Effect of CYP2D1 inhibition on the behavioural effects of d-amphetamine.
In rats, amphetamine (AMP) conversion to 4-OH-AMP is metabolized by CYP2D1, the rat equivalent of the human enzyme CYP2D6. To determine the impact of impaired AMP metabolism on its behavioural effects, AMP-induced hyperactivity, AMP discrimination and AMP self-administration were examined in male Wistar rats with or without pretreatment with the CYP2D1 inhibitors quinine and budipine. In vivo, quinine (20 mg/kg) and budipine (10 mg/kg) increased the plasma area under the curve of AMP 4-fold and 3.6-fold respectively, and decreased the plasma levels of 4-OH-AMP, 3-fold and 8.6-fold, confirming that the doses used suppressed CYP2D1 activity. Both inhibitors prolonged AMP-induced hyperactivity (0.3 mg/kg) and prolonged the duration of AMP-appropriate responding for periods of up to 90 min post-AMP administration in a drug discrimination procedure. In rats given a preload dose of AMP (0.8 mg/kg) 3 h prior to the self-administration test session, CYP2D1 inhibition resulted in fewer AMP infusions being taken compared with rats receiving the AMP preload dose alone. These studies indicate that AMP is responsible for the behavioural effects seen in rats and that a rat phenocopy model of the human CYP2D6 deficiency state can be produced by CYP2D1 inhibitors.
Tomkins
D M
DM
Addiction Research Foundation, Toronto, Ontario, Canada.
Otton
S V
SV
Joharchi
N
N
Berns
T
T
Wu
D
D
Corrigall
W A
WA
Sellers
E M
EM
D000429:Alcohol Oxidoreductases; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D000072467:Cytochrome P450 Family 2; D003913:Dextroamphetamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005795:Generalization, Stimulus / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration / Q000523:psychology; D010136:p-Hydroxyamphetamine / Q000097:blood
D000697:Central Nervous System Stimulants; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D010880:Piperidines; D011803:Quinine; D000429:Alcohol Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; C504568:Cyp2d1 protein, rat; D000072467:Cytochrome P450 Family 2; D010136:p-Hydroxyamphetamine; C026710:budipine; D003913:Dextroamphetamine