research

Our laboratory’s focus is on the neurobiology of addiction. This problem represents a particularly appealing area of research for a number of reasons: 1) addiction greatly impacts individuals and society, leading to tremendous personal suffering, 2) addiction presents a window into brain function, allowing the study of important phenomena, such as neuronal plasticity and compulsive behavior. Continued drug exposure leads to compensatory changes in neuronal elements such as ion channels, leading to drug tolerance, that may strongly influence subsequent behavior, 3) our understanding of the mechanisms of addiction have taken a quantum leap in recent years, presenting the opportunity to develop pharmacological strategies to reduce craving and addictive behavior.

We use a constellation of techniques and preparations to discover the mechanisms underlying addiction.

Outcomes:

The use of these preparations and techniques have resulted in some important conceptual breakthroughs in our understanding of the acute and long-term consequences of drugs of abuse, such as:

1) We can determine not just the proteins, but the particular functional states of the protein that are responsive to alcohol, a drug previously thought to be non-specific in its actions. Thus, the gating of calcium and potassium channels is perturbed by ethanol, whereas other parameters of function, such as voltage-sensitivity and ion selectivity are not.
2) We have found that different compartments of the same neuron are differentially sensitive to drugs such as alcohol. Previously, it was thought that differences might reside at the level of brain regions or individual neurons.
3) Chronic exposure to alcohol leads to a decrease drug sensitivity and up- or downregulation of the density of the channel on the cell surface (and these changes are channel-specific). These changes underlie drug tolerance, and a further understanding of the mechanisms of these changes (such as channel protein internalization) will lead to both a better understanding of addiction and possible, treatments for addiction. Ongoing research in the laboratory is using explant cultures the hypothalamus-pituitary to answer questions such as the temporal characteristics of changes in sensitivity and density, and the consequenes of selective drug exposure to different neuronal compartments. These data will help to illuminate the mechanisms of drug-induced plasticity seen, and will be helpful in the development of therapeutic strategies to combat addiction.
4) The alcohol sensitivity of drug targets such as the BK potassium channel is modulated by the lipid composition of the artificial membranes we study. For example, significant reductions in sensitivity are observed when cholesterol in the membrane is elevated. Cholesterol content of brain cell membranes is known to be altered by drug exposure.



			Our laboratory’s focus is on the neurobiology of addiction. This problem represents a particularly appealing area of research for a number of reasons: 1) addiction greatly impacts individuals and society, leading to tremendous personal suffering, 2) addiction presents a window into brain function, allowing the study of important phenomena, such as neuronal plasticity and compulsive behavior. Continued drug exposure leads to compensatory changes in neuronal elements such as ion channels, leading to drug tolerance, that may strongly influence subsequent behavior, 3) our understanding of the mechanisms of addiction have taken a quantum leap in recent years, presenting the opportunity to develop pharmacological strategies to reduce craving and addictive behavior. We use a constellation of techniques and preparations to discover the mechanisms underlying addiction. Outcomes: The use of these preparations and techniques have resulted in some important conceptual breakthroughs in our understanding of the acute and long-term consequences of drugs of abuse, such as: 1) We can determine not just the proteins, but the particular functional states of the protein that are responsive to alcohol, a drug previously thought to be non-specific in its actions. Thus, the gating of calcium and potassium channels is perturbed by ethanol, whereas other parameters of function, such as voltage-sensitivity and ion selectivity are not. 2) We have found that different compartments of the same neuron are differentially sensitive to drugs such as alcohol. Previously, it was thought that differences might reside at the level of brain regions or individual neurons. 3) Chronic exposure to alcohol leads to a decrease drug sensitivity and up- or downregulation of the density of the channel on the cell surface (and these changes are channel-specific). These changes underlie drug tolerance, and a further understanding of the mechanisms of these changes (such as channel protein internalization) will lead to both a better understanding of addiction and possible, treatments for addiction. Ongoing research in the laboratory is using explant cultures the hypothalamus-pituitary to answer questions such as the temporal characteristics of changes in sensitivity and density, and the consequenes of selective drug exposure to different neuronal compartments. These data will help to illuminate the mechanisms of drug-induced plasticity seen, and will be helpful in the development of therapeutic strategies to combat addiction. 4) The alcohol sensitivity of drug targets such as the BK potassium channel is modulated by the lipid composition of the artificial membranes we study. For example, significant reductions in sensitivity are observed when cholesterol in the membrane is elevated. Cholesterol content of brain cell membranes is known to be altered by drug exposure.