Methamphetamine (METH) users have compromised frontal-striatal brain systems, which include brain areas associated with inhibitory control, decision-making, working memory, and impulse control. Also, METH-induced terminal cell degeneration and neuronal apoptosis have been associated with multiple underlying events, including oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammatory responses. Mitochondria-related mechanisms have been suggested to mediate METH toxicity. For example, METH impairs enzymatic activity in the Krebs cycle and mitochondrial respiratory chain, and a single dose of METH causes mitochondrial dysfunction and oxidative stress in rat brain. Our preliminary data provides the first evidence that METH uses have decreased frontal phosphocreatine (PCr) levels compared to healthy controls. Thus, METH users may have a distinct pattern of bioenergetic dysfunction related to creatine kinase (CK), the enzyme that is directly involved in regeneration of adenosine triphosphate (ATP) from PCr. In the current application, we propose to use phosphorus-31 magnetization transfer image-selected in vivo spectroscopy (31P MT ISIS) to measure forward CK activity (kfor) and flux (kflux) in METH users and controls. This method will (1) utilize 31P volume coil for favorable spatial localization (2) minimize scalp muscle contamination with six outer volume 31P saturation bands, and (3) calculate the apparent relaxation rate (R'1) instead of the intrinsic relaxation rate (1/T1) to reduce the time required for direct measurement of T1. Neurodegenerative conditions such as Alzheimer's disease and Huntington's disease are associated with significant reductions in CK activity. Considering that structural and functional brain changes in METH users are similar to those found in neurodegenerative conditions and mitochondria are the major source of reactive oxygen species within neurons, we anticipate that measurement of CK kfor and kflux will provide new insights into how the PCr-creatine-CK system is affected by oxidative stress in METH use disorders. During the period of I/START funding, we propose to study twenty-three METH users and twenty-three age- and sex-matched healthy controls. We hypothesize that METH users will have bioenergetic dysfunction which is related to CK. Should abnormal kfor or kflux be identified in METH users, these observations would provide support for possible creatine supplementation to modify the PCr-creatine-CK system in METH users, since the potential therapeutic utility of creatine for the enhancement of bioenergetic metabolism has been documented in neurodegenerative disorders and creatine supplementation is reported to improve cognitive performance and mood.
The present phosphorus magnetization transfer spectroscopy (31P MT MRS) study will provide new insights into the potentially compromised creatine kinase enzyme activity and flux associated with high energy phosphate metabolism in methamphetamine (METH) users. This 31P MT MRS research project may ultimately contribute to the identification of novel substrates for treatment of METH abuse and dependence.
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