Dopamine beta-hydroxylase knockout mice have alterations in dopamine signaling and are hypersensitive to cocaine.
Multiple lines of evidence demonstrate that the noradrenergic system provides both direct and indirect excitatory drive onto midbrain dopamine (DA) neurons. We used DA beta-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.
Schank
Jesse R
JR
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
Ventura
Rossella
R
Puglisi-Allegra
Stefano
S
Alcaro
Antonio
A
Cole
Charlene D
CD
Liles
L Cameron
LC
Seeman
Philip
P
Weinshenker
David
D
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009638:Norepinephrine / Q000172:deficiency; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D018765:Dopamine Uptake Inhibitors; D018377:Neurotransmitter Agents; D000661:Amphetamine; D004299:Dopamine beta-Hydroxylase; D003042:Cocaine; D004298:Dopamine; D009638:Norepinephrine