| The commonly abused drug methamphetamine (METH) is toxic to monoamine axon terminals, and cause neuron death. However, the mechanisms and events following neurotoxic METH exposure are not fully understood. For example, numerous studies with rodent models of METH--induced damage show a disparity in the duration of neuron death. Additionally, the striatal volume of some human users is enlarged after METH, and is accompanied by normal cognitive and motor performance. However, participants with smaller striatal volume after METH have poor cognitive outcome. Gliogenesis and swelling from inflammation have been proposed as reasons for volume changes. However, explanations for variability in the time course of METH-induced cell death have not been addressed until now. Presented in this thesis are results from neurochemical and behavioral studies, which provide evidence that cytogenesis is in part, a mechanism for cognitive but not motor recovery after toxic METH damage. Cytogenesis is accompanied by increased striatal volume in adult mice. A significant proportion of the new cells die in a protracted manner over three months, accounting for the disparities in time course of METH-induced cell death. Furthermore, the results suggest volume changes may be due to both gliogenesis and neurogenesis because proportions of the newly generated cells remaining at 12 weeks express histochemical markers for astrocytes, microglia, and neurons. Small sub-populations of the new neurons express histochemical markers for parvalbumin and choline acetyltransferase interneurons that were lost during acute METH damage. Neuron maturation is accompanied by improved habit learning on a reinforced T-maze task. However, motor deficits persist and even worsen as METH-treated mice age. Measures of activity in the open-field suggest these behavioral effects were not due to anxiety, as METH-treated mice also show deficits in motor related measures but hardly differ from control mice on anxiety measures. More studies are needed to advance understanding of the underlying mechanisms of damage and facilitate recovery from the effects of this increasingly abused substance. Therefore, studies designed to identify the remaining new cells and the role damage-induced cytogenesis may play in addiction and motor disorders are not only needed, but are logical extensions of the data presented. |
