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.
Key Words
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Article info
Publication history
Published online: May 21, 2008
Accepted:
April 9,
2008
Received in revised form:
March 22,
2008
Received:
October 10,
2007
Identification
Copyright
Published by Elsevier Inc.
