Dopamine is released in the striatum in response to alcohol and other drugs and is critical for drug reward that leads to addiction. Much of what we know about neural responses to ethanol and other drugs of abuse is based on the use of microdialysis in small animal models of drug abuse. Because of the poor temporal resolution of microdialysis, rapidly occurring neurochemical events cannot be captured. A method for assaying dynamic changes in neurotransmitters, in vivo, is needed and the focus of this proposal is the development of such methods. PET would offer many advantages over microdialysis because it is noninvasive, quantitative, and can image the brain with high temporal resolution. What has been lacking so far has been the necessary combination of kinetic modeling, experimental design and parameter estimation techniques required to derive a time course of the short-lived changes in neurotransmitter concentration from ? dynamic PET data. ? ? The specific aims for this proposal are: ? 1. To determine the identifiability -via simulations of realistic data and non-linear parameter estimation- of model parameters of a two kinetic models (one using arterial input, the other using a reference region) of a PET tracer binding to a receptor in the presence of a non-steady endogenous competitor. ? 2. To evaluate methods to improve the identifiability of model parameters by application of prior knowledge. ? 3. To maximize the precision of the parameter estimates via optimal experiment design. ? 4. To use the method developed herein, in conjunction with a small animal PET scanner, to fully characterize the continuous dopamine kinetics in the striata of rats following either acute alcohol or cocaine challenge. ? ? The goal of this proposal is to create the necessary mathematical framework so that small animal PET ? studies with receptor-tracers can be used to reconstruct precisely transient changes in concentration of ? endogenous dopamine in the brains of selectively bred rats who actively seek alcohol and of unselected rats. ? ? Our long-range goal is to probe temporal changes in neurotransmitters (e.g., dopamine and serotonin) in the brains of experimental animals, in vivo, to determine the relevant temporal characteristics of neurotransmitter responses to drugs and other stimuli. We seek to determine whether long-term changes in the dynamics of neurotransmitter responses underlie the development of addiction, loss of memory, or other neuropsychiatric conditions or diseases. The methods to be developed will easily translate to human imaging studies. ? ? ?
