of genetic and pharmacological DBH inhibition on DA system function and drug addiction.