Abstract
Dopamine transporter (DAT) inhibitors are expected to decrease dopamine (DA) clearance from the extracellular space of the brain. However, mazindol and cocaine have been reported to “anomalously” increase DA clearance rate. To better understand in vivo DAT activity both in the absence and presence of DAT inhibitors, clearance of exogenously applied DA was measured in dorsal striata of urethane-anesthetized rats using high-speed chronoamperometry. As higher amounts of DA were ejected, DA signal amplitudes, but not time courses, increased. Clearance rates increased until near maximal rates of 0.3 to 0.5 μM/s were attained. Provided baseline clearance rates were relatively low (< 0.1 μM/s), local application of either nomifensine or cocaine markedly increased exogenous DA signal amplitudes and time courses. Relative to the low baseline group, locally applied nomifensine decreased clearance rate when baseline clearance was high (∼0.4 μM/s). However, even when baseline clearance rates were high, systemic injection of nomifensine, mazindol, GBR 12909, or benztropine increased DA signal amplitudes to a greater extent than time courses, consistent with the observed increases in clearance rates. In contrast, despite low baseline clearance rates, systemic injection of cocaine, WIN 35,428, ord-amphetamine preferentially increased DA signal time course, consistent with the observed decreases in clearance rates. Our results emphasize that as extracellular DA concentrations increase, DAT velocity increases to a maximum, partially explaining the ability of DAT inhibitors to increase DA clearance rates. However, by itself, kinetic activation is not sufficient to explain the ability of certain systemically administered DAT inhibitors to anomalously increase DA clearance.
Footnotes
-
Send reprint requests to: Dr. Nancy R. Zahniser, Department of Pharmacology C-236, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262. E-mail:nancy.zahniser{at}uchsc.edu
-
↵1 This work was supported by National Institutes of Health Grants DA04216 (N.R.Z.), NS09199, and AG06434 (G.A.G.), and Research Scientist Development Awards DA00174 (N.R.Z.) and MH01245 (G.A.G.). A preliminary report of this work has been presented: Zahniser NR, Larson GA and Gerhardt GA (1996) Soc Neurosci Abstr22:1577.
- Abbreviations:
- CFT
- (−)2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane or WIN 35,428
- DA
- dopamine
- DAT
- dopamine transporter
- GBR 12909
- 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine
- KT
- transporter affinity
- Vmax
- maximal velocity
- Received August 13, 1998.
- Accepted November 24, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|