chronic inhibition of dopamine β-hydroxylase facilitates behavioral responses to cocaine in mice慢性抑制多巴胺β-hydroxylase促进行为反应可卡因的老鼠.pdfVIP

Chronic Inhibition of Dopamine b-Hydroxylase Facilitates Behavioral Responses to Cocaine in Mice 1 1 2 1 Meriem Gaval-Cruz , Larry Cameron Liles , Paul Michael Iuvone , David Weinshenker * 1 Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America, 2 Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, United States of America Abstract The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine b-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh 2/ 2) mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/ 2) and Dbh 2/ 2 mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups ¨ were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naıve Dbh 2/ 2 mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/ 2 mice. Chronic disulfiram administration facili