Faculty Members' Research Interests Dr. Charles Inturrisi
Dr. Inturrisi's research activities are directed toward the development of methods for the alleviation of pain and drug addiction. To test the hypothesis that glutamatergic receptors in the spinal cord dorsal horn (SCDH) mediate the neuronal plasticity that is manifest as pain following injury, his lab has developed a conditional (spatial-temporal) knockout of the NMDA receptor that is confined to the lumbar spinal cord. This model is being extended to other glutamatergic receptors (AMPA) and other effects (spinal opioid tolerance). The role of glutamatergic receptors in the addictive behaviors resulting from the administration of cocaine and opioids and mediated by the mesolimbic dopamine system are being investigated by preparing spatial-temporal knockouts of NMDA and AMPA receptors in the nucleus accumbens and ventral tegmental reward areas of the brain. At the clinical level, his group discovered that the d isomer of methadone is a nonopioid NMDA receptor antagonist in animal studies and they now plan to evaluate the safety and efficacy of this compound in patients with pain.
Dr. Hazel Szeto
Dr. Szetos laboratory is involved in the development of peptide drugs that target cell-surface receptors, with special emphasis on opioid, vasopressin and oxytocin receptors. These receptors play important roles in the regulation of pain processing, blood pressure, adrenocorticotropin release, and uterine contraction, respectively. The laboratory has developed some of the most selective ligands for the mu opioid receptor and for the vasopressin V1b receptors. In addition to receptor selectivity and potency, we also design peptide drugs with druggable properties, including good systemic and oral bioavailability, and long elimination half-lives. The second project focuses on the development of drugs that protect against oxidative damage and mitochondrial dysfunction. Mitochondrial dysfunction is implicated in ischemia-reperfusion damage, neurodegenerative diseases, diabetes, and aging. The lab has identified several small cell-permeable antioxidant drugs that target mitochondria and protect against mitochondrial permeability transition and apoptosis.
Dr. Betty Casey
The Casey lab uses both functional and structural magnetic resonance imaging (MRI) to examine brain circuitry involved in reinforcement learning and principles of decision making. Specifically, the lab is examining how common polymorphisms in the dopamine system are related to attentional functioning and functionality of attentional neural systems. These approaches are used to test hypothesis about developmental and individual human behavioral differences in reward related behavior and decision making processes implicated in substance use and abuse in adolescents.
Dr. Hugh Hemmings, Jr
At clinically relevant concentrations, most general anesthetics depress excitatory synaptic transmission, while some facilitate inhibitory synaptic transmission. There is good evidence for both presynaptic and postsynaptic mechanisms for these effects, including presynaptic reductions in excitatory neurotransmitter release, inhibition of postsynaptic responses to excitatory neurotransmitters, and facilitation of postsynaptic responses to inhibitory neurotransmitters. However, the precise molecular mechanisms involved in these effects are unknown. The lab is studying the effects of general anesthetics on neurotransmitter release (e.g., glutamate, GABA, norepinephrine, dopamine, neuropeptides). The mechanisms of these effects are being probed by studying anesthetic effects on presynaptic ion channels coupled to transmitter release in isolated neurohypophysial nerve terminals by patch clamp electrophysiological analysis, and on specific presynaptic proteins involved in the control of neurotransmitter release (e.g., SNAREs) using purified recombinant proteins. The role of protein kinase as a target of general anesthetic actions is also being studied.
Dr. Samie Jaffrey
The Jaffrey laboratory is interested in signaling pathways that regulate neuronal morphogenesis, synaptogenesis, and synaptic plasticity. A particular interest is the mechanisms that underlie synaptic plasticity that occurs in addiction. A variety of drugs of abuse, such as morphine, cocaine and more recently nicotine, have been shown to activate the transcription factor CREB (cAMP response element binding protein) in the brain, which mediates cAMP-dependent gene expression. Recent work from the Jaffrey laboratory has revealed a novel mechanism for how signals in axon terminals can regulate CREB-dependent gene transcription in the nucleus. CREB mRNA is found in axon terminals of developing neurons, and CREB is locally made within axons in response to various stimuli, including neurotrophins. Upon synthesis, CREB is phosphorylated, and retrogradely trafficked to the nucleus, where it regulates gene transcription. The Jaffrey laboratory is investigating the signaling pathways that couple synaptic stimulation induced by drugs of abuse to transcription in the nucleus. These studies focus on the possibility that CREB signaling induced by drugs of abuse is mediated by dendritic translation and subsequent nuclear trafficking of CREB.
Dr. Barry Kosofsky
Dr. Kosofsky is a clinician scientist who employs bi-directional translational research to understand the consequences of the impact of prenatal exposure to drugs of abuse on the developing brain. He uses animal models to gain molecular mechanistic insights into the neuropathologic, behavioral, electrophysiologic and neurochemical alterations induced by gestational exposure to cocaine. In addition, the lab utilizes high resolution structural (MR microscopy) and functional (fMRI) magnetic resonance brain imaging methods in rodents to identify structural and functional consequences of recurrent exposure to cocaine during development and in adult animals. Clinical studies utilize computer-based methods for morphometric analyses of the MR scans of 9 to12 year old children following intrauterine exposure to drugs of abuse.
Dr. Mary Jeanne Kreek
Dr. Kreek is interested in the biological basis of four addictive diseases: opiate addiction, cocaine addiction, nicotine addiction and alcoholism. Basic laboratory and clinical studies focus on determining the role of the endogenous opioid system in addictive diseases and the roles of specific opioid peptides and receptors in the normal and abnormal physiology of the neuroendocrine, immune and gastrointestinal systems. A major effort focuses on determining the effects of cocaine, opioids and alcohol on the endogenous opioid system and relevant interrelationships of the glutamatergic, dopaminergic, serotonergic and noradrenergic systems involved in the networks impacted upon or altered by neuroadaptation following chronic drug exposure.
Dr. Lonny Levin
Dr. Levin co-discovered soluble adenylyl cyclase (sAC) with Dr. Jochen Buck, and they have combined their laboratories to study sAC biochemistry and physiology. The second messenger molecule cAMP, which modulates cell growth and differentiation in organisms from bacteria to higher eukaryotes, is produced by adenylyl cyclases. Mammals possess two distinct classes of adenylyl cyclase, the hormone-responsive, transmembrane adenylyl cyclases (tmAC) and the bicarbonate-regulated Soluble Adenylyl Cyclase (sAC). Recent studies revealed that sAC is the source of cAMP which is required for both NGF stimulation of neuritogenesis and for netrin1 induced axonal growth cone reorganization.
Dr. Teresa Milner
The lab is using combined anatomical and physiological approaches to determine how the hormonal milieu modulates endogenous hippocampal opioid systems and hippocampal responses (e.g., long-term potentiation) to exogenous opiates. The results will elucidate potential mechanisms and sites where ovarian steroids, by affecting hippocampal opioid systems, may influence hippocampal-dependent learning relevant to drug abuse. We currently are assessing the effects of long-term developmental exposure to therapeutic doses of ritalin in rats on the adult rat brain. For this, quantitative immunocytochemical methods are employed and focus is on the dopamine system; the ascending noradrenergic system; the ascending serotonergic system; the cholinergic basal forebrain system; cortical glutamatergic systems; and adult neurogenesis. These studies are important for understanding the long-term consequences of ritalin maintenance on children diagnosed with attention deficit hyperactivity disorder.
Dr. Gavril Pasternak
Dr. Pasternak's laboratory is primarily dedicated towards understanding the molecular mechanisms of opioid receptor action, particularly as it relates to mu opioid receptor heterogeneity. The overriding goal is to correlate behavior with molecular pharmacology. His group is exploring the concept mu opioid receptor heterogeneity at the molecular level. His group has identified a host of novel MOR-1 splice variants in mice, rats and human. The major group of variants involves splicing at the tip of the intracellular C-terminus. These variants all contain identical transmembrane domains, which comprise the binding pocket. Thus, it is not surprising that they all displayed high affinity and selectivity in receptor binding assays. However, they differ in respect to their functional activation by the mu opioids. Future work involves the isolation of additional variants and their characterization biochemically, anatomically and pharmacologically.
Dr. Virgina Pickel
Ongoing research has four separately funded projects having implications for psychiatric disorders including drug addiction and for the brain's homeostatic adaptations to chronic elevations in blood pressure. This broadly based research program is multidisciplinary, but relies most heavily on light and electron microscopic immunocytochemistry. Training opportunities are available in studies of the cellular and molecular basis for functional interactions between neurons containing monoamines and other transmitters and modulators in the brain's reward and autonomic regulatory circuits.
Dr. Miklos Toth
The lab is interested in postnatal developmental disorders: pathomechanisms and pharmacological rescue in transgenic animal models. The lab is interested in specifying the pathomechanism of selected postnatal neurodevelopmental disorders and designing rational therapies to cure or at least normalize some of the symptoms of these diseases. Since mechanistic studies require the ability to manipulate many of these developmental processes, we use animal models in our studies. The Toth lab is employing three diseases/models: 1) a mouse line with the deletion of the serotonin 5-HT1A receptor that shows an increased anxiety-like phenotype, 2) a mouse strain with a deletion of the Jerky protein that shows epileptic seizures and 3) a mouse line that lacks the fragile X mental retardation protein (FMRP) displaying sensory information-processing deficit and hyperactivity reproducing the symptoms of attention deficit hyperactivity disorder (ADHD), a frequent childhood condition.
Dr. Harel Weinstein
The lab is studying the structure and function of neurotransmitter transporters (NTs) and interactions of hallucinogens with 5-HT2a receptors. The work is entirely computational and involves the development and/or application of powerful state-of-the-art methods for molecular simulation and structure-function analysis from theoretical chemistry and molecular biophysics, as well as new tools in bioinformatics, computer science, and mathematical modeling and simulation of integrated complex systems (e.g., cellular signal transduction). For the NTs, the long term goal is to understand the systems in a discrete structural context, for both the membrane proteins and their ligands, in a manner that offers mechanistic insight into function at the molecular level. For the hallucinogen-focused research, the goal is to understand the molecular mechanism of actions of hallucinogenic drugs of abuse at a level of molecular detail that will enable structure-based design from molecular models of the receptors and the development, from simulations of mechanisms of action, of effective therapeutic methods of intervention.