Methamphetamine induces low levels of neurogenesis in striatal neuron subpopulations and differential motor performance.

Methamphetamine (METH) causes significant loss of some striatal projection and interneurons. Recently, our group reported on the proliferation of new cells 36 h after METH and some of the new cells survive up to 12 weeks (Tulloch et al., Neuroscience 193:162-169, 2011b). We hypothesized that some of these cells will differentiate and express striatal neuronal phenotypes. To test this hypothesis, mice were injected with METH (30 mg/kg) followed by a single BrdU injection (100 mg/kg) 36 h after METH. One week after METH, a population of BrdU-positive cells expressed the neuronal progenitor markers nestin (18 %) and ß-III-tubulin (30 %). At 8 weeks, 14 % of the BrdU-positive cells were also positive for the mature neuron marker, NeuN. At 12 weeks, approximately 7 % of the BrdU-positive cells co-labeled with ChAT, PV or DARPP-32. We measured motor coordination on the rotarod and psychomotor activity in the open-field. At 12 weeks, METH-injected mice exhibited delayed motor coordination deficits. In contrast, open-field tests revealed that METH-injected mice compared to saline mice displayed psychomotor deficits at 2.5 days but not at 2 or more weeks after METH. Taken together, these data demonstrate that some of the new cells generated in the striatum differentiate and express the phenotypes of striatal neurons. However, the proportion of these new neurons is low compared to the proportion that died by apoptosis 24 h after the METH injection. More studies are needed to determine if the new neurons are functional.

A single high dose of methamphetamine induces apoptotic and necrotic striatal cell loss lasting up to 3 months in mice.

Methamphetamine (METH) is an addictive agent that poses a public health problem due to its toxic effects on neural tissue. We have shown that METH induces striatal lesions (cell loss) within 24 h of administration. Because cell proliferation has been found to follow excitotoxic and other types of lesions in adult brain, we tested the hypothesis that cell proliferation would follow METH-induced striatal cell death. To that end, METH (30 mg/kg i.p.) was injected into adult male mice followed by a single injection of the proliferation marker 5-bromo-2'-deoxyuridine (BrdU, 100 mg/kg i.p.) at various times post-METH up to 12 weeks. Immunohistochemical analysis of striatal tissue showed that METH-treated animals incorporated BrdU between 24-48 h post-METH. To determine the survival of the newly generated cells, a subgroup of animals received BrdU 36 h after METH and were sacrificed at various times up to 12 weeks post-METH. Morphological analysis of striatal tissue from these animals showed that by 12 weeks post-METH, approximately 42% and 30% of the newly generated cells showed pyknotic or necrotic morphology, respectively. Thus, approximately 30% of the newly generated cells survive up to 12 weeks post-METH. Striatal volume was increased by METH and normalized to control levels by 12 weeks after METH. The data demonstrate that a single bolus injection of METH induces cellular changes and responses that persist for months after exposure to METH.