The effects of cocaine on regional brain glucose metabolism is attenuated in dopamine transporter knockout mice.
Cocaine's ability to block the dopamine transporter (DAT) is crucial for its reinforcing effects. However the brain functional consequences of DAT blockade by cocaine are less clear since they are confounded by its concomitant blockade of norepinephrineand serotonin transporters. To separate the dopaminergic from the non-dopaminergic effects of cocaine on brain function we compared the regional brain metabolic responses to cocaine between dopamine transporter deficient (DAT(-/-)) mice with that of their DAT(+/+) littermates. We measured regional brain metabolism (marker of brain function) with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and microPET (muPET) before and after acute cocaine administration (i.p. 10 mg/kg). Scans were conducted 2 weeks apart. At baseline DAT(-/-) mice had significantly greater metabolism in thalamus and cerebellum than DAT(+/+). Acute cocaine decreased whole brain metabolismand this effect was greater in DAT(+/+) (15%) than in DAT(-/-) mice (5%). DAT(+/+) mice showed regional decreases in the olfactory bulb, motor cortex, striatum, hippocampus, thalamus and cerebellum whereas DAT(-/-) mice showed decreases only in thalamus. The differential pattern of regional responses to cocaine in DAT(-/-) and DAT(+/+) suggests that most of the brain metabolic changes from acute cocaine are due to DAT blockade. Cocaine-induced decreases in metabolism in thalamus (region with dense noradrenergic innervation) in DAT(-/-) suggest that these were mediated by cocaine's blockade of norepinephrine transporters. The greater baseline metabolism in DAT(-/-) than DAT(+/+) mice in cerebellum (brain region mostly devoid of DAT) suggests that dopamine indirectly regulates activity of these brain regions.
Thanos
Panayotis K
PK
Behavioral Neuropharmacology Lab, Medical Department, Brookhaven National Laboratory, Upton, New York 11973-5000, USA. thanos@bnl.gov
Michaelides
Michael
M
Benveniste
Helene
H
Wang
Gene Jack
GJ
Volkow
Nora D
ND
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D001923:Brain Chemistry / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D049268:Positron-Emission Tomography
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D019788:Fluorodeoxyglucose F18; D003042:Cocaine; D005947:Glucose; D004298:Dopamine