We have combined PET imaging with continuous 18F-deoxy-glucose PET and dynamic 1H-MRS focused on the prefrontal cortex in a rodent model of substance abuse. During imaging, animals received an intravenous injection of saline, alcohol, cocaine, or nicotine. Cocaine administration reduced the regional cerebral metabolic rate of glucose (rCMRGlu) as measured by PET, but increased prefrontal glucose and creatine levels as measured with dynamic MRS. Furthermore, alcohol administration significantly influenced the prefrontal concentration of ethanol, glucose, creatine, and glutamate. Finally, our data show that alcohol induces a transient decrease in prefrontal glutamate coinciding with the peak in ethanol concentration.