Effects of cocaine in 5-lipoxygenase-deficient mice.
5-Lipoxygenase (5-LOX), along with 12-lipoxygenase and cyclooxygenases, metabolizes arachidonic acid into eicosanoids. In rodents, 12-lipoxygenase deficiency alters behavioral responses to cocaine. We used 5-LOX-deficient mice and their controls to investigate cocaine's actions. After repeated cocaine injections, the increase in locomotor activity was greater in 5-LOX-deficient mice. Since the 5-LOX pathway may regulate the levels/metabolism of arachidonoylethanolamide (AEA) we assayed the AEA levels in the striatum, the binding of the endogenous AEA to the cannabinoid receptor CB1R, and anandamide hydrolase (FAAH) activity in the striatum, hippocampus, and cortex. Striatal AEA levels decreased after repeated cocaine injections. Cocaine also decreased CB1R binding in all brain regions studied and the only significant differences between 5-LOX-deficient and control mice was the greater hippocampal FAAH activity in 5-LOX-deficient mice. Our results demonstrated that a 5-LOX deficiency alters sensitivity to repeated cocaine. It should be investigated whether a human 5-LOX gene polymorphism affects cocaine's actions.
Kurtuncu
M
M
Department of Psychiatry, The Psychiatric Institute, University of Illinois, Chicago, IL, USA.
Battista
N
N
Uz
T
T
D'Agostino
A
A
Dimitrijevic
N
N
Pasquariello
N
N
Manev
R
R
Maccarrone
M
M
Manev
H
H
D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency* / Q000235:genetics; D001095:Arachidonic Acids / Q000032:analysis / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D063388:Endocannabinoids; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000187:drug effects; D053284:Polyunsaturated Alkamides / Q000032:analysis / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001094:Arachidonate 5-Lipoxygenase; D001095:Arachidonic Acids; D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide