TY - JOUR
T1 - Varied Access to Intravenous Methamphetamine Self-Administration Differentially Alters Adult Hippocampal Neurogenesis
AU - Mandyam, Chitra D.
AU - Wee, Sunmee
AU - Crawford, Elena F.
AU - Eisch, Amelia J.
AU - Richardson, Heather N.
AU - Koob, George F.
N1 - Funding Information:
Funds from the National Institute on Drug Abuse (DA010072 to GFK, DA022473 to CDM) supported the study. We acknowledge the excellent technical assistance of Ron Smith for volumetric analysis; Mike Pham, Hanan Jammal, and Krisha Begalla from the independent study program at University of California, San Diego; and Simon Huynh and Guadalupe Coronado from the Harvey Mudd College Upward Bound Program for assistance with animal behavior and immunohistochemistry. We thank Drs. Xiaoying Lu and Donna Gruol for assistance with confocal microscopy and Caroline Lanigan for assistance with statistical analysis. We appreciate the technical support of Robert Lintz, Yanabel Grant, and Dr. Thomas Greenwell; the editorial assistance of Mike Arends; and Dr. Olivier George for critical reading of the manuscript. This is publication number 19005 from The Scripps Research Institute.
PY - 2008/12/1
Y1 - 2008/12/1
N2 - 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.
AB - 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.
KW - Bromodeoxyuridine
KW - Ki-67
KW - doublecortin
KW - extended access
KW - psychostimulant
KW - subgranular zone
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U2 - 10.1016/j.biopsych.2008.04.010
DO - 10.1016/j.biopsych.2008.04.010
M3 - Article
C2 - 18490002
AN - SCOPUS:54549098178
SN - 0006-3223
VL - 64
SP - 958
EP - 965
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 11
ER -