Addictions; Drug abuse; Behavioral pharmacology; Gene therapy; Molecular and Cellular Biology; Neurobiology; Gene Expression; Neuropharmacology
My laboratory seeks to understand the neurobiology of motivation and how these systems can be "highjacked" by abused substances. Substance abuse and addiction are wide-spread problems that have an enormous economic and emotional toll. Reports indicate that it costs the US upwards to $600 billion a year to deal with the health and criminal consequences and loss of productivity from substance abuse. Despite this, there are few effective treatments to combat this illness. The brain has natural systems responsible for motivating an organism to participate in behaviors that are necessary for survival, such as eating, exercise and reproduction. These same brain regions are highly sensitive to drugs of abuse, including cocaine, heroin and marijuana. My laboratory seeks to understand how these brain regions are affected by exposure to abused drugs, and in particular how the motivation to take drugs is altered by various molecular mediators in the neurons on these regions. The two basic questions we are interested in are 1) how projections from the cortex to the striatum influence drug seeking behaviors, and 2) how neurotransmitter receptors, particularly dopamine and cannbinoid receptors in these regions influence drug seeking. Our technical approaches include a number of basic behavioral models including measurements of locomotor activity, catalepsy, conditioned place preference and drug self-administration. In order to probe the circuitry of these brain regions, we use a number of advanced molecular techniques to activate and inactivate neuronal populations including optogenetics and artificial receptors. We probe the molecular pathways within the neurons by over expressing genes or knocking down expression using RNA interference. Gene delivery is accomplished using recombinant adeno-associated virus (rAAV) and several projects in the laboratory focus on improving this approach and exploring potential gene therapy applications for these vectors. The ultimate goal is to understand the basic neurobiology and molecular biology of addiction in order to develop more effective treatments for addiction.
Molecular and Cellular Biology; Neurobiology; Neuropharmacology
The goal of my research is to elucidate the endogenous role of two neuropeptide systems and their potential as therapeutic targets; urotensin II (UII) and neuropeptide S (NPS). Both of these peptides regulate basal ganglia function through G protein-coupled receptor (GPCR) mediated intracellular signals. The basal ganglia are critical in motivated behavior (e.g. food seeking), voluntary movement, and the expression of habits (e.g. compulsions). Basal ganglia dysfunction results in neurological disorders as diverse as Parkinsonism and drug addiction. GPCRs are proven to be amenable to drug development and are targeted by over 30 percent of present day pharmaceuticals. My goal is to exploit the UII and NPS systems to improve the medical treatment of neurological disorders. Currently my lab is pursuing the following: 1) Determine the role of UIIR activation and the UIIR expressing neurons in reward-related behaviors:. Our results support the need for further investigation of the UII-system as a therapeutic target for treating drug abuse disorders. In addition, we are investigating the i) bias-signaling properties of the endogenous UIIR ligands, and ii) the impact of UIIR single-nucleotide polymorphisms on receptor signaling. 2) We designed a toxin that selectively targets UIIR expressing neurons (cholinergic PPT). In rats the toxin-mediated lesion mimics Progressive Supranuclear Palsy (the most common atypical parkinsonism) on multiple fronts: selective ablation of cholinergic PPT neurons, impaired motor function, and deficits in acoustic startle reaction (MacLaren et al, 2014a; MacLaren et al, 2014b). Our selective cholinergic depletion and a viral-mediated tauopathy rat models are the first to specifically model PSP, and we are further characterizing these models in hope of using them for future drug discovery. 3) During my graduate and post-doctoral training it was found that the central brain administration of neuropeptide S (NPS) in mice enhances memory, is anxiolytic-like (reduced anxiety) and produces hyperlocomotor (increased movement) (Xu et al., 2004; Jungling et al., 2008; Duangdao et al., 2009; Okamura et al., 2011). This is a highly unique behavioral profile. Typically drugs that induce activity and arousal increase anxiety-like behaviors, while drugs that are anxiolytic generally have sedative effects and impair memory. Therefore, the NPS-system could be a therapeutic target for disorders for which fast-acting anxiolytics that augment memory formation would be beneficial (e.g. post-traumatic stress disorder (PTSD)). In collaboration with the Drug Discovery Center at Research Triangle Institute, we are testing new small molecule NPSR-targeted drug-like compounds.
Addictions; Drug abuse; Behavioral pharmacology; Cytoskeleton and cell motility; Gene Expression; Gene therapy; Neurobiology; Neuropharmacology; Signal Transduction; Transcription and Translation
Drug addiction is a disabling psychiatric disease leading to enormous burdens for those afflicted, their friends and family, as well as society as a whole. Indeed, the addict will seek out and use illicit substances even in the face of severe negative financial, family and health consequences. It is believed that drugs of abuse ultimately “hijack” the reward circuitry of the CNS leading to cellular adaptations that facilitate the transition to the “addicted” state As is the case with both rodent models of drug taking, and well as throughout the global human population, not all individuals exposed to drugs of abuse will meet the classical definition of being truly “addicted”. We are looking at how molecular and behavioral plasticity mediates susceptibility to drug abuse and relapse like behaviors.
Drug abuse; Behavioral pharmacology; Signal Transduction; Neuropharmacology; Circadian Rhythm/Chronobiology
My lab‘s research seeks to understand the mechanism of action of the hormone melatonin at the MT1 and MT2 G-protein coupled receptors. We study these receptors in the brain and through the body with the goal of identifying ligands that exhibit useful binding affinity and therapeutic potential. Our team of undergraduate and graduate students, postdoctoral fellows, technicians and senior scientists work with each other and with expert co-investigators in medicinal chemistry to discover and develop novel molecules that can mimic or counteract the actions of melatonin. These molecules may help treat a variety of diseases and conditions including insomnia, circadian sleep disorders, depression, seasonal affective disorders, and cardiovascular disease. Our laboratory pursues these investigations from several angles. We assess the localization of the melatonin receptors, examine their cellular and molecular signaling mechanisms,and investigate receptor fate following prolonged exposure to melatonin. We study the distinct roles of selective MT1 and MT2 melatonin receptor ligands in modulating circadian rhythms, methamphetamine‘s ability to induce both sensitization to prolonged exposure, and stimulation of the reward system. We also study cell proliferation, survival, and neurogenesis in the brain, and the changes in gene expression underlying all these processes. Our research ultimately aims to discover novel drugs with differential actions at the MT1 and MT2 receptors. We use molecular-based drug design, computer modeling and medicinal chemistry to design and synthesize small molecules that target these receptors as agonists, inverse agonists and/or antagonists. We then pharmacologically and functionally characterize these molecules using cell-based assays and bioassays and test them in circadian and behavioral animal models.
Children and Adults; Psychiatry; Molecular and Cellular Biology; Neuropharmacology; Signal Transduction
Research Interests: Calcium Metabolism in Affective Disorders; Psychopharmacology; Psychosomatic Medicine; Medical Education. Clinical specialties: mood disorders, psychosis, interactions between medical and psychiatric disorders, psychopharmacology, difficult diagnoses, complex clinical entities
Psychiatry; Neurobiology; Neuropharmacology
I am Board Certified in Psychiatry and I work as an adult psychiatrist at Erie County Medical Center. I am primarily involved in Outpatient psychiatry however also work as Inpatient psychiatrist. I regularly care for acutely ill patients in the inpatient setting and also manage the long term care for the patients in the community with diagnosis ranging from Depressive disorders to Bipolar disorder and Schizophrenia.
Neuroimmunology; Behavioral pharmacology; Gene therapy; Immunology; Molecular and Cellular Biology; Molecular Basis of Disease; Neurobiology; Gene Expression; Signal Transduction; Protein Function and Structure; Neuropharmacology
My research spans three interrelated fields: chronic pain, depression and inflammation. Experiments in my laboratory focus on how brain-derived pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF), function as modulators of brain-body interactions during neuropathic pain and how brain-TNF is involved in the mechanism of action of antidepressant drugs. My overall goal is to advance knowledge of, and therapeutic efficacy for pain, depression, neuro-inflammation and drug addiction. This research is based on my earlier work showing that neurons produce the pro-inflammatory cytokine TNF and that the production of TNF by macrophages is regulated by neurotransmitters. Cytokines and neurotransmitters are principal signaling molecules that mediate bidirectional communication between the nervous and immune systems--the crosstalk important in maintaining homeostasis. Consequently, aberrant production of either of these two classes of mediators could profoundly affect signaling by the other, thereby impacting health. A shift in balanced cytokine-neuron interactions that regulate neurotransmitter release in the central nervous system (CNS), and that have potential behavioral consequences, manifest themselves as states of depression and chronic pain. My research uses both cell systems and animal models to test these hypotheses. Colleagues and I use a combination of imaging techniques to localize cytokine production, bioassays and ELISA (enzyme-linked immunosorbent assays) for pharmacological and functional analyses, electrophysiological (brain slice stimulation) and molecular methods for our studies. In addition to investigating neuron functioning in the brain, trainees in my laboratory also study the peripheral macrophage, a major source of TNF during inflammation. Specifically studying neurotransmitter regulation of TNF production in the periphery is enhancing our knowledge of how the brain controls a peripheral inflammatory lesion. Our studies are designed to investigate the mechanisms of centrally mediated pain as associated with immune dysfunction and to elucidate mechanisms of drugs used to treat such pain states. My projects are evolving to investigate the mechanisms and neural pathways involved in TNF neuromodulator functions during chronic pain (due to peripheral nerve injury and diabetes) and stress-induced depressive behavior. We also study mechanisms contributing to the comorbidity of chronic pain and depression. I collaborate with researchers in several UB departments and at other institutions. Our projects include using noninvasive methods for delivery of anti-TNF therapeutics for chronic pain, elucidating the neural-immune mechanisms involved in the rapid recovery afforded by centrally administered anti-TNF therapy and using nanotechnology-mediated, targeted gene silencing within the CNS. I am invested in helping my undergraduate and graduate students, medical residents and postdoctoral fellows realize their potential and achieve their goals. Previous students have advanced professionally and hold clinical, academic and industrial positions.
Ion channel kinetics and structure; Molecular and Cellular Biology; Neurobiology; Neuropharmacology
Our research program focuses on brain development, studying the development of the oligodendroglial and astroglial cell lineages in the central nervous system in normal, mutant and transgenic mice. The primary focus in the laboratory is on ion channels that regulate specification, migration and differentiation of these glial cells. The oligodendrocyte generates CNS myelin, which is essential for normal nervous system function. Thus, investigating the regulatory and signaling mechanisms that control its differentiation and the production of myelin is relevant to our understanding of brain development and of adult pathologies such as multiple sclerosis. We have recently discovered that voltage-gated Ca++ channels are necessary for normal myelination acting at multiple steps during oligodendrocyte progenitor cells (OPCs) development, however nothing is known about its role in demyelination or remyelination events. Our research aims to determine if voltage-gated Ca++ channels plays a functional role in myelin repair. Using transgenic mice and new imaging techniques we are testing the hypothesis that voltage-gated Ca++ entry promotes OPC survival and proliferation in the remyelinating adult brain. Therefore, this work is relevant to developing means to induce remyelination in myelin degenerative diseases and for myelin repair in damaged nervous tissue. Astrocytes are the most abundant cell of the human brain. They perform many functions, including biochemical support of endothelial cells that form the blood brain barrier, provision of nutrients to the nervous tissue and a role in the repair and scarring process of the brain and spinal cord following traumatic injuries. Our lab has made the novel finding of voltage-gated Ca++ channels function in astrocyte Ca++ homeostasis, and this has implications for plasticity in astrocyte development and for Ca++ regulation in general. We are testing the hypothesis that voltage-gated Ca++ entry plays a key role in astrocyte function and glial-neuronal interactions. We have generated a conditional knockout mice for voltage-gated Ca++ channels in astrocytes, these conditional knockout mice will allow the functional analysis of voltage-gated Ca++ channels in astroglia of the postnatal and adult brain. Analyzing such mice using a combination of behavioral, electrophysiological, imaging, and immunohistochemical techniques will provide new insights in our understanding of astroglial contribution to brain function. These projects have been supported for many years by grants from the NIH and the National Multiple Sclerosis Society.
Behavioral pharmacology; Neurobiology; Neuropharmacology; Regulation of metabolism; Signal Transduction
Catecholamines such as dopamine and norepinephrine in the brain play important roles in a wide range of disparate physiological and behavioral processes such as reward, stress, sleep-wake cycle, attention and memory. The catecholamines are also well known for their treatment of neural disorders and many other diseases. Therefore, the examination of the catecholamines is of great importance not only in pharmaceutical formulations but also for diagnostic and clinical processes. The role and contribution of catecholaminergic innervation in the limbic system to biological functions and behavior are still poorly understood, however, due to the complicated functional heterogeneity, the small size of the limbic brain nuclei. In vivo and in vitro electrochemical measurement at microelectrodes has enabled direct monitoring of neuronal communication by chemical messengers in real time, which provides new insight into the way in which information is conveyed between neurons. Such information enables to study the basis for understanding the mechanisms that regulate it, the behavioral implications of the chemical messengers, and the factors regulate normal and altered chemical communication in various disease states (e.g. cardio vascular disease, degenerative nerve diseases, and drug addiction). My overall research focuses on two areas. Firstly, the design and implementation of development of new types of electrochemistry-based sensors and ancillary tools to monitor catecholamines and nonelectroactive neurochemicals in a chemically complex environment in the peripheral and central nervous systems of test animals. Secondly, application of the newly developed analytical techniques or existing methodologies for real-time monitoring of the neurochemicals i) to understand role of the neurochemicals in the brain in stress- and reward-related behaviors, ii) define and understand dysfunctions of the central and peripheral nervous systems in disease states by observing fundamental changes in neurochemical transmission in anesthetized and awakened animals.
Neurodegenerative disorders; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular Basis of Disease; Neurobiology; Neuropharmacology; Protein Function and Structure; Signal Transduction
We investigate the activation mechanisms of fast neurotransmitter receptors. We seek to define the activation pathway, modulatory mechanisms and structure-function relationships of the N-methyl-D-aspartate (NMDA) receptor to better understand the roles played by this protein in the brain. NMDA receptors are the most abundant glutamate-stimulated, Ca2+-conducting ion channels in brain and spinal cord. They are the predominant molecular devices for controlling synaptic development and plasticity and govern memory and learning processes. Understanding the mechanisms that control their activity may lead to more effective strategies to treat neuropathies including stroke, neurodegenerative conditions, chronic pain and addiction as well as mental disorders such as schizophrenia and epilepsy.
Gene Expression; Gene therapy; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Neuropharmacology; Transcription and Translation
The efforts in my lab are broadly directed at the translational research of neuroprotective/neurorestorative agents. Specifically, I am focused on the preclinical and clinical development of therapies used to prevent behavioral and cognitive deficits following traumatic brain injury (TBI) and stroke. Over 800,000 patients each year in the US suffer stroke and more than twice that number suffer TBI. Unfortunately there are currently no FDA approved therapies for TBI. TPA is the only therapy approved for stroke but is only applied in about 4% of stroke patients. Furthermore, while TPA is thrombolytic, it does not limit the cascade of pathology initiated by the original occlusion. We have demonstrated that low dose methamphetamine is highly neuroprotective when administered as an acute treatment (within 12 hours after injury) following severe stroke or TBI. We have show that treatment with methamphetamine significantly improve cognition and functional behavior in rat models of these injuries. This effect is primarily mediated through the activation of a dopamine/PI3K/AKT signaling cascade and results in the preservation of primary neurons, and axons, as well as enhanced granule cell neurogenesis and white mater track remodeling. Furthermore, gene expression analysis suggests methamphetamine treatment significantly reduces pro-inflammatory signals and stabilizes the blood brain barrier. These observations led us to further investigate the potential of low dose methamphetamine to reduce or prevent post-traumatic epilepsy. Using long-term video/EEG monitoring, we determined that methamphetamine treatment significantly reduces the incidence and susceptibility to post traumatic epilepsy/seizures after severe TBI in rats. This becomes quite relevant when one considers that many patients with post-traumatic epilepsy are pharmacoresistant. We are continuing to use the TBI model to investigate the causes of post-traumatic epilepsy and test novel therapeutics. In addition to single severe injury, we are also very interested in the effects of repeated mild TBIs. It has now been observed that multiple mild TBIs can cause clinical seizures in about 50% of rats. Therefore, we are also using this model to investigate the causes of post-traumatic epilepsy and potential therapeutic interventions. We have now completed a phase I human trial of methamphetamine in healthy volunteers and are moving to conduct a phase IIa dose escalation safety study in TBI patients. In addition, we are currently using NGS to examine plasma miRNA changes as potential biomarkers and objective measures of activity to support the phase IIa study. In addition to small molecules, my lab also is investigating the development of Adeno- associated virus (AAV) vector based gene therapy approaches to the treatment of CNS injuries such as post-traumatic epilepsy. Specifically, we are using recombinant AAV vectors to modulate targeted gene expression in a temporal, tissue-specific and cell type-specific manner within the CNS.
Gene therapy; Genomics and proteomics; Immunology; Infectious Disease; Neurobiology; Neuropharmacology; Viral Pathogenesis; Virology
As a postdoctoral fellowship in the Division of Allergy, Immunology & Rheumatology at University at Buffalo I received a NIDA funded National Research Service Award (NRSA) F32 to study the mechanisms of cocaine-induced HIV-1 infection in astrocytes. This was a two year fellowship award ($99,224). I received several Young Investigator Travel Awards to attend and present my research at national conferences including the Society for NeuroImmune Pharmacology, the College on Problems of Drug Dependence and the International Society for NeuroVirology. I was the first to demonstrate that cocaine enhances the replication of HIV in astrocytes, specialized glial cells in the central nervous system. During this time I was first author on 3 publications and contributed as a co-author on 6 publications in internationally recognized, peer reviewed journals including the Journal of Immunology, Brain Research and Biochimica et Biophysica Acta. As a Research Assistant Professor in the Division of Immunology I was funded through a NIDA Mentored Research Scientist Development Award (K01) award to investigate targeted nanoparticles for gene silencing in the context of HIV and drug abuse. This K01, was a five year award, $785000 that allowed for advanced training in nanotechnology and immunology. I applied this new expertise in nanotechnology to the development of innovative methods to control HIV-1 infections, particularly those associated with methamphetamine abuse. I was an invited panel speaker at the International Symposium on NeuroVirology and the American College of Neuropsychopharmacology. During this time, I published approximately 30 peer-reviewed publications in internationally recognized, peer-reviewed journals, including journals such as the Journal of Immunology, Brain Research, and the Journal of Pharmacology Experimental Therapeutics. Six as first author, 1 as senior author and 23 as a co-author. Presently, I am a Associate Professor and Proposal Development Officer in the Department of Medicine at University at Buffalo where I continue to develop my research in drug delivery methods. I am currently investigating exosomes as potential delivery vehicles. Exosomes are one of several types of membrane vesicles known to be secreted by cells including microvesicles, apoptotic bodies, or exosome-like vesicles. Exosomes, unlike synthetic nanoparticles, are released from host cells and have the potential to be novel nanoparticle therapeutic carriers I have recently been invited to be a panel speaker at the American Society of Nanomedicine and the American Society of Gene & Cell Therapy conferences. I have been a principal investigator and co-instigator on NIH funded projects studying multimodal nanoparticles for targeted drug delivery and immunotherapy in Tuberculosis and HIV and a co-investigator on a NYS Empire Clinical Research Investigator Program (ECRIP) to develop a Center for Nanomedicine at UB and Kaleida Health. I have had over eight years of NIH supported funding.
Behavioral pharmacology; Cardiac pharmacology; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular Basis of Disease; Neurobiology; Neuropharmacology; Signal Transduction; Transgenic organisms
With over 400 genes coding for them in humans, ion channels play a significant role in most physiological functions. Drug-induced channel dysfunction often leads to a variety of disorders and results in significant incidence of serious injury and death. We investigate molecular mechanisms underlying neurodegenerative disorders and cardiac arrhythmias induced by ion channel dysfunction arising from genetic factors and/or drug interactions. The tools used for these investigations include genetic, electrophysiologic, pharmacologic, molecular and cell culturing methods. Preparations used for experiments include Drosophila as a genetic model system, and human cell lines expressing human ion channels that play an important role in critical-to-life functions including cardiac rhythm, respiration and the central nervous system.
Behavioral pharmacology; Neuropharmacology; Toxicology and Xenobiotics
Research in my laboratory centers on the study of psychoactive drugs with special emphasis on nootropics and drugs of abuse. In collaboration with Dr. Richard Rabin of this department, behavioral data are correlated with biochemical indices of drug action in an attempt to understand at the receptor level the effects in intact animals of psychoactive drugs. Behavioral data are obtained using the techniques of operant behavior with special emphasis on the phenomenon of drug-induced stimulus control. Current interests include the serotonergic basis for the actions of indoleamine and phenethylamine hallucinogens including LSD and [-]-DOM as well as their interactions with selective monoamine reuptake inhibitors such as fluoxetine [Prozac]. In the area of nootropics, recent studies have examined the effects of EGb 761, an extract of Ginkgo biloba; for these investigations, a delayed non-matching to position task in a radial maze is employed. Currently, studies are in progress to assess the serotonergic basis for the cognitive effects of drugs of abuse including LSD and MDMA [Ecstasy]. Behavioral pharmacology of psychoactive drugs, including psychotherapeutic agents and drugs of abuse; mechanisms of action of hallucinogens. Research in Dr. Jerrold Winter‘s laboratory seeks to understand the ways in which drugs alter behavior. Many chemicals are candidates for study but attention in the last few years has centered on hallucinogens such as LSD, phencyclidine, DOM, and ibogaine. Another area of major interest is age-related memory impairment and those natural materials, including ginseng and gingko biloba, which are purported to influence that impairment. The behavioral effects of these drugs are studied in rats trained with the techniques of operant conditioning. Specific variables in use at the present time include drug-induced stimulus control, radial maze acquisition and performance, and conditioned place preference and aversion. In addition, Dr. Winter actively collaborates with Dr. Richard Rabin of the Department of Pharmacology and Toxicology in order to correlate behavioral effects with biochemical indices of action at the receptor level and with functional efficacies in second messenger systems.
Neurodegenerative disorders; Pathophysiology; Cytoskeleton and cell motility; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Neuropharmacology; Signal Transduction
Synaptic Mechanisms of Mental Health and Disorders Our research goal is to understand the synaptic action of various neuromodulators that are linked to mental health and illness, including dopamine, stress hormones, and disease susceptibility genes. Specifically, we try to understand how these neuromodulators regulate glutamatergic and GABAergic transmission in prefrontal cortex (PFC), which is important for emotional and cognitive control under normal conditions. We also try to understand how the aberrant action of neuromodulators under pathological conditions leads to dysregulation of synaptic transmission in PFC, which is commonly implicated in brain disorders. The major techniques used in our studies include: • whole-cell patch-clamp recordings of synaptic currents, • viral-based in vivo gene transfer, • biochemical and immunocytochemical detection of synaptic proteins, • molecular analysis of genetic and epigenetic alterations, • chemogenetic manipulation of neuronal circuits, • behavioral assays. By integrating the multidisciplinary approaches, we have been investigating the unique and convergent actions of neuromodulators on postsynaptic glutamate and GABAA receptors, and their contributions to the pathogenesis of a variety of mental disorders, including ADHD, autism, schizophrenia, depression, PTSD and Alzheimer‘s disease.