Biphasic dopamine regulation in mesoaccumbens pathway in response to non-contingent binge and escalating methamphetamine regimens in the Wistar rat

Courtney M. Keller, Michael Francis Salvatore, Brandon S. Pruett, Glenn F. Guerin, Nicholas E. Goeders

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)

Abstract

Rationale Methamphetamine (MA) increases extracellular dopamine (DA) and at chronic high doses induces toxicity as indicated by decreased expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT). Notably, rats will self-administer MA in escalating quantities producing such toxicity. However, the impact of MA at sub-toxic doses on DA regulation is not well established. Objective The temporal dynamics of DA regulation following cessation of sub-toxic escalating and binge doses of non-contingent MA were investigated as changes therein may be associated with escalation of MA intake. Materials and methods MA was administered 3×/day using an established 14-day escalating-dose regimen (0.1-4.0mg/kg) or a single-day binge-style administration (3×4 mg/kg). DA tissue content, DA turnover, TH protein, TH phosphorylation, DAT, and vesicular monoamine transporter 2 were measured in nigrostriatal and mesoaccumbens pathways 48 h and 2 weeks after MA cessation. Results Changes in striatal DA regulation were limited to increased DA turnover. However, in the mesoaccumbens pathway, escalating MA had biphasic effects. DA was increased in ventral tegmental area (VTA) and decreased in nucleus accumbens at 48 h post-MA while the reverse was seen at 2 weeks. These changes were matched by similar changes in TH protein and, in the VTA, by changes in DAT. Conclusion Escalation of MA intake produces both transient and long-lasting effects upon DA, TH, and DAT in the mesoaccumbens pathway. The eventual decrease of DA in the VTA is speculated to contribute to craving for MA and, thus, may be associated with MA escalation and resulting dopaminergic toxicity.

Original languageEnglish
Pages (from-to)513-526
Number of pages14
JournalPsychopharmacology
Volume215
Issue number3
DOIs
StatePublished - 1 Jun 2011

Fingerprint

Methamphetamine
Wistar Rats
Dopamine
Tyrosine 3-Monooxygenase
Dopamine Plasma Membrane Transport Proteins
Ventral Tegmental Area
Poisons
Vesicular Monoamine Transport Proteins
Corpus Striatum
Nucleus Accumbens
Proteins
Phosphorylation

Keywords

  • Dopamine
  • Dopamine transporter
  • Methamphetamine
  • Nigrostriatal
  • Nucleus accumbens
  • Signal transduction
  • Striatum
  • Substantia nigra
  • Tyrosine hydroxylase
  • Ventral tegmental area
  • Vesicular monoamine transporter

Cite this

@article{b70e5e499c4641a3a8bad72fa6a808c9,
title = "Biphasic dopamine regulation in mesoaccumbens pathway in response to non-contingent binge and escalating methamphetamine regimens in the Wistar rat",
abstract = "Rationale Methamphetamine (MA) increases extracellular dopamine (DA) and at chronic high doses induces toxicity as indicated by decreased expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT). Notably, rats will self-administer MA in escalating quantities producing such toxicity. However, the impact of MA at sub-toxic doses on DA regulation is not well established. Objective The temporal dynamics of DA regulation following cessation of sub-toxic escalating and binge doses of non-contingent MA were investigated as changes therein may be associated with escalation of MA intake. Materials and methods MA was administered 3×/day using an established 14-day escalating-dose regimen (0.1-4.0mg/kg) or a single-day binge-style administration (3×4 mg/kg). DA tissue content, DA turnover, TH protein, TH phosphorylation, DAT, and vesicular monoamine transporter 2 were measured in nigrostriatal and mesoaccumbens pathways 48 h and 2 weeks after MA cessation. Results Changes in striatal DA regulation were limited to increased DA turnover. However, in the mesoaccumbens pathway, escalating MA had biphasic effects. DA was increased in ventral tegmental area (VTA) and decreased in nucleus accumbens at 48 h post-MA while the reverse was seen at 2 weeks. These changes were matched by similar changes in TH protein and, in the VTA, by changes in DAT. Conclusion Escalation of MA intake produces both transient and long-lasting effects upon DA, TH, and DAT in the mesoaccumbens pathway. The eventual decrease of DA in the VTA is speculated to contribute to craving for MA and, thus, may be associated with MA escalation and resulting dopaminergic toxicity.",
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year = "2011",
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language = "English",
volume = "215",
pages = "513--526",
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Biphasic dopamine regulation in mesoaccumbens pathway in response to non-contingent binge and escalating methamphetamine regimens in the Wistar rat. / Keller, Courtney M.; Salvatore, Michael Francis; Pruett, Brandon S.; Guerin, Glenn F.; Goeders, Nicholas E.

In: Psychopharmacology, Vol. 215, No. 3, 01.06.2011, p. 513-526.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Biphasic dopamine regulation in mesoaccumbens pathway in response to non-contingent binge and escalating methamphetamine regimens in the Wistar rat

AU - Keller, Courtney M.

AU - Salvatore, Michael Francis

AU - Pruett, Brandon S.

AU - Guerin, Glenn F.

AU - Goeders, Nicholas E.

PY - 2011/6/1

Y1 - 2011/6/1

N2 - Rationale Methamphetamine (MA) increases extracellular dopamine (DA) and at chronic high doses induces toxicity as indicated by decreased expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT). Notably, rats will self-administer MA in escalating quantities producing such toxicity. However, the impact of MA at sub-toxic doses on DA regulation is not well established. Objective The temporal dynamics of DA regulation following cessation of sub-toxic escalating and binge doses of non-contingent MA were investigated as changes therein may be associated with escalation of MA intake. Materials and methods MA was administered 3×/day using an established 14-day escalating-dose regimen (0.1-4.0mg/kg) or a single-day binge-style administration (3×4 mg/kg). DA tissue content, DA turnover, TH protein, TH phosphorylation, DAT, and vesicular monoamine transporter 2 were measured in nigrostriatal and mesoaccumbens pathways 48 h and 2 weeks after MA cessation. Results Changes in striatal DA regulation were limited to increased DA turnover. However, in the mesoaccumbens pathway, escalating MA had biphasic effects. DA was increased in ventral tegmental area (VTA) and decreased in nucleus accumbens at 48 h post-MA while the reverse was seen at 2 weeks. These changes were matched by similar changes in TH protein and, in the VTA, by changes in DAT. Conclusion Escalation of MA intake produces both transient and long-lasting effects upon DA, TH, and DAT in the mesoaccumbens pathway. The eventual decrease of DA in the VTA is speculated to contribute to craving for MA and, thus, may be associated with MA escalation and resulting dopaminergic toxicity.

AB - Rationale Methamphetamine (MA) increases extracellular dopamine (DA) and at chronic high doses induces toxicity as indicated by decreased expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT). Notably, rats will self-administer MA in escalating quantities producing such toxicity. However, the impact of MA at sub-toxic doses on DA regulation is not well established. Objective The temporal dynamics of DA regulation following cessation of sub-toxic escalating and binge doses of non-contingent MA were investigated as changes therein may be associated with escalation of MA intake. Materials and methods MA was administered 3×/day using an established 14-day escalating-dose regimen (0.1-4.0mg/kg) or a single-day binge-style administration (3×4 mg/kg). DA tissue content, DA turnover, TH protein, TH phosphorylation, DAT, and vesicular monoamine transporter 2 were measured in nigrostriatal and mesoaccumbens pathways 48 h and 2 weeks after MA cessation. Results Changes in striatal DA regulation were limited to increased DA turnover. However, in the mesoaccumbens pathway, escalating MA had biphasic effects. DA was increased in ventral tegmental area (VTA) and decreased in nucleus accumbens at 48 h post-MA while the reverse was seen at 2 weeks. These changes were matched by similar changes in TH protein and, in the VTA, by changes in DAT. Conclusion Escalation of MA intake produces both transient and long-lasting effects upon DA, TH, and DAT in the mesoaccumbens pathway. The eventual decrease of DA in the VTA is speculated to contribute to craving for MA and, thus, may be associated with MA escalation and resulting dopaminergic toxicity.

KW - Dopamine

KW - Dopamine transporter

KW - Methamphetamine

KW - Nigrostriatal

KW - Nucleus accumbens

KW - Signal transduction

KW - Striatum

KW - Substantia nigra

KW - Tyrosine hydroxylase

KW - Ventral tegmental area

KW - Vesicular monoamine transporter

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U2 - 10.1007/s00213-011-2301-9

DO - 10.1007/s00213-011-2301-9

M3 - Article

VL - 215

SP - 513

EP - 526

JO - Psychopharmacologia

JF - Psychopharmacologia

SN - 0033-3158

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