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