Elsevier

Experimental Neurology

Volume 207, Issue 1, September 2007, Pages 42-51
Experimental Neurology

Escalating dose-multiple binge methamphetamine exposure results in degeneration of the neocortex and limbic system in the rat

https://doi.org/10.1016/j.expneurol.2007.05.023Get rights and content

Abstract

Abuse of stimulant drugs such as methamphetamine (METH) and cocaine has been associated with long-lasting persistent behavioral alterations. Although METH-induced changes in the striatal dopaminergic system might play a role in these effects, the potential underlying neuroanatomical substrate for the chronic cognitive dysfunction in METH users is unclear. To investigate the involvement of non-dopaminergic systems in the neurotoxic effects of METH, we treated rats with an escalating dose-multiple binge regimen, which we have suggested may more closely simulate human METH exposure profiles. Combined neuropathological and stereological analyses showed that 30 days after the last binge, there was shrinkage and degeneration in the pyramidal cell layers of the frontal cortex and in the hippocampal CA3 region. Further immunocytochemical analysis showed that METH exposure resulted in loss of calbindin interneurons in the neocortex and selective damage to pyramidal neurons in the CA3 region of the hippocampus and granular cells in the dentate gyrus that was accompanied by microglial activation. Taken together, these studies suggest that selective degeneration of pyramidal neurons and interneurons in the neocortex and limbic system might be involved in the cognitive alterations in METH users.

Introduction

Methamphetamine (METH) abuse has been associated with persistent behavioral changes and relatively long-lasting functional alterations (Kalechstein et al., 2003, London et al., 2004, Nordahl et al., 2003, Sim et al., 2002, Simon et al., 2002, Volkow et al., 2001b, Volkow et al., 2001c). Most efforts to study potential underlying neuroanatomical/neurochemical substrates have focused on dopamine (DA) systems, particularly striatal DA, because DA appears to play a critical role in the behavioral and reinforcing effects of METH-like stimulants (Creese and Iversen, 1974, Koob et al., 1998, Swerdlow et al., 1986, Wise and Rompre, 1989), and because striatal DA appears to be particularly susceptible to persistent alterations when exposed to high doses of this drug. In animal models, acute administration of high doses of METH results in decrements in markers of striatal DA nerve terminals (Maragos et al., 2002, Ricaurte et al., 1982, Ricaurte et al., 2002). Similarly, METH abusers also exhibit striatal DA decrements, and these alterations can persist for prolonged periods (McCann et al., 1998, Sekine et al., 2001, Volkow et al., 2001a). While the neurotoxic effects of METH in the nigral system might explain some of the behavioral and motor alterations, the anatomical bases for the cognitive disturbances in these patients are less well understood and suggest that other neuronal populations in the neocortex and limbic system might be affected by METH.

In support of this possibility, previous studies have shown that in addition to striatal DA, other non-striatal, non-DA systems are altered by exposure to METH. For example, early studies indicated that METH promoted persistent decrements in serotonin, particularly in the hippocampus (see, for example, (Ricaurte et al., 1980)), and more recently METH-induced damage to neurons in the somatosensory cortex has been characterized by TUNEL staining (Deng et al., 2001), and documented utilizing fluoro-Jade detection (Schmued and Bowyer, 1997) and other techniques (O'Dell and Marshall, 2000, Pu et al., 1996). Likewise, in human METH abusers, persistent alterations and structural abnormalities have been reported in brain regions receiving relatively sparse DA innervation (Volkow et al., 2001b). Moreover, recent studies have shown that in HIV patients with a history of METH abuse there is considerable damage to calbindin-immunoreactive interneurons in the neocortex and striatum (Langford et al., 2003) that is associated with the memory deficits in these patients (Chana et al., 2006). Taken together, these studies suggest that METH might damage other non-DA neuronal populations involved in cognitive function. However, very limited experimental data are currently available about neuronal populations affected in models of METH toxicity.

To further examine potential neuronal damage associated with METH exposure, we treated animals with an escalating dose-multiple binge (ED-MB) treatment regimen which we have suggested may more closely simulate human METH exposure profiles (Segal and Kuczenski, 1997, Segal et al., 2003), and combined neuropathological, stereological and immunocytochemical analyses were used to assess potential alterations. Our analyses revealed decrements in two unique populations of neurons in the neocortex and hippocampus.

Section snippets

Animals

For these studies a total of 30 male Sprague–Dawley rats (Harlan Labs, San Diego, CA) weighing 325–350 g at the beginning of drug treatment, were housed for at least 1 week prior to treatment in groups of two or three in wire mesh cages, with ad libitum access to food and water, in a temperature- and humidity-controlled room. The room was maintained on a reversed 12 h dark (0700–1900), 12 h light cycle to enable experimentation during the normal active phase of the awake/sleeping cycle. During

Degeneration of pyramidal neurons in the neocortex and hippocampus after METH binge

To investigate the patterns of neurodegeneration after the ED-MB treatment, neuropathological analysis was performed in cresyl violet-stained sections. Compared to saline-treated controls (Figs. 1A, D, G), at 3 days after the last binge with METH, pyramidal neurons in the frontal cortex and the CA3 region of the hippocampus displayed mild shrinkage and disorganization that at 30 days after the last administration of METH became more severe (Figs. 1B, E, H). Stereological analysis showed that

Discussion

The present study shows that, in addition to the well-known METH-induced disruption of striatal dopaminergic nerve terminals, prolonged METH exposure also results in extensive damage to pyramidal cells and interneurons in the neocortex and hippocampus. Importantly, persistent METH-induced alterations in cortical and hippocampal systems have also been documented in HIV+ patients with a history of METH abuse (Langford et al., 2003). Although no corroborating studies have been performed in non-HIV

Acknowledgments

This work was supported by NIH Grants MH59745, MH45294, MH58164, DA12065, DA01568, and DA02854, and a HNRC pilot project award. The HIV Neurobehavioral Research Center (HNRC) is supported by the Center award MH 62512 from NIMH.

References (59)

  • M.P. Paulus et al.

    Decision making by methamphetamine-dependent subjects is associated with error-rate-independent decrease in prefrontal and parietal activation

    Biol. Psychiatry

    (2003)
  • M.P. Paulus et al.

    Behavioral and functional neuroimaging evidence for prefrontal dysfunction in methamphetamine-dependent subjects

    Neuropsychopharmacology

    (2002)
  • G.A. Ricaurte et al.

    Dopamine nerve terminal degeneration produced by high doses of methylamphetamine in the rat brain

    Brain Res.

    (1982)
  • G.A. Ricaurte et al.

    Long-term effects of repeated methylamphetamine administration on dopamine and serotonin neurons in the rat brain: a regional study

    Brain Res.

    (1980)
  • R. Salo et al.

    Preliminary evidence of reduced cognitive inhibition in methamphetamine-dependent individuals

    Psychiatry Res.

    (2002)
  • L. Schmued et al.

    Methamphetamiine exposure can produce neuronal degeneration in mouse hippocampal remnants

    Brain Res.

    (1997)
  • N.R. Swerdlow et al.

    The neural substrates for the motor-activating properties of psychostimulants: a review of recent findings

    Pharmacol. Biochem. Behav.

    (1986)
  • D.M. Thomas et al.

    Microglial activation is a pharmacologically specific marker for the neurotoxic amphetamines

    Neurosci. Lett.

    (2004)
  • H. Barbas et al.

    Relationship of prefrontal connections to inhibitory systems in superior temporal areas in the rhesus monkey

    Cereb. Cortex

    (2005)
  • G. Chana et al.

    Cognitive deficits in HIV+ methamphetamine users

    Neurology

    (2006)
  • J.E. Crandall et al.

    Cocaine exposure decreases GABA neuron migration from the ganglionic eminence to the cerebral cortex in embryonic mice

    Cereb. Cortex

    (2004)
  • I. Creese et al.

    The role of forebrain dopamine systems in amphetamine induced stereotyped behavior in the rat

    Psychopharmacologia

    (1974)
  • T.C. Dumas et al.

    Overexpression of calbindin D(28k) in dentate gyrus granule cells alters mossy fiber presynaptic function and impairs hippocampal-dependent memory

    Hippocampus

    (2004)
  • G. Flora et al.

    Methamphetamine-induced TNF-alpha gene expression and activation of AP-1 in discrete regions of mouse brain: potential role of reactive oxygen intermediates and lipid peroxidation

    Neuromol. Med.

    (2002)
  • A.D. Kalechstein et al.

    Methamphetamine dependence is associated with neurocognitive impairment in the initial phases of abstinence

    J. Neuropsychiatry Clin. Neurosci.

    (2003)
  • H. Koller et al.

    HIV-1 protein Tat reduces the glutamate-induced intracellular Ca2+ increase in cultured cortical astrocytes

    Eur. J. Neurosci.

    (2001)
  • R. Kuczenski et al.

    Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine

    J. Neurosci.

    (1995)
  • D. Langford et al.

    Patterns of selective neuronal damage in methamphetamine-user AIDS patients

    J. Acquir. Immune Defic. Syndr.

    (2003)
  • A. Lawton-Craddock et al.

    Cognitive efficiency in stimulant abusers with and without alcohol dependence

    Alcohol Clin. Exp. Res.

    (2003)
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