The Neurobiology of Substance Abuse

The Faculty ...

James D. Belluzzi
Using behavioral and neurophysiological methods, Dr. Belluzzi studies those brain systems and neurotransmitters that modulate reinforcement and memory processes. Dr. Belluzzi's main focus is on dopaminergic mediation of stimulant abuse. Using animal models of intravenous drug self-administration, he studies the role that dopamine receptor subtypes play in controlling cocaine abuse.

Laurence F. Cahill
Dr. Cahill focuses his research on the neural mechanisms by which emotional arousal influences long-term memory storage. Substantial research suggests that emotional arousal modulates memory consolidation via the interaction of at least two principal elements- peripheral adrenergic hormones and the amygdala. Dr. Cahill's current research involves pharmacological, psychophysiological, neuropsychological, and brain imaging approaches with human subjects all aimed at the issue of emotional memory, also in its relationship to drug abuse.

Olivier Civelli
Dr. Civelli's laboratory is focussed on the isolation of novel neurotransmitters and neuropeptides and on the identification of their physiological roles. Among the receptors that govern brain activities, the most numerous are the G protein-coupled receptors (GPCR). Many of the cloned GPCR do not recognize any of the presently known neurotransmitters or neuropeptides, and are called "orphan GPCR". Dr. Civelli's laboratory utilizes orphan GPCR as targets for the identification and isolation of their specific natural ligands. The unknown ligands are purified from brain extracts and characterized biochemically, pharmacologically and physiologically. The ultimate goal of Dr Civelli's research is to define whether novel neurotransmitter or neuropeptide systems can be used in treating human disorders.

Sue P. Duckles
Dr. Duckles is a neuroscientist and cardiovascular pharmacologist interested in the cerebral circulation and the interactions between various cell types in the vascular system: smooth muscle cells, adrenergic and non-adrenergic nerves and endothelial cells. Current research in her laboratory focuses on three major areas: influence of gender and sex steroid hormones on vascular reactivity, control of the cerebral circulation, and the role of the pineal hormone melatonin in cardiovascular control.

Frederick J. Ehlert
Dr. Ehlert is a molecular neuropharmacologist investigating the function of muscarinic receptor subtypes in brain and peripheral tissues. In addition, Dr. Ehlert specializes in the analysis of drug-receptor interactions and in the development of novel subtype-selective irreversible antagonists. Muscarinic acetylcholine receptors constitute a group of five receptor subtypes (M1 - M5) that mediate cellular responses by activating heterotrimeric G proteins. These receptors are abundantly expressed throughout the central and peripheral nervous systems and play an important role in numerous physiological processes. Some of these include learning and memory, adjusting the amount of light that impinges on the retina, and regulating various organs innervated by autonomic nerves (e.g., gastrointestinal tract, heart, trachea and exocrine glands). In recent years, the signaling pathways of G protein-linked receptors have been worked out in great detail. Dr. Ehlert's lab takes advantage of this technology to discover new cellular responses and new mechanisms for receptor interaction (cross-talk). One of the aims of Dr. Ehlert's research is to identify the functional roles of M2 muscarinic receptors in smooth muscle. Dr. Ehlert's lab identified the signaling pathways of M2 and M3 receptors in smooth muscle (inhibition of adenylyl cyclase and stimulation of phosphoinositide hydrolysis). His lab also developed a novel drug that inactivates M3 receptors selectively, and he is currently developing an irreversible antagonist for the M2 receptor. This work led to the initial demonstration that M2 receptors mediate muscular contraction by inhibiting the action of smooth muscle relaxants. These discoveries have led to new approaches for the development of selective therapeutic drugs for diseases of smooth muscle. Another area of Dr. Ehlert's research is the analysis of models for drug-receptor interactions. Dr. Ehlert has developed a model for receptor-G protein interactions that explains the concepts of affinity and intrinsic efficacy. Dr. Ehlert has also developed a means of characterizing the interaction of allosteric drugs with receptors.

James Fallon
Dr Fallon is a neuroanatomist. His present research interests are in three areas. One is on the systems analysis of human imaging data from PET, fMRI, MRI, SPECT, EEG data in normal subjects and patients with neurodegenerative disorders, affective disorders, and drug abuse A second group of studies is directed at morphological, mathematical and statistical analyses of the developing human cortex. A third focus of research is on the role of several growth factors on stem cell proliferation, migration, and differentiation in the forebrain using neurotoxicological models of neurodegeneration, in situ nucleic acid hybridization, immunocytochemistry, and sensory/motor behavioral analyses.

Ron Frostig
Dr Frostig's long-term interest is in the dynamic aspects of cortical functional organization. The research is focussed on three levels: (1) how cortical neurons code and communicate sensory information to other neurons; (2) how cortical neurons functionally organize into networks; (3) how functional networks of neurons organize to produce sensory maps. Recent research from the laboratory emphasizes that cortical acetylcholine receptors contribute to the organization and modulation of these sensory maps. The members of his laboratory study how each level affects other and how all levels are modifiable by learning and behavior. The studies are performed in the somatosensory cortex of the rat and the visual cortex of the cat. The emphasis of the lab is on the use of interactive, in vivo techniques, such as the recently developed technique of optical imaging of intrinsic signals to obtain high-resolution images of cortical maps. This technique is coupled to simultaneous, single-unit recording of and analysis to study functional networks. Using these complementary methods enables the Frostig's lab to study the rules by which sensory maps are able to modify themselves in relation to learning and behavior in adult animals.

Kelvin W. Gee
Dr. Gee is a neuropharmacologist whose principal interests lie in the elucidation of mechanisms of regulation of receptor-effector coupling and in the identification of novel signal transduction-based therapeutic strategies for the treatment of disorders amenable to modulation of signal transduction pathways. His laboratory is currently characterizing the pharmacology of two novel allosteric modulatory sites on the GABAA receptor complex (GRC) using tissue and recombinant receptors as well as studying the behavioral consequences of modulatory site activation. These sites include one for certain neurally active steroids known as epalons and another for atypical benzodiazepines and quinoline antibiotics. The laboratory is also involved in the characterization of novel neuropeptide antagonists as inhibitors of cell survival signals in cancer cells. The overall mission of the lab is to identify and characterize novel modulatory sites that may be potential targets for novel therapeutic agents useful in the treatment of human diseases.

Laurence Jamner
Dr. Jamner A major theme of Dr Jamner work is the study of individual differences, both psychological and physiological, as they relate to responses to pharmacological probes, coping with stress, the perception of pain, and both cardiovascular and neuroendocrine function. Dr. Jamner's program of research focuses not only on describing mind-body relationships, but also on delineating the mechanisms underlying these associations. Dr. Jamner's current research activities reflect his interests in three major areas: 1) the influences of situational/contextual and trait factors as predictors of susceptibility to tobacco-dependence; 2) the neurobiological mechanisms underlying dispositional traits including hostility, aggression, and impulsivity; and 3) the significance of repressive and defensive coping styles for behavior, emotions, memory, psychophysiological functioning and health.

Diana N. Krause
Dr Krause is a neuropharmacologist with a major research interest in characterizing the pharmacology and function of receptors for melatonin, a hormone from the pineal gland that regulates biological rhythms. Her current research is focused on melatonin receptors in the cardiovascular system. She has found that melatonin has both constrictor and dilator effects in arteries of the brain and skin. These actions may be important for optimizing cerebral blood flow and thermoregulation during the night when melatonin is secreted. Dr. Krause is also investigating the effects of estrogen and other gonadal hormones on the function and biochemistry of arteries and brain microvessels. Recently her group has discovered that estrogen modulates the vasoconstrictor response to melatonin indicating an interaction between the pineal circadian system and the gonadal reproductive system.

Frances Leslie
Dr. Leslie is a neuropharmacologist whose primary interests lie in the effects of drugs of abuse on cellular development. She is particularly interested in characterizing the expression and functional roles of the endogenous opioid and nicotinic cholinergic systems, which are activated by heroin and nicotine, respectively. Several techniques are used for visualization of these neurotransmitters and their related receptors in developing brain and body. These include in situ hybridization for analysis of mRNA expression, and quantitative autoradiography and immunocytochemistry for localization of proteins. In order to test the effects of drugs of abuse on cellular development, drug-induced changes in neurotransmitter release are examined in brain slices and primary neuronal cultures. Changes in gene expression and behavior are also examined in vivo following acute and chronic drug treatments. The overall goal of the lab's research is to characterize the normal function of opioid and nicotinic cholinergic systems in neural development, and to identify the long-term consequences of abnormal activation of these systems by drugs of abuse.

John F. Marshall
The focus of research in this laboratory concerns the causes and consequences of injury to dopaminergic pathways of the brain. An important component of this interest concerns the ability of stimulant drugs of abuse to injure brain dopaminergic and other brain neurons. A variety of neuroanatomical (tracing, fluorescence histochemistry, immunocytochemistry, in situ hybridization) and neurochemical (microdialysis) methods have been combined with behavioral analysis of abused stimulant drugs, especially methamphetamine. In the past two years this laboratory has begun a long-term collaboration to examine brain regions, circuits, and neuron subpopulations that subserve the ability of environmental stimuli to reinstate cocaine-seeking behavior in animals with a prior history of cocaine self administration.

James L. McGaugh
Research in the McGaugh laboratory investigates neuromodulatory systems, including hormonal and neurotransmitter systems involving in regulating memory storage. Current research focuses on the role of the nuclei of the amygdaloid complex in orchestrating the interactions of adrenergic, GABA-ergic, opioid peptidergic systems influencing the storage of recently acquired information.

Diane K. O'Dowd
The O'Dowd lab uses two model systems, one in Drosophila and one in mouse, both of which are amenable to molecular genetics studies, in which to examine the regulation of electrical excitability and synaptic connectivity in the developing nervous system. Electrophysiological analysis of mutants has demonstrated that functional sodium channels encoded by the para gene are expressed in embryonic Drosophila neurons. Amplification of messages from individual neurons using single cell PCR has revealed that specific alternatively spliced para sodium channels mRNAs correlate with expression of sodium currents. A second line of investigation focuses on the development of synaptic connections in the mammalian CNS. Use of lipophilic dyes and confocal image analysis has allowed the lab to examine the morphological features of the developing afferent pathway between the thalamus and the cortex. Whole-cell recordings obtained from cortical neurons in a slice preparation has allowed the O'Dowd lab to examine the developmental changes in the electrophysiological properties of the newly formed functional synaptic contacts. Current experiments are aimed at understanding both the biophysical and molecular properties of the ion channels that mediate the electrical excitability and synaptic connectivity of cortical neurons using single cell PCR.

Daniele Piomelli
Dr. Piomelli was trained in neuroscience and pharmacology. Research in his lab is focused on the function of lipid-derived messengers, with particular emphasis on the endogenous cannabinoids, anandamide and 2-arachidonylglycerol. Current research efforts converge on three areas: formation and inactivation of anandamide and 2-arachidonylglycerol; physiological roles of the endogenous cannabinoid system; development of therapeutic agents that target anandamide and 2-arachidonylglycerol metabolism. Primary neural cell cultures and state-of-the-art analytical techniques (including gas-chromatography/mass-spectrometry and liquid chromatography/mass-spectrometry) are used to investigate formation and inactivation of anandamide and 2-arachidonylglycerol in brain cells. Protein purification and cloning approaches are employed to characterize the molecular mechanisms underlying these processes. Cellular pharmacology and medicinal chemistry, in collaboration with leading chemical labs in the USA and abroad, are used to identify pharmacological agents that interfere with various aspects of endogenous cannabinoid function, and their therapeutic potential is explored in vitro and in vivo.

Ralph E. Purdy
Dr. Purdy is a cardiovascular pharmacologist whose research addresses all aspects of neurotransmission in blood vessels. He is particularly interested in the properties of neuro-humoral receptors that regulate dilation and constriction of blood vessels. Dr. Purdy uses a variety of experimental techniques to characterize the second messenger processes associated with vascular receptors. In addition to isometric contraction, changes in cytosolic calcium levels are detected using single cell calcium imaging in cells loaded with fluorescent calcium dyes such as Fura 2. The biochemical second messengers either mediating or preventing calcium mobilization are also assessed. These include the phosphoinositide metabolites, inositol trisphosphate and diacylglycerol, novel tyrosine kinase second messengers, as well as the intracellular messengers, cAMP and cGMP. The methods described above are applied to determine possible mechanisms of coronary artery vasospasm, a component of heart attack.

Marylou Solbrig MD
Marylou Solbrig MD is a board-certified neurologist with subspecialty training in movement disorders, behavioral pharmacology and infectious diseases. Interested in viral-induced neuropharmacologic disorders, she has developed an animal model of persistent viral encephalitis with remarkable sensitivity to drugs of abuse, based on the neurotropic virus, Borna Disease virus. Behavior pharmacology, in situ hybridization, quantitative receptor autoradiography, and brain region RNAse Protection Assay techniques are applied to the Borna Disease rat to elucidate aspects of psychostimulant (cocaine, d-amphetamine, nicotine) sensitivity, opiate sensitivity and withdrawal, and neuroadaptive changes associated with chronic drug administration. In vivo experiments are complemented by evaluation of the molecular properties of opioid-expressing cells when infected.

Larry Stein
Dr. Stein is a neuropharmacologist interested in behavior. Specific interests include reward, punishment, and memory mechanisms as they pertain to psychiatric disease and drug abuse. Dr. Stein has used brain self-stimulation and drug self-administration methods to identify dopamine and opioid brain systems important in reward. He is currently studying the operant conditioning of single neurons in hippocampal slices in an attempt to understand the molecular mechanisms of cellular reinforcement.

Katumi Sumikawa
The synthesis and assembly of multi-subunit neurotransmitter receptors, followed by their transport to and insertion within appropriate sites of the membrane, constitute essential events in the constitution of functional synapses. Accordingly, understanding the molecular and biochemical processes that guide these events is an important issue in neurobiology. The expression of functional receptors involves complex processes including (1) transcription of several genes, (2) processing of transcript, (3) translation, (4) and post-translational events such as subunit modification, assembly, transport, membrane insertion and accumulation beneath the nerve ending. These last steps presumably provide for the complementarity between the type of neurotransmitter and the type of receptor. Regulation of any of these steps during expression of receptor molecules could affect the number of functional receptors and/or alter receptor function so as to change neuronal activity. Dr. Sumikawa's research goal is to understand the molecular and biochemical processes that regulate the numbers and properties of receptors under the nerve endings. To pursue this goal, Dr. Sumikawa's lab currently uses the nicotinic acetylcholine receptor (AchR) as a model system and study the following questions by expressing normal and mutant AchRs in Xenopus oocytes and other cells: (1) What kinds of post-translational modification are required for assembly and insertion into the plasma membrane? (2) Are there sequences on subunits for directing the multi-subunit assembly? (3) How do cells prevent the abnormal and incompletely assembled receptors from reaching the plasma membrane? (4) How do AchRs accumulate beneath the nerve endings?

Qun-Yong Zhou
Dr. Zhou is a molecular biologist interested in dopamine neurotransmission. Malfunctioning of dopamine signaling in the CNS has been linked to a number of neurological and psychiatric disorders such as Parkinson's disease, schizophrenia, and drug abuse. A dozen genes that are unique to dopamine signaling have been identified in the past decade. Dr. Zhou's research goal is to provide rational strategies for therapeutic intervention of dopamine-associated disorders by contributing to the understanding of dopamine signaling mechanisms. The laboratory is focused on two areas: the development of clinically relevant transgenic mouse models, and the elucidation of molecular mechanisms of dopamine receptor trafficking and signaling. By combining knock-out and knock-in techniques, Dr. Zhou has developed transgenic mice that are specifically deficient in the neurotransmitter dopamine. The dopamine-deficient mice mimic the locomotion deficit observed in Parkinson's disease. Currently, Dr. Zhou utilizes the dopamine-deficient mice as in vivo models for testing the efficacy of potential therapeutic agents for Parkinson's disease. Dr. Zhou's laboratory also aims at creating transgenic models for schizophrenia and drug abuse.