TY - JOUR
T1 - Dopamine β-hydroxylase knockout mice have alterations in dopamine signaling and are hypersensitive to cocaine
AU - Schank, Jesse R.
AU - Ventura, Rossella
AU - Puglisi-Allegra, Stefano
AU - Alcaro, Antonio
AU - Cole, Charlene D.
AU - Liles, L. Cameron
AU - Seeman, Philip
AU - Weinshenker, David
PY - 2006/10/7
Y1 - 2006/10/7
N2 - Multiple lines of evidence demonstrate that the noradrenergic system provides both direct and indirect excitatory drive onto midbrain dopamine (DA) neurons. We used DA β-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.
AB - Multiple lines of evidence demonstrate that the noradrenergic system provides both direct and indirect excitatory drive onto midbrain dopamine (DA) neurons. We used DA β-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.
KW - Amphetamine
KW - Cocaine
KW - Dopamine
KW - Dopamine β-hydroxylase
KW - Mice
KW - Norepinephrine
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U2 - 10.1038/sj.npp.1301000
DO - 10.1038/sj.npp.1301000
M3 - Article
C2 - 16395294
AN - SCOPUS:33748770069
VL - 31
SP - 2221
EP - 2230
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 10
ER -