Biomedical subjects

Annette E Fleckenstein

Publications and source records attributed to Annette E Fleckenstein.

28 records · Page 2Linked to original sources

PubMed2003

Methamphetamine rapidly decreases mouse vesicular dopamine uptake: role of hyperthermia and dopamine D2 receptors.

Multiple high-dose administrations of the dopamine-releasing agent, methamphetamine, rapidly and persistently decrease vesicular dopamine uptake in purified vesicles prepared from striata of treated rats. Because important differences in the neurotoxic effects of stimulants have been documented in rats and mice, the purpose of this study was to determine if methamphetamine-induced effects in rats occur in mice and to elucidate mechanisms underlying these effects. Results reveal methamphetamine treatment rapidly decreased mouse striatal vesicular dopamine uptake; a phenomenon associated with a subcellular redistribution of vesicular monoamine transporter-2 (VMAT-2) immunoreactivity. Both methamphetamine-induced hyperthermia and dopamine D2 receptor activation contributed to the stimulant-induced deficits in vesicular dopamine uptake. Unlike methamphetamine, the dopamine reuptake inhibitors, methylphenidate and cocaine, rapidly increased vesicular dopamine uptake. The implications of these phenomena are discussed.

Animals↗

PubMed2003

Ceramide-induced alterations in dopamine transporter function.

The purpose of this study was to determine the effects of ceramide on dopamine and serotonin (5-HT, 5-hydroxytryptamine) transporters. Exposure of rat striatal synaptosomes to C2-ceramide caused a reversible, concentration-dependent decrease in plasmalemmal dopamine uptake. In contrast, ceramide exposure increased striatal 5-HT synaptosomal uptake. This increase did not appear to be due to an increased uptake by the 5-HT transporter. Rather, the increase appeared to result from an increase in 5-HT transport through the dopamine transporter, an assertion evidenced by findings that this increase: (1) does not occur in hippocampal synaptosomes (i.e., a preparation largely devoid of dopamine transporters), (2) occurs in striatal synaptosomes prepared from para-chloroamphetamine-treated rats (i.e., a preparation lacking 5-HT transporters), (3) is attenuated by pretreatment with methylphenidate (i.e., a relatively selective dopamine reuptake inhibitor) and (4) is inhibited by exposure to exogenous dopamine (i.e., which presumably competes for uptake with 5-HT). Taken together, these results reveal that ceramide is a novel modulator of monoamine transporter function, and may alter the affinity of dopamine transporters for its primary substrate.

Animals↗

PubMed2003

Methylphenidate alters vesicular monoamine transport and prevents methamphetamine-induced dopaminergic deficits.

It has been hypothesized that high-dose methamphetamine treatment rapidly redistributes cytoplasmic dopamine within nerve terminals, leading to intraneuronal reactive oxygen species formation and well characterized persistent dopamine deficits. We and others have reported that in addition to this persistent damage, methamphetamine treatment rapidly decreases vesicular dopamine uptake, as assessed in purified vesicles prepared from treated rats; a phenomenon that may contribute to aberrant intraneuronal dopamine redistribution proposedly caused by the stimulant. Interestingly, post-treatment with dopamine transporter inhibitors protect against the persistent dopamine deficits caused by methamphetamine; however, mechanisms underlying this phenomenon have not been elucidated. Also of interest are findings that dopamine transporter inhibitors, including methylphenidate, rapidly increase 1) vesicular dopamine uptake, 2) vesicular monoamine transporter-2 (VMAT-2) ligand binding, and 3) VMAT-2 immunoreactivity in a vesicular subcellular fraction prepared from treated rats. Therefore, we hypothesized that methylphenidate post-treatment might protect against the persistent striatal dopamine deficits caused by methamphetamine by rapidly affecting VMAT-2 and vesicular dopamine content. Results reveal that methylphenidate post-treatment both prevents the persistent dopamine deficits and reverses the acute decreases in vesicular dopamine uptake and VMAT-2 ligand binding caused by methamphetamine treatment. In addition, methylphenidate post-treatment reverses the acute decreases in vesicular dopamine content caused by methamphetamine treatment. Taken together, these findings suggest that methylphenidate prevents persistent methamphetamine-induced dopamine deficits by redistributing vesicles and the associated VMAT-2 protein and presumably affecting dopamine sequestration. These findings not only provide insight into the neurotoxic effects of methamphetamine but also mechanisms underlying dopamine neurodegenerative disorders, including Parkinson's disease.

Adrenergic Uptake Inhibitors↗

PubMed2002

Inhibitory effect of reserpine on dopamine transporter function.

Previous studies indicate that reserpine may disrupt dopamine transporter activity. Results presented herein reveal that it also inhibits potently synaptosomal [3H]dopamine uptake. In addition, reserpine administration to rats decreased the V(max) of synaptosomal dopamine transport, as assessed ex vivo 12 h after treatment. This decrease appeared, at least in part, dissociated from concurrent inhibition of the vesicular monoamine transporter-2 (VMAT-2). In separate experiments, synaptosomal dopamine uptake did not differ between wild-type and heterozygous VMAT-2 knockout mice, and reserpine treatment did not inhibit [3H]dopamine uptake into cells heterogously expressing the human dopamine transporter. Taken together, these data suggest that reserpine may transiently alter dopamine transporter function in a noncompetitive, indirect manner.

Animals↗

PubMed2002

Methylphenidate redistributes vesicular monoamine transporter-2: role of dopamine receptors.

It is well accepted that methylphenidate (MPD) inhibits dopamine (DA) transporter function. In addition to this effect, this study demonstrates that MPD increases vesicular [3H]DA uptake and binding of the vesicular monoamine transporter-2 (VMAT-2) ligand dihydrotetrabenazine (DHTBZ) in a dose- and time-dependent manner in purified striatal vesicles prepared from treated rats. This change did not result from residual MPD introduced by the original in vivo treatment, because application of MPD in vitro (< or =1 miccrom) was without effect, and higher concentrations decreased vesicular [3H]DA uptake. In addition, MPD treatment increased and decreased VMAT-2 immunoreactivity in striatal vesicle subcellular and plasmalemmal membrane fractions, respectively. The MPD-induced increase in both VMAT-2 immunoreactivity and DHTBZ binding was attenuated by pretreatment in vivo with either the DA D(1) receptor antagonist SCH23390 or the DA D2 receptor antagonist eticlopride. Coadministration of these antagonists in vivo inhibited completely the MPD-induced increase in DHTBZ binding in the purified vesicular preparation. These observations suggest a role for DA in the MPD-induced redistribution of VMAT-2. The implications of this phenomenon will be discussed.

Animals↗

PubMed2002

Differential trafficking of the vesicular monoamine transporter-2 by methamphetamine and cocaine.

High-dose administration of cocaine or methamphetamine to rats acutely (< or = 24 h) alters vesicular dopamine transport. This study elucidates the nature of these changes. Results reveal a differential redistribution of the vesicular monoamine transporter-2 (VMAT-2) within striatal synaptic terminals after drug treatment. In particular, cocaine shifts VMAT-2 protein from a synaptosomal membrane fraction to a vesicle-enriched fraction, as assessed ex vivo in fractions prepared from treated rats. In contrast, methamphetamine treatment redistributes VMAT-2 from a vesicle-enriched fraction to a location that is not retained in a synaptosomal preparation. These data suggest that psychostimulants acutely and differentially affect VMAT-2 subcellular localization.

Animals↗

PubMed2002

Phencyclidine increases vesicular dopamine uptake.

Phencyclidine (PCP) rapidly (within 1 h) increased vesicular dopamine uptake and binding of the vesicular monoamine transporter-2 (VMAT-2) ligand, dihydrotetrabenazine. Uptake returned to basal values 3 h in the striatum after a high-dose administration of this drug (15 mg/kg i.p.). In contrast, a similar pretreatment with another non-competitive NMDA receptor antagonist, dizocilpine;([5R,10S]-[+]-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine; MK-801; 1 mg/kg, i.p.), was without effect on vesicular dopamine uptake. Pretreatment with the dopamine D2 receptor antagonist, eticlopride, blocked the increase in vesicular dopamine uptake caused by PCP administration. These data demonstrate a heretofore unreported mechanism that may contribute to the ability of PCP to influence dopamine neuronal function and exert its pharmacological effects.

Animals↗

PubMed2002

Tolerance to the neurotoxic effects of methamphetamine in young rats.

The present study examined whether exposure to methamphetamine during adolescence (as determined in post-natal day 40 rats) might alter its effects when used in young adulthood (as assessed in post-natal day 90 rats). Results confirm that high-dose methamphetamine administration (4x10 mg/kg/injection, s.c., 2-h intervals) decreases striatal dopamine uptake and transporter ligand binding in post-natal day 90 rats; effects that were blocked if animals received six biweekly methamphetamine pretreatments (15 mg/kg; s.c.) beginning at post-natal day 40. This neuroprotection was not likely due to pharmacokinetic tolerance, since brain methamphetamine concentrations did not differ 1 h after the high-dose methamphetamine regimen among treated rats regardless of pretreatment. The methamphetamine biweekly pretreatment attenuated the hyperthermia caused by the neurotoxic methamphetamine regimen; a phenomenon that may have contributed to the neuroprotection.

Age Factors↗

PubMed2002

Methylenedioxymethamphetamine decreases plasmalemmal and vesicular dopamine transport: mechanisms and implications for neurotoxicity.

Administration of a high-dose regimen of methamphetamine (METH) rapidly and profoundly decreases plasmalemmal and vesicular dopamine (DA) transport in the striatum, as assessed in synaptosomes and purified vesicles, respectively. To determine whether these responses were common to other amphetamines of abuse, effects of methylenedioxymethamphetamine (MDMA) on the plasmalemmal DA transporter (DAT) and vesicular monoamine transporter-2 (VMAT-2) were assessed. Similar to effects of METH reported previously, multiple high-dose MDMA administrations rapidly (within 1 h) decreased plasmalemmal DA uptake, as assessed ex vivo in synaptosomes prepared from treated rats. Unlike effects of multiple METH injections, this deficit was reversed completely 24 h after drug treatment. Also in contrast to effects of multiple METH injections, 1) MDMA caused little or no decrease in binding of the DAT ligand WIN35428, and 2) neither prevention of hyperthermia nor prior depletion of DA prevented the MDMA-induced reduction in plasmalemmal DA transport. However, a role for phosphorylation was suggested because pretreatment with protein kinase C inhibitors attenuated the deficit caused by MDMA in an in vitro model system. In addition to affecting DAT function, MDMA rapidly decreased vesicular DA transport as assessed in striatal vesicles prepared from treated rats. Unlike effects of multiple METH injections reported previously, this decrease partially recovered by 24 h after drug treatment. Taken together, these results reveal several differences between effects of MDMA and previously reported METH on DAT and VMAT-2; differences that may underlie the dissimilar neurotoxic profile of these agents.

Animals↗

PubMed2002

A single methamphetamine administration rapidly decreases vesicular dopamine uptake.

Recent studies demonstrated that vesicular dopamine (DA) uptake can be rapidly altered in synaptic vesicles purified from the striata of stimulant-treated rats. Specifically, a single administration of the plasmalemmal DA transporter inhibitor, cocaine, or the DA D(2) agonist, quinpirole, increases vesicular DA uptake in vesicles purified from the striata of treated rats. These effects of cocaine are prevented by pretreatment with a D(2), but not D(1), DA receptor antagonist. The purpose of the present study was to characterize the effect of a mechanistically different psychostimulant, methamphetamine (METH), on vesicular DA uptake. Results demonstrated that a single administration of this DA-releasing agent rapidly and reversibly decreased vesicular DA uptake. The METH-related decrease in vesicular DA uptake was attenuated by pretreatment with the D(2) antagonist, eticlopride, but not the D(1) antagonist, SCH23390 (R-[+]-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine). Core body temperature did not contribute to the effects of METH on vesicular DA uptake. Neither quinpirole nor cocaine increased vesicular DA uptake when rats were concurrently treated with METH. These studies provide further evidence that psychostimulants rapidly and differentially modify vesicular DA uptake. In addition, these studies demonstrate a complex role for D(2) DA receptors in altering vesicular DA transport.

Animals↗