title: Varied access to intravenous methamphetamine self-administration differentially alters adult hippocampal neurogenesis.
abstract: BACKGROUND
  Chronic abuse of methamphetamine produces deficits in hippocampal function, perhaps by altering hippocampal neurogenesis and plasticity. We examined how intravenous methamphetamine self-administration modulates active division, proliferation of late progenitors, differentiation, maturation, survival, and mature phenotype of hippocampal subgranular zone (SGZ) progenitors.
  
  
  METHODS
  Adult male Wistar rats were given access to methamphetamine 1 hour twice weekly (intermittent short), 1 hour daily (short), or 6 hours daily (long). Rats received one intraperitoneal injection of bromodeoxyuridine (BrdU) to label progenitors in the synthesis (S) phase, and 28-day-old surviving BrdU-immunoreactive (IR) cells were quantified. Ki-67, doublecortin (DCX), and activated caspase-3 (AC-3) were used to visualize and quantify proliferating, differentiating, maturing, and apoptotic cells. Terminal corticosterone was measured to determine changes in adrenal steroids.
  
  
  RESULTS
  Intermittent access to methamphetamine increased Ki-67 and DCX-IR cells, but opposing effects on late progenitors and postmitotic neurons resulted in no overall change in neurogenesis. Daily access to methamphetamine decreased all studied aspects of neurogenesis and reduced hippocampal granule neurons and volume, changes that likely are mediated by decreased proliferative and neurogenic capacity of the SGZ. Furthermore, methamphetamine self-administration relative to the amount of methamphetamine intake produced a biphasic effect on hippocampal apoptosis and reduced corticosterone levels.
  
  
  CONCLUSIONS
  Intermittent (occasional access) and daily (limited and extended access) self-administration of methamphetamine impact different aspects of neurogenesis, the former producing initial pro-proliferative effects and the latter producing downregulating effects. These findings suggest that altered hippocampal integrity by even modest doses of methamphetamine could account for pronounced pathology linked to methamphetamine abuse.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA. cmandyam@scripps.edu
authors.forename: Chitra D
authors.initials: CD
authors.lastname: Mandyam
authors.forename: Sunmee
authors.initials: S
authors.lastname: Wee
authors.forename: Elena F
authors.initials: EF
authors.lastname: Crawford
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Eisch
authors.forename: Heather N
authors.initials: HN
authors.lastname: Richardson
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001973:Bromodeoxyuridine / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D003345:Corticosterone / Q000097:blood; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007276:Injections, Intraventricular / Q000379:methods; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009479:Neuropeptides / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration / Q000379:methods; D013997:Time Factors
chemical_list: D000697:Central Nervous System Stimulants; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005904:Glial Fibrillary Acidic Protein; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D008694:Methamphetamine; D001973:Bromodeoxyuridine; D003345:Corticosterone