Short Communication
Differential effects of psychostimulants and related agents on dopaminergic and serotonergic transporter function

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Abstract

High-dose administrations of amphetamine, methamphetamine, cathinone, methcathinone or methylenedioxymethamphetamine rapidly decrease dopamine and serotonin transporter function in vivo, as assessed in striatal synaptosomes obtained from drug-treated rats. In contrast, high-dose injections of fenfluramine, cocaine or methylphenidate had little or no effect on the activity of these transporters. Interestingly, the capacity of these agents to directly alter dopamine and serotonin uptake, as assessed in vitro by direct application to rat striatal synaptosomes, did not predict their potential to modulate transporter activity following in vivo administration. These findings demonstrate heretofore-unreported differences in the effects of these agents on monoamine transporter function, and a distinction between drug effects after direct application in vitro vs. administration in vivo.

Introduction

This laboratory has reported that both a single and multiple administrations of methamphetamine cause a rapid and reversible decrease in striatal dopamine transporter activity; effects attributable to decreases in Vmax of transport Fleckenstein et al., 1997b, Kokoshka et al., 1998b. These transient decreases do not reflect loss and subsequent replacement of dopamine transporters, since: (1) methamphetamine does not cause an acute loss of transporter protein (Kokoshka et al., 1998b); and (2) the time necessary to recover transporter function (<1 day) is much less than that likely required to synthesize dopamine transporters de novo (the t1/2 for dopamine transporter turnover is ≈6 days; Fleckenstein et al., 1996). Moreover, these decreases are not due to the direct effects of residual methamphetamine introduced by the original subcutaneous (s.c.) injection Fleckenstein et al., 1997b, Kokoshka et al., 1998b. Instead, we believe that these rapid and reversible effects of methamphetamine provide evidence of a previously uncharacterized mechanism whereby transporter activity can be modulated rapidly in vivo.

Recent evidence suggests that dopamine contributes to the acute decrease in dopamine transporter function following multiple administrations of methamphetamine since this effect is attenuated by prior dopamine depletion with the tyrosine hydroxylase inhibitor, α-methyl-para-tyrosine (Metzger et al., 1998b). Consistent with this finding, direct application of dopamine to striatal synaptosomal preparations decreases dopamine transporter activity (Berman et al., 1996). Since many psychostimulants alter dopamine uptake and release, it might be expected that these, too, might effect the rapid and reversible decrease in dopamine transporter activity caused by methamphetamine. Hence, the purpose of this study was to determine whether other psychostimulants and related agents alter dopamine transporter function. Since methamphetamine effects a rapid and reversible decrease in serotonin transporter function as well (Kokoshka et al., 1998a), effects on serotonin uptake were also assessed. For comparison, effects on dopamine and serotonin uptake after direct application of psychostimulant or related agent of interest to striatal synaptosomes in vitro were also assessed since these assays are employed commonly to predict effects of these agents on transporter function in vivo. The results reveal differential effects of psychostimulants on dopamine and serotonin transporter function, and indicate that the capacity of a compound to alter monoamine uptake in vitro does not predict its potential to modulate monoamine transporters after administration in vivo.

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Animals

Male Sprague–Dawley rats (250–300 g; Simonsen Laboratories, Gilroy, CA) were housed at 23°C with a alternating light/dark cycle (lights on 14 h/day). Food and water were provided ad libitum. Rats were sacrificed by decapitation. All experiments were conducted in accordance with National Institute of Health guidelines.

Drugs and chemicals

[7,8-3H]Dopamine (46 Ci/mmol) was purchased from Amersham Life Sciences (Arlington Heights, IL). 5-[1,2-3H(N)]-hydroxytryptamine (30 Ci/mmol) was purchased from New England Nuclear

Results

We reported previously that a single administration of methamphetamine, methylenedioxymethamphetamine or methcathinone decreased striatal [3H]dopamine uptake to 63%–72% of control values in striatal synaptosomes prepared 1 h after drug administration (Metzger et al., 1998a). Results presented in Table 1 demonstrate that high-dose administration of cathinone or amphetamine decreased [3H]dopamine uptake as well (i.e., to 78% and 80% of control values, respectively). In contrast, a single

Discussion

Recent evidence has suggested that dopamine is necessary for the rapid and reversible decrease in dopamine transporter function caused by multiple injections of methamphetamine (Metzger et al., 1998b). This may be due to findings that dopamine promotes the formation of oxygen radicals (Graham, 1978) which can oxidize and inactivate dopamine transporters Berman et al., 1996, Fleckenstein et al., 1997a. Consistent with this hypothesis, direct application of dopamine to striatal synaptosomal

Acknowledgements

This research was supported by PHS grants DA 00869, DA 04222, DA 11389 and DA 00378.

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