Neuronal dopamine transporter activity, density and methamphetamine inhibition are differentially altered in the nucleus accumbens and striatum with no changes in glycosylation in rats behaviorally sensitized to methamphetamine

Nicole L. Bjorklund, Barbara A. Sorg, James O. Schenk

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16 Citations (Scopus)

Abstract

Animals sensitized to methamphetamine (METH) have altered dopaminergic systems, including dopamine transporter (DAT) activity. We investigated the effects induced by a sensitizing dose (5 mg/kg, i.p. per day for 5 days) of METH on rat behavior, DA transport by the DAT, DAT density, and inhibition of DA transport by METH in both the nucleus accumbens and striatum. We further investigated possible changes to glycosylation of the DAT after METH sensitization. The dosing paradigm caused an increased stereotyped response in rats treated with METH compared with saline controls. In animals treated with METH, DA transport velocities were increased by 6.4% in the nucleus accumbens and decreased by 21% in the striatum. Western blots demonstrated that DAT density was unchanged in the nucleus accumbens of METH-treated animals, but striatal DAT density was decreased by 20%. Further studies investigating METH inhibition of DA transport found that in the nucleus accumbens of METH-treated animals, the IC50 was shifted to a larger value (from 0.81 to 1.45 μM). In the striatum, the IC50 was decreased by 19% (from 1.00 to 0.81 μM) in METH-treated animals. Studies using glycosidase treatments and Western blots revealed that glycosylation was effectively removed by N-glycanase and neuraminidase, but not O-glycosidase or α-mannosidase. These studies also suggest that glycosylation was not altered in METH-treated animals. This study demonstrates that in animals sensitized to METH, the DAT is differentially regulated in different areas of the brain important for drug abuse, and that DA transport changes induced by METH are not due to DAT density, but to changes in the kinetics of the DAT. Additionally, this study suggests that glycosylation may not play a role in DAT activity changes after METH exposure.

Original languageEnglish (US)
Pages (from-to)736-745
Number of pages10
JournalSynapse
Volume62
Issue number10
DOIs
StatePublished - Oct 2008
Externally publishedYes

Fingerprint

Dopamine Plasma Membrane Transport Proteins
Methamphetamine
Nucleus Accumbens
Glycosylation
Glycoside Hydrolases
Inhibitory Concentration 50
Western Blotting
Mannosidases
Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
Corpus Striatum
Neuraminidase
Substance-Related Disorders

Keywords

  • Drugs of abuse
  • Glycosylation
  • Neuroadaptation
  • Rotating disk electrode voltammetry

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology
  • Pharmacology
  • Advanced and Specialized Nursing

Cite this

@article{d3ff042aaaed42dd9e8a4648b9636a2e,
title = "Neuronal dopamine transporter activity, density and methamphetamine inhibition are differentially altered in the nucleus accumbens and striatum with no changes in glycosylation in rats behaviorally sensitized to methamphetamine",
abstract = "Animals sensitized to methamphetamine (METH) have altered dopaminergic systems, including dopamine transporter (DAT) activity. We investigated the effects induced by a sensitizing dose (5 mg/kg, i.p. per day for 5 days) of METH on rat behavior, DA transport by the DAT, DAT density, and inhibition of DA transport by METH in both the nucleus accumbens and striatum. We further investigated possible changes to glycosylation of the DAT after METH sensitization. The dosing paradigm caused an increased stereotyped response in rats treated with METH compared with saline controls. In animals treated with METH, DA transport velocities were increased by 6.4{\%} in the nucleus accumbens and decreased by 21{\%} in the striatum. Western blots demonstrated that DAT density was unchanged in the nucleus accumbens of METH-treated animals, but striatal DAT density was decreased by 20{\%}. Further studies investigating METH inhibition of DA transport found that in the nucleus accumbens of METH-treated animals, the IC50 was shifted to a larger value (from 0.81 to 1.45 μM). In the striatum, the IC50 was decreased by 19{\%} (from 1.00 to 0.81 μM) in METH-treated animals. Studies using glycosidase treatments and Western blots revealed that glycosylation was effectively removed by N-glycanase and neuraminidase, but not O-glycosidase or α-mannosidase. These studies also suggest that glycosylation was not altered in METH-treated animals. This study demonstrates that in animals sensitized to METH, the DAT is differentially regulated in different areas of the brain important for drug abuse, and that DA transport changes induced by METH are not due to DAT density, but to changes in the kinetics of the DAT. Additionally, this study suggests that glycosylation may not play a role in DAT activity changes after METH exposure.",
keywords = "Drugs of abuse, Glycosylation, Neuroadaptation, Rotating disk electrode voltammetry",
author = "Bjorklund, {Nicole L.} and Sorg, {Barbara A.} and Schenk, {James O.}",
year = "2008",
month = "10",
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T1 - Neuronal dopamine transporter activity, density and methamphetamine inhibition are differentially altered in the nucleus accumbens and striatum with no changes in glycosylation in rats behaviorally sensitized to methamphetamine

AU - Bjorklund, Nicole L.

AU - Sorg, Barbara A.

AU - Schenk, James O.

PY - 2008/10

Y1 - 2008/10

N2 - Animals sensitized to methamphetamine (METH) have altered dopaminergic systems, including dopamine transporter (DAT) activity. We investigated the effects induced by a sensitizing dose (5 mg/kg, i.p. per day for 5 days) of METH on rat behavior, DA transport by the DAT, DAT density, and inhibition of DA transport by METH in both the nucleus accumbens and striatum. We further investigated possible changes to glycosylation of the DAT after METH sensitization. The dosing paradigm caused an increased stereotyped response in rats treated with METH compared with saline controls. In animals treated with METH, DA transport velocities were increased by 6.4% in the nucleus accumbens and decreased by 21% in the striatum. Western blots demonstrated that DAT density was unchanged in the nucleus accumbens of METH-treated animals, but striatal DAT density was decreased by 20%. Further studies investigating METH inhibition of DA transport found that in the nucleus accumbens of METH-treated animals, the IC50 was shifted to a larger value (from 0.81 to 1.45 μM). In the striatum, the IC50 was decreased by 19% (from 1.00 to 0.81 μM) in METH-treated animals. Studies using glycosidase treatments and Western blots revealed that glycosylation was effectively removed by N-glycanase and neuraminidase, but not O-glycosidase or α-mannosidase. These studies also suggest that glycosylation was not altered in METH-treated animals. This study demonstrates that in animals sensitized to METH, the DAT is differentially regulated in different areas of the brain important for drug abuse, and that DA transport changes induced by METH are not due to DAT density, but to changes in the kinetics of the DAT. Additionally, this study suggests that glycosylation may not play a role in DAT activity changes after METH exposure.

AB - Animals sensitized to methamphetamine (METH) have altered dopaminergic systems, including dopamine transporter (DAT) activity. We investigated the effects induced by a sensitizing dose (5 mg/kg, i.p. per day for 5 days) of METH on rat behavior, DA transport by the DAT, DAT density, and inhibition of DA transport by METH in both the nucleus accumbens and striatum. We further investigated possible changes to glycosylation of the DAT after METH sensitization. The dosing paradigm caused an increased stereotyped response in rats treated with METH compared with saline controls. In animals treated with METH, DA transport velocities were increased by 6.4% in the nucleus accumbens and decreased by 21% in the striatum. Western blots demonstrated that DAT density was unchanged in the nucleus accumbens of METH-treated animals, but striatal DAT density was decreased by 20%. Further studies investigating METH inhibition of DA transport found that in the nucleus accumbens of METH-treated animals, the IC50 was shifted to a larger value (from 0.81 to 1.45 μM). In the striatum, the IC50 was decreased by 19% (from 1.00 to 0.81 μM) in METH-treated animals. Studies using glycosidase treatments and Western blots revealed that glycosylation was effectively removed by N-glycanase and neuraminidase, but not O-glycosidase or α-mannosidase. These studies also suggest that glycosylation was not altered in METH-treated animals. This study demonstrates that in animals sensitized to METH, the DAT is differentially regulated in different areas of the brain important for drug abuse, and that DA transport changes induced by METH are not due to DAT density, but to changes in the kinetics of the DAT. Additionally, this study suggests that glycosylation may not play a role in DAT activity changes after METH exposure.

KW - Drugs of abuse

KW - Glycosylation

KW - Neuroadaptation

KW - Rotating disk electrode voltammetry

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U2 - 10.1002/syn.20528

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