title: Biphasic dopamine regulation in mesoaccumbens pathway in response to non-contingent binge and escalating methamphetamine regimens in the Wistar rat.
abstract: BACKGROUND
  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.
  
  
  METHODS
  MA was administered 3×/day using an established 14-day escalating-dose regimen (0.1-4.0 mg/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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Sciences Center in Shreveport, Shreveport, LA 71130, USA.
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Keller
authors.forename: Michael F
authors.initials: MF
authors.lastname: Salvatore
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Pruett
authors.forename: Glenn F
authors.initials: GF
authors.lastname: Guerin
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Goeders
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine