Vol. 281, Issue 1, 508-513, 1997

Differential Regulation of Dopamine Transporter after Chronic Self-administration of Bupropion and Nomifensine¹

Srihari R. Tella, Bruce Ladenheim and Jean Lud Cadet

Department of Pharmacology, Georgetown University School of Medicine, Washington DC (S.R.T.), Molecular Neuropsychiatry Section, National Institutes of Health/National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland (B.L., J.L.C.)

Inhibition of dopamine (DA) transporter function is thought to be the principal mechanism underlying cocaine's addictive effects. In contrast to cocaine, several other inhibitors of DA transporter function are not considered to possess abuse liability. One of the neuroadaptive changes to chronic cocaine self-administration is the up-regulation of DA transporters. In the present study, we investigated the reinforcing and neuroadaptive effects of two other DA reuptake inhibitors, namely bupropion and nomifensine. Drug-naive rats readily acquired and subsequently maintained consistent self-administration of 3 and 1 mg/kg/infusion doses of bupropion and nomifensine, respectively, during 2-hr daily sessions over a prolonged period. Similarly, self-administration responding at low doses of bupropion (0.75 and 1.5 mg/kg/infusion) and nomifensine (0.1 and 0.3 mg/kg/infusion) showed some consistency during the initial weeks of testing which gradually declined or tended to decline to levels similar to that of the water control group during the later weeks of testing. Bupropion self-administration dose-dependently up-regulated DA transporters in caudate putamen and nucleus accumbens. In contrast, nomifensine self-administration did not alter DA transporter levels. These data provide evidence for heterogeneity among DA reuptake inhibitors, with some of these drugs being able to up-regulate DA transporters after their self-administration, whereas others lack this neuroadaptive response.