Calcitriol and Methamphetamine Neurotoxicity

Methamphetamine (METH) is a potent psychomotor stimulant that has high potential for abuse in humans. METH is also a neurotoxin, affecting primarily central dopamine (DA) and serotonin (5-HT) neurons. The abuse potential of METH, together with its neurotoxic effects, make METH an important drug from the standpoint that chronic use by humans may lead to long-term or permanent changes in brain neurochemistry and function. The experiments in this R21 exploratory grant proposal will focus on the ability of calcitriol, the active metabolite of vitamin 0, to prevent the neurotoxic effects of METH on brain monoamine neurons and to restore function to damaged neurons. Several reports have indicated that calcitriol provides significant neuroprotection against various lesions, possibly by upregulating trophic factors such as GDNF. GDNF has been shown to have protective and restorative effects for brain DA neurons. Thus, it is possible that systemic administration of calcitriol may be able to prevent or reduce METH-induced damage to monoamine neurons and help restore function to neurons previously damaged by METH. It is hypothesized that calcitriol will protect against the neurotoxic effects of METH on striatal DA and 5-HT terminals, and that calcitriol will be effective in reversing METH-induced damage to striatal DA and 5-HT terminals. This hypothesis will be tested by addressing the following two specific aims: 1) Does pretreatment with calcitriol prevent or reduce METH-induced reductions in striatal monoamine release and content? and 2) Can calcitriol treatment accelerate recovery of striatal monoamine release and content in animals previously administered neurotoxic doses of METH? For these experiments rats will be treated with calcitriol before or after administration of saline or neurotoxic doses of METH. Microdialysis studies and post-mortem monoamine analyses will be carried out to investigate protective and restorative effects, Calcitriol induced upregulation of GDNF will be examined as an initial investigation into the mechanism of any neuroprotective or restorative effects observed. Relevance to Public Health: METH abuse and addiction is a major public health issue in the United States. The results of the experirnents in this proposal will help determine the extent to which calcitriol can protect against the neurotoxic effects of METH, and if calcitriol can restore damage resulting from neurotoxic doses of METH. If calcitriol proves effective, the results of the proposed studies could lead to novel therapeutic strategies for treating individuals who chronically abuse METH. Furthermore, if calcitriol is effective, it could have therapeutic applications in other disease processes where there is a loss of monoamine neurons, such as in Parkinson's disease.