Elsevier

Biological Psychiatry

Volume 64, Issue 11, 1 December 2008, Pages 958-965
Biological Psychiatry

Archival Report
Varied Access to Intravenous Methamphetamine Self-Administration Differentially Alters Adult Hippocampal Neurogenesis

https://doi.org/10.1016/j.biopsych.2008.04.010Get rights and content

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.

Section snippets

Animals, Bromodeoxyuridine Injections, and Tissue Preparation

Adult male Wistar rats (Charles River, Wilmington, Massachusetts), weighing 250–300 g at the start of the experiment, were housed two/cage in a temperature-controlled vivarium under a reversed light/dark cycle (lights off 10:00 am–10:00 pm). Food and water were available ad libitum, except during the food training period. Rats were subjected to methamphetamine self-administration (6 hours long access [LgA group; n = 6], 1 hour short access [ShA group; n = 9], or 1 hour intermittent short access

Methamphetamine Self-Administration Alters Proliferation, Maturation, and Survival of Hippocampal Progenitor

Intermittent and daily access models of intravenous methamphetamine self-administration were used to investigate methamphetamine-induced alterations in adult hippocampal neurogenesis (Figure 1). Total methamphetamine intake was significantly different in each access group [intake over 49 days: I-ShA, 7.8 ± .01 mg/kg; ShA, 20.6 ± .03 mg/kg; LgA, 128.7 ± .44 mg/kg; F(2,20) = 84960, p < .0001], and methamphetamine self-administration during the first hour was considerably higher in LgA versus ShA

Discussion

The self-administration data from the I-ShA, ShA, and LgA rats provide evidence that distinct patterns of methamphetamine intake might be related to human patterns of methamphetamine abuse: recreational, chronic, and dependent. Given that experimenter-administered methamphetamine in rodents decreases hippocampal-dependent memory (42), that methamphetamine-dependent individuals show hippocampal dysfunction (2), and that hippocampal behavior is partly maintained by the generation of new

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