Senior Research Scientist
Research Assistant Professor, Pharmacology and Toxicology
Mechanisms and regulation of synaptic transmission in the
central nervous system; the impact of stress and stress hormones on
synaptic transmission and plasticity in monoaminergic nuclei; role
of endogenous cannabinoids “endocannabinoids” in the
regulation of neuronal excitability.
The goal of this study is to help develop inhibitors for Fatty Acid Binding Proteins (FABPs) in the brain to aid in new treatments of anxiety disorders and addiction.
The endocannabinoid (eCB) system composed of the CB1 and CB2 receptors, their endogenous lipid agonists known as endocannabinoids (i.e. anandamide and 2-arachidonoylglycerol) and the enzymes that produce and metabolize the endocannabinoids has emerged as a key regulator of stress homeostasis and addiction. It is generally accepted that a dysfunction of the eCB system is a major contributor factor to stress-related mental disorders including anxiety, depression and additions. Indeed, results from behavioral studies in animal have reported that blockade of CB1 receptors or inhibition of eCBs synthesis, manipulation that reduces eCB signaling increases anxiety and alter addiction-related behaviors. In contrast, enhancement of eCB signaling via blockade of eCB hydrolysis and/ or uptake exerts anxiolytic–like effects and reduces the behavioral responses to drugs of abuse. Collectively, these preclinical studies suggest that drugs that modulate eCB signaling, including anandamide, represent new strategy for the treatment of anxiety disorders and addiction. However, progress along this line of research requires a better understanding of the various mechanisms that regulate eCB signaling, in particular the role of Fatty Acid Binding Proteins (FABPs), key intracellular anandamide transporters in the regulation of eCB function. In this application, we seek to address these issues by directly assessing the impact of selective inhibition or genetic deletion of FABPs on eCB-mediated modulation of glutamate synapses of ventral tegmental area dopamine neurons, a brain area critically involved in the regulation of stress homeostasis and addictions.
The study’s co-investigator is Martin Kaczocha, PhD, of Stony Brook University.
This one-year project for 2013-14 is funded by a $10,000 grant from SUNY REACH.
Deutsch | Haj-Dahmane
The main goal of this study was to help develop pharmaceutical drugs that may help remedy pain, stress and/or withdrawal from drug abuse.
A novel drug target called the fatty acid binding proteins (FABPs) was discovered by Dr. Dale Deutsch’s group at Stony Brook University. The action of drugs at this target (inhibitors) would raise the levels of naturally occurring “marijuana-like” compounds in the body, endocannabinoids, (eCB) and lead to remedies for pain, stress, and withdrawal from drug abuse. Studies conducted by Dr. Samir Haj-Dahmane at RIA have established that eCBs are released “on demand” by ventral tegmental area (VTA) dopamine neurons, playing a central role in mediating short- and long- term plasticity of glutamate synapses impinging on VTA DA neurons. Together, the researchers investigated whether competitive FABP inhibitors prevent the endocannabinoids from reaching their breakdown enzymes (FAAH and MAGL) and as a result, raise the levels of the endocannabinoids outside the cell at the CB receptors. This research addresses a brain area critically involved in the regulation of stress-related behaviors, such as addiction. The main goal of this study is to develop pharmaceutical drugs that selectively target FABPs, intracellular transporters of eCB, and test their in vitro neurophysiological effects on VTA DA neurons. The working hypothesis is that inhibition of FABPs will elevate eCB levels in the brain, in turn enhancing the neurophysiological effects of eCBs at glutamate synapses of VTA DA neurons. This two-year collaborative project was funded through SUNY REACH (SUNY Research Excellence in Academic Health serving NY at UB, Upstate Medical University, Downstate Medical Center and Stony Brook), 2011-13.
In the current investigation, Dr. Roh-Yu Shen and her research team will extend previous research in which she and Dr. Samir Haj-Dahmane found that prenatal ethanol exposure results in a persistent increase in glutamate synaptic transmission in dopamine (DA) neurons located in the ventral tegmental area (VTA), an effect thought to be a critical cellular mechanism for addiction. The team will use a multidisciplinary approach to further characterize the detailed cellular/molecular mechanims of these effects. Specifically, they will seek to confirm whether prenatal ethanol exposure leads to an increased expression of GluR2-lacking AMPA receptors. They will also investigate how prenatal ethanol exposure induces a blockade of endocannabinoid (eCB)-mediated long-term depression (LTD). Lastly, they will investigate if increased glutamate synaptic transmission mediated by these two cellular mechanisms in VTA DA neurons indeed leads to increased addiction propensity in prenatal ethanol exposed animals. The results generated from the proposed studies will have important implications in understanding the cellular/molecular mechanisms mediating prenatal ethanol exposure-induced increase in addiction propensity; help clarify the complex eCB signaling mechanisms within the mesolimbic/mesocortical DA systems; and may have broad impact beyond fetal alcohol spectrum disorders (FASD). Increased addiction propensity caused by other conditions such as prenatal psychostimulant or stress exposure also alters the function of DA systems, raising the possibility that a common brain mechanism mediates increased addiction propensity. The results from this investigation may provide insights to a common brain mechanism mediating increased addiction propensity and the prevention of addiction in general. Dr. Shen's co-investigators are Dr. Haj-Dahmane and Dr. Cynthia Dlugos of UB’s Department of Pathology and Anatomical Sciences in the School of Medicine and Biomedical Sciences. Consultants on the study include Dr. Jerry Richards and Dr. Paul Vezina, University of Chicago. Funded by a grant of $1,768,383 from NIAAA, 2010-2015.
Haj-Dahmane | Wood
Dr. Haj-Dahmane investigated the role of the endocannabinoid (eCB) system in regulation of stress responses and anxiety-related behaviors which play a role in addicted behaviors. The long-term objective of this research is to delineate the cellular and molecular mechanisms by which stress modulates eCB signaling in dorsal raphe (DR) serotonergic (5-HT) neurons. A combination of electrophysiological, pharmacological and neurochemical approaches was used to 1) test the hypothesis that glucocorticoids acutely enhance eCB systhesis/release in DR 5-HT neurons, 2) elucidate the signal transduction mechanisms by which glucocorticoids enhance eCB signaling in DR 5-HT neurons, 3) determine the mechanisms of severe stress-induced down-regulation of eCB signaling in DR 5-HT neurons. Given the role of 5-HT and eCB systems in the regulation of stress-related behaviors, the results from the proposed research should improve understanding of the etiology of anxiety disorder and may contribute to the development of more effective anxiolytics (anti-anxiety medications). Co-investigator on the study is Dr. Troy Wood, UB’s Department of Chemistry. Funded by a grant of $1,688,468 from NIMH, 2007-2012.
Dr. Samir Haj-Dahmane used electrophysiological, pharmacological, and immunohistochemical techniques to characterize the cellular mechanism by which D2-like dopamine receptor activation increased the excitability of dorsal Raphe nucleus serotonergic (5-HT) neurons. The results of this research will further our understanding of the functional interaction between the dopamine and serotonergic systems in the dorsal Raphe nucleus, and thus contribute to the identification of novel and effective treatment strategies for psychiatric disorders such as major depression. Funded by a grant of $781,209 from NIMH, 2001-2005.
Dr. Samir Haj-Dahmane investigated the neurophysiological effects of acetylcholine (an endogenous neurotransmitter) in the cerebral cortex. The results of this study may better our understanding of the cholinergic function in the cerebral cortex and further advance the treatment of mental disorders such as schizophrenia. Funded by a grant of $60,000 from the National Alliance for Research in Schizophrenia and Depression (NARSAD), 1998-2001.