David Lovinger, Ph.D.

Research in the Laboratory for Integrative Neuroscience (LIN) examines the molecular, cellular and circuit basis of acute alcohol intoxication, alcohol seeking behavior, addiction and habitual behavior. An important unifying theme of LIN research is investigation of forebrain mechanisms involved in aspects of cognition and behavioral control that contribute to addiction. We seek to understand the neural basis of addiction-related brain functions such as decision-making, goal-directed behavior, habit formation and habitual behavior. We are also examining mechanisms underlying specific responses to addictive drugs, including acute intoxication and neural adaptations to chronic drug exposure, such as tolerance and dependence. Gaining an understanding of these functions will necessarily involve determining which neural circuits mediate these processes, what physiological and synaptic mechanisms underly circuit function and plasticity, and what neural and synaptic molecules play key parts in synaptic, neuronal and circuit function. We believe that these goals can best be achieved by bringing together investigators with a shared interest in these subjects and with diverse technological expertise so that we can approach the problem at multiple levels of analysis.

At the molecular and cellular level, research in LIN has focused on two main areas. We have continued our long-standing efforts to understand the cellular and molecular mechanisms underlying plasticity at GABAergic and glutamatergic synapses in the striatum. This work led to an interest in the role of endogenous cannabinoids (endocannabinoids) in synaptic modulation and plasticity in this brain region. Our interest in striatal synaptic plasticity has always been driven by a desire to better understand information storage in this brain region that plays crucial roles in action-outcome, habit and skill learning. Newly developed striatal-specific gene-targeted mouse models, as well as approaches to measure and manipulate striatal cellular function are now making it possible for us to determine if striatal synaptic plasticity plays important roles in learning and memory. Our long-term goal in this project is to understand how the molecules and cells of the striatum contribute to the types of learning and memory involving that brain region, and to develop pharmacological and genetic manipulations that can alter striatal-based information storage.

A second long-term goal is to understand acute alcohol actions that contribute to intoxication and adaptations to long-term alcohol exposure that contribute to cognitive impairment and alcohol misuse. We continue to explore mechanisms of ethanol (EtOH) action ion channels using a combination of molecular biological, electrophysiological and kinetic approaches. We have also initiated studies aimed at characterizing pre-synaptic actions of EtOH that contribute to potentiation of GABAergic transmission. Our studies have established the presynaptic terminal as the likely site of this EtOH action. Studies have also focused on comparison of electrophysiological and behavioral effects of EtOH in gene-targeted mice lacking molecules that are targets for acute alcohol actions. These studies are designed to examine the effects of acute ethanol as well as neuroadaptations brought about the chronic alcohol exposure.

Research in LIN also focuses on neural mechanisms of skill learning, goal-directed behavior, habit formation and addiction. One of the major areas of emphasis is on the role of cortical-basal ganglia circuitry in these neural functions. Assessment of the role of particular molecules within these brain regions is also an area of emphasis. To this end, members of LIN have worked with other laboratories in NIAAA to developed advanced methodology for in vivo electrophysiological and optical recording in awake mice during different phases of task learning. These techniques have been applied to analysis of transgenic and gene-targeted mice. Members of the laboratory are also designing and using sophisticated behavioral paradigms to assess goal-directed and habit learning in mice.

We envision that the shared interests of LIN investigators and the interactive nature of the laboratory will allow investigators from different groups to combine their expertise in the analysis of neural function at multiple levels. For example, changes in addiction-related behavior in a particular mouse model can be examined in conjunction with analysis of neuronal morphology, signaling in subcellular compartments, and neural circuit function at the micro and macro levels. Examination of molecular expression, location and function can also be applied in the same animals. Ultimately, this should allow us to gain a thorough understanding of the way in which particular neuronal molecules contribute to cellular and circuit functions that ultimately influence behavior. We also envision that interactions and collaborations with other NIAAA laboratories will enhance our ability to analyze these neural functions from the molecule to the whole mouse.

One theme that brings together the different lines of research within LIN is an interest in mechanisms of addiction and habitual behavior. We predict that gaining a better understanding of synaptic plasticity in the striatum and related brain regions will help us to better appreciate how information relevant to habit formation becomes encoded. Our overarching hypothesis is that effects of addictive substances on synaptic structure and transmission will interface with natural plasticity mechanisms to focus habits on drugs of abuse as well as associated stimuli and responses. Thus, understanding the neural basis of habit formation and the molecular actions of intoxicating/addictive substances will allow us to gain a more thorough understanding of addiction. Ultimately, it is hoped that these lines of research can contribute to development of better therapies for neurological disorders and alcoholism.

Dr. Lovinger received a B.A. in Psychology from the University of Arizona in 1981 and a Ph.D. in Psychology from Northwestern University in 1987. At Northwestern, he worked with Dr. Aryeh Routtenberg studying the roles of Protein Kinase C and its substrate, the GAP-43/F1 protein, in hippocampal long-term potentiation. His postdoctoral research at the NIAAA focused on the effects of alcohol on ligand-gated ion channels. In 1991 Dr. Lovinger moved to the Vanderbilt University School of Medicine as an Assistant Professor, where in 1998 he rose to the rank of Professor. At Vanderbilt he was also the Deputy Director for Biomedical Science and the Director of the Neuroscience Core within the Kennedy Center. Dr. Lovinger joined the NIAAA in 2001 as a Senior Investigator and Chief of the Laboratory of Integrative Neuroscience. In 2023 he was appointed as Scientific Director of the NIAAA Division of Intramural Clinical and Biological Research. His laboratory is currently studying the modulation and plasticity of synaptic transmission at corticostriatal synapses and the mechanisms by which abused substances affect synaptic transmission and neuronal activity to induce intoxication and substance use disorders.