In vivo characterization of locally applied dopamine uptake inhibitors by striatal microdialysis

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Abstract
In vivo brain microdialysis was used to characterize the effects of some dopamine uptake inhibitors on the extracellular concentrations of dopamine (DA) and its metabolitesdihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striata of awake, freely moving rats. d-Amphetamine, GBR 12909, cocaine, nomifensine, methylphenidate, bupropion, and benztropine were administered directly to the striatum via the perfusion fluid in increasing concentrations (1–1,000 μM). All drugs increased extracellular DA in a dose-dependent manner; however, only d-amphetamine produced dose-dependent decreases in DOPAC and HVAconcentrations. The shapes of the dose-reponse functions differed considerably between the drugs. At 100 and 1000 μM d-amphetamine had biphasic effects (an increase followed by a decrease) on dialysate DA concentration. GBR 12909, methylphenidate, and benztropine also had biphasic effects when applied at the 1,000 μM concentration. In contrast, cocaine, nomifensine, and bupropion produced relatively monophasic increases in extracellular DA. Tetrodotoxin (TTX), which prevents action potentials by blocking voltage-dependent Na+ channels, did not prevent d-amphetamine induced increases in extracellular DA, but blocked completely the effects of cocaine, nomifensine, bupropion, and methylphenidate. While low doses (10 μM) of GBR 12909 and benztropine were highly sensitive to TTX, the toxin was only partially effective against higher doses of the compounds. The rank order of potency of the drugs as determined by the increases in extracellular DA produced by 10 or 100 μM (following correction for dialysis efficiency of the test compounds in vitro) was GBR 12909< benztropine< amphetamine= nomifensine= methylphenidate< cocaine< bupropion. The in vivo characterization of changes in extracellular DA following direct, local application of DA uptake inhibitors can be used to provide useful information aboout the mechanisms of action and potency of these compounds.

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