Senior Research Scientist
Research Associate Professor, Psychology
Research Assistant Professor, Pathology and Anatomical Sciences
Brain dopamine systems; alcohol craving; fetal alcohol syndrome.
The goal of this study is to investigate the effects of stimulant drugs such as methylphenidate on the effectiveness of sensory reinforcers. We have previously hypothesized that stimulant drugs prevent normally occurring decreases (habituation) in the reinforcing effectiveness of sensory stimuli. We believe that the ability of stimulant drugs to make the effects of sensory reinforcers longer lasting may play and important role in stimulant addiction. This study will be the first to examine the ability of stimulant drugs to make sensory reinforcers longer lasting. Individuals with Attention Deficit Hyperactivity Disorder (ADHD) who are prescribed stimulant drugs to increase attention will be studied. This project is designed to test the hypothesis that stimulant drugs increase attention in ADHD individuals by making the effects of sensory/social reinforcers longer lasting. Funded by RIA's Howard T. Blane Director’s Award for Development of Innovative Research in the Addictions (BDAA), 2014-2015.
A novel brain neurotransmitter, the neuropeptide urotensin II, has recently been shown to modulate the brain “reward pathway,” which plays an important role in modulating addictive behaviors. The study will use cellular electrophysiology and behavioral methods to study how urotensin II can affect the reward pathway and influence the cocaine-seeking behavior in rodents. Our studies will give us a better understanding of the fundamental functions of the urotensin II system. This is important in determining whether the urotensin II system could be used as a therapeutic target for the treatment of addiction. Funded by RIA's Howard T. Blane Director’s Award for Development of Innovative Research in the Addictions (BDAA), 2014-2015.
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. Consultants on the study include Dr. Jerry Richards and Dr. Paul Vezina, University of Chicago.
Roh-Yu Shen, PhD
Research Institute on Addictions
Samir Haj-Dahmane, PhD
Research Institute on Addictions
Cynthia Dlugos, PhD
Department of Pathology and Anatomical Sciences
University at Buffalo
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Attention deficit/hyperactivity disorder is a prominent behavioral symptom in children with fetal alcohol spectrum disorders (FASD). Attention problems have been linked to a dysfunction of the mesolimbic/cortical dopamine (DA) systems. Previous research from Dr. Shen’s laboratory showed that prenatal ethanol exposure in rats leads to a persistent reduction in the number of spontaneously active DA neurons in the ventral tegmental area (VTA), the origin of the mesolimbic/cortical DA systems. Therefore, the reduced DA neuron activity may contribute to the dysfunction of the mesolimbic/cortical DA systems and attention problems in individuals with FASD. The reduced number of spontaneously active VTA DA neurons caused by prenatal ethanol exposure is not due to a neuronal loss and can be reversed by acute administration of inhibitory agents such as DA agonists and psychostimulants (e.g. amphetamine, methylphenidate), or by increasing inhibitory input. This led to the hypothesis that prenatal ethanol exposure leads to the reduction in the number of spontaneously active VTA DA neurons by the mechanism of depolarization inactivation Ð cessation of action potentials due to over-excitation. This model predicted qualitative changes in the responses of VTA DA neuron to input signals and terminal DA release and an overall dysregulation of the mesolimbic/cortical systems. In this study, Dr. Shen identified key cellular mechanisms that could mediate the over-excitation in VTA DA neurons. The results should provide better understanding of the neural mechanisms underlying attention problems in individuals with FASD and allow for the development of effective phamacological treatment for attention problems. In addition, it sheds light on potential neural mechanism or the treatment of other mental illnesses, as reduced number of spontaneously active VTA DA neurons by depolarization inactivation is also observed after chronic exposure to drugs of abuse and prenatal stress exposure. Funded by a grant of $641,926 from NIAAA, 2007-2011.
Abnormal dopamine neurotransmission is suggested to cause the attention and hyperactivity problems often observed in children with fetal alcohol effect/fetal alcohol syndrome (FAE/FAS). This study investigated how prenatal ethanol exposure influences the postnatal development of dopamine neurotransmission, how dopamine neurotransmission can be normalized by amphetamine-like stimulants, and more about the cellular mechanisms leading to these changes. The results of this study may lead to the development of more appropriate pharmacologic treatments for specific behavioral problems of FAE/FAS. Funded by a grant of $1,162,538 from NIAAA, 1999-2005.
Dr. Roh-Yu Shen investigated the neurological basis of craving with electrophysiological method. The results obtained further characterize the brain mechanims of craving utlizing electrophysiological, neurochemical, and behavioral techniques. Funded by a grant of $199,362 from NIAAA, 1997-2001.