EFFECT OF DOPAMINERGIC DRUGS ON THE IN-VIVO BINDING OF [H-3] WIN-35,428 TO CENTRAL DOPAMINE TRANSPORTERS

[C-11]WIN 35,428 (also designated [C-11]CFT) is now being used in seve ral positron emission tomography (PET) centers to image dopamine (DA) transporter sites in the mammalian brain. Whether and to what extent i n vivo WIN 35,428 binding is influenced by intra- and extrasynaptic do pamine levels are largely unknown. The purpose of the present study wa s to evaluate the effects of various drugs, known to affect DA levels and release, on the binding of [H-3]WIN 35,428 to central DA transport ers in the mouse brain. D-Amphetamine, which releases DA from neurons and blocks the DA transporter directly, inhibited striatal [H-3]WIN 35 ,428 binding in dose-dependent manner. Similarly, alpha-methyl-DL-p-ty rosine, an inhibitor of tyrosine hydroxylase, blocked [H-3]WIN 35,428 binding, possibly via competitive inhibition by the metabolite p-hydro xyamphetamine. Specific binding of [H-3]WIN 35,428 was insensitive to changes in synaptic DA levels caused by pretreatment of the animals wi th high doses of D-2 receptor agonists (apomorphine, bromocriptine), a ntagonists (haloperidol) or the inhibitor of dopaminergic neuron firin g gamma-butyrolactone (GEL). High doses (> 50 mg/kg) of L-DOPA (in com bination with benserazide), however, reduced [H-3]WIN 35,428 binding s ignificantly, yet for a relatively short time (approximately 2.5 h). C hronic treatment with L-deprenyl elicited no changes in in vivo [H-3]W IN 35,428 accumulation in the striatum. Neurotoxic damage of DA neuron s caused by administration of high doses of amphetamine was detected i n the striatum by a significant reduction in [H-3]WIN 35,428 binding 7 days after cessation of amphetamine treatment. Thus, [H-3]WIN 35,428 binding was only affected by neurotoxic loss of neurons, by administra tion of uptake inhibitors, or by some treatments which significantly e levate DA levels. Compounds which inhibit DA release or deplete DA acu tely do not increase [H-3]WIN 35,428 binding, suggesting that normal o r ''resting'' levels of DA are not sufficient to alter [H-3]WIN 35,428 binding in vivo. These findings are important for our understanding o f the function and regulation of the DA transporter, as well as the in vivo binding of the radioligand [H-3/C-11]WIN 35,428. Moreover, they will be important for the interpretation of PET studies in which [C-11 ]WIN 35,428 is used to assess the integrity of dopaminergic neurons. ( C) 1996 Wiley-Liss, Inc.