Dr. Steven N. Treistman Dr. Steven N. Treistman

Adjunct Professor (Professor and Director of Institute of Neurobiology)
Institute of Neurobiology, Lab 203-206, 309-310
steven.treistman@upr.edu
787-721-4149

Interests: Mechanism of action of alcohol and opiate drugs.

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. At the whole cell level, we study vasopressin and oxytocin-releasing neurons, whose cell bodies and dendritic processes reside in the hypothalamus, and whose terminals reside in the posterior pituitary. This topographic separation offers a unique opportunity to determine differences in drug action within compartments of individual neurons. We also examine neurons from the nucleus accumbens, that play a major role in the reward pathways of the brain, and are likely to participate in addictive behaviors.

At a more reductionist level, we express cloned channel proteins in host cells such as oocytes and human embryonic kidney cells, and study the actions of drugs on these proteins of known composition and homogeneity.

At the most reductionist level, we study cloned proteins that have been removed from transfected cell lines, and incoporate them into artificial planar bilayers. Thus, we have control over both the protein and the lipid environment.

Our techniques include:

  1. electrophysiological approaches, including single channel recordings, that allow us to monitor the activity of an individual channel protein, either in biological membrane, or in artificial lipid environments,

  2. imaging techniques, such as calcium imaging, that allow us to monitor levels of intracellular calcium, which is an important mediator of drug action and neuronal function,

  3. Powerful biophysical techniques, such as atomic force microscopy, that allow us to relate the physical properties of the membrane lipid matrix to the function and pharmacology of individual membrane proteins.

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.

Selected Publications: