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Keywords: addiction, nicotine, relapse, glutamate, synaptic plasticity
The goal of our research is to identify novel neurobiological and behavioral mechanisms to guide the treatment of addiction. Our lab focuses on glutamatergic, dopaminergic, neuroimmune, and ovarian hormone mechanisms underlying addiction to various drugs of abuse during young adulthood and during the female reproductive transition of menopause. Our projects focus on nicotine, heroin, and oxycodone/cocaine co-use.
To date, our work has revealed novel neurobiological mechanisms of nicotine addiction, and has the potential to contribute to the development of novel therapeutic options aimed at reversing nicotine-induced alterations and thus improve smoking cessation outcomes. This work has resulted in translational collaborations to examine clinical efficacy of pharmacotherapeutics in promoting smoking cessation.
The lab examines the neurobiological underpinnings of cue-triggered motivation and conditioned reinforcement, specifically examining alterations in synaptic plasticity via dendritic spine morphology and glutamatergic signaling in self-administration and reinstatement. This research utilizes both in vivo and in vitro methodologies to study rapid alterations in synaptic plasticity (measured as changes in dendritic spines or AMPA/NMDA ratios) during or immediately following behavior (specifically, during reinstatement of drug seeking in a preclinical model of relapse).
1. Mapping the Neural Circuitry of Nicotine Addiction
Elucidating additional neural mechanisms underlying nicotine addiction and relapse is necessary for the development of novel therapeutic options. Historically, the tools available to map the neural circuitry of
nicotine addiction in a cell type- and pathway specific-manner have suffered from low resolution, such as pharmacological inhibition of brain regions that does not allow for pathway specificity. Recent advancements in technology have led to unprecedented progress in unraveling the complexities of the addicted brain. Our research, funded by a R21 awarded by NIDA, is examining the role of cholinergic interneurons within the reward circuitry (specifically, the nucleus accumbens core) in nicotine seeking motivation. To investigate this we use a multidisciplinary approach to examine nicotine-induced neurobiological changes, and employ cutting-edge techniques including specific chemogenetic modulation of accumbens neuronal signaling in transgenic rats. Chemogenetic control of neuronal signaling is an innovative technique used to examine the link between signaling of specific cell types as well as neural circuitry underlying addiction-related behaviors. Unraveling the neural circuitry of nicotine addiction is crucial to our understanding of how addiction changes the brain, and how we can begin efforts to reverse these changes. Results from the R21 award will be the first to uncover an outsized role of a very small proportion of neurons (less than 1%) within the reward pathway in driving nicotine addiction.
Funding Source: NIDA R21 DA044479 (Gipson-Reichardt, PI)
2. Nicotine Reduction Strategies to Decrease Smoking
In the United States, the Food and Drug Administration (FDA) recently gained the authority to regulate the amount of nicotine in cigarettes. Specifically, reduction of nicotine content in tobacco products is a control strategy intended to decrease smoking dependence that reduces nicotine content over time, which is posited to produce reductions of nicotine dependence. Nicotine reduction strategies could include either reduction to a very low dose, or to a moderate dose for a more gradual reduction policy. Our preliminary studies directly challenge the positive clinical literature, showing that abrupt reduction of nicotine dose decreases craving. Rather, our data indicate that nicotine reduction increases the essential value of nicotine, and exacerbates nicotine relapse. Because it is unclear if immediate nicotine reduction to a very low nicotine dose leads to promotion of smoking cessation, my research (R03 awarded from NIDA), is designed to determine if this will be an efficacious strategy to inhibit nicotine relapse as well as associated rapid, transient plasticity using a behavioral economics approach. Additionally, as smokers may compensate for reduced nicotine content by increasing smoke intake/puff volume, my research is systematically examining if rats compensate intake following an abrupt reduction in nicotine dose. Results from these studies will help guide regulatory policy executed by the FDA.
Funding Source: NIDA R03 DA045881 (Gipson-Reichardt, PI)
3. Mechanisms of and Treatments for Opioid and Cocaine Polysubstance Abuse
Opioid use disorder (OUD) is a leading public health crisis in the United States that has led to a decrease in life expectancy. Individuals with OUD often use other substances, including cocaine. Stimulant use during opioid withdrawal may represent an attempt to ameliorate opioid withdrawal effects, but combined use of cocaine with opioids increases overdose risk. As I have previously found, drug-motivated behaviors are regulated by glutamate signaling within corticostriatal circuitry. Specifically, withdrawal from cocaine renders synapses in a potentiated state (Gipson et al., 2013, Neuron), whereas withdrawal from heroin induces depotentiation of synapses. These results illustrate glutamate as a conserved neural mechanism underlying drug-motivated in both opioid and cocaine use, and suggest that glutamate signaling underlies this pattern of polysubstance use. Thus, in collaboration with clinical researchers at the University of Kentucky including Drs. William Stoops, Craig Rush, Josh Lile, and Michael Wesley, we have a pending translational grant to NIDA to determine if (1) persistent brain glutamate changes induced by chronic opioid use exacerbates use of cocaine during opioid physical dependence and withdrawal in both humans
and animals, and (2) if N-Acetylcysteine (NAC), a glutamate agent that has shown translational promise for treating use of cocaine and opioids, will ameliorate glutamatergic dysregulation and thus will reduce both oxycodone and cocaine use. Should NAC show promise for ameliorating glutamate dysregulation, reducing cocaine use and/or mitigating opioid withdrawal signs, our collaborative team plans to advance this compound as an adjunct treatment in opioid dependent individuals with comorbid cocaine use. Completion of these translational studies will guide clinical targets for human research by broadening our understanding of the role of glutamate as a neural biomarker in opioid/cocaine co-use.
Funding Source: NIDA R21-R33 DA049130 (Pending; MPIs Gipson-Reichardt, Stoops)
4. Novel Glutamatergic Treatments for Heroin Seeking
Chronic use of drugs of abuse induces long-lasting changes in glutamate homeostasis that enhance glutamate signaling in key brain areas. For example, I have found that inhibition of the GluN2B-subtype of NMDA receptors reduces nicotine relapse (Gipson et al., 2013, PNAS). Thus, antagonism of these receptors has been proposed as a valid target for relapse prevention. In collaboration with Dr. Foster Olive and NeurOp, a small business, we received funding from NIDA (R41 DA046266) to study efficacy of a new compound that selectively targets this receptor. We hypothesize that NP10679, a selective NMDA receptor inhibitor, could provide benefit as a treatment to prevent relapse to opiate use.
Funding Source:NIDA R41 DA046266 (Gipson-Reichardt, PI of subcontract, Olive, Co-I)
5. Aging, Hormones, and Nicotine Addiction
Women are typically more vulnerable to substance use disorders and clinical trials have shown that long-term smoking cessation is more difficult to achieve in women than men. Clinical research studies suggest that the menstrual cycle phase in women can affect cigarette craving and propensity to relapse to smoking following abstinence. We began by examining sex-specific efficacy of NAC in reducing nicotine seeking motivation. Through funding from the Institute on Social Science Research at ASU, we found that NAC reduces nicotine seeking in male but not female rats As well, the lack of reduction in nicotine seeking was not estrous cycle-dependent (Goenaga*, Powell*, et al., 2019, Addiction Biology). These results illustrate the importance of tailoring clinical treatment for nicotine addiction in a sex-specific manner. Our next step is to explore the impact of ovarian hormones on aging and addiction. Lifetime smoking is correlated with premature menopause, illustrating smoking as an important factor in reproductive health in aging women. Our research, funded by the Arizona Alzheimer’s Consortium, will uncover the impact of the cessation of hormones on nicotine addiction as well as the underlying neural circuitry in young and aged females. Importantly, there is a large gap in the literature with regard to aging and nicotine addiction. In collaboration with Dr. Bimonte-Nelson, this project will be the first to uncover neurobehavioral mechanisms related to normal aging and nicotine addiction.
Funding Source: Arizona Alzheimer’s Consortium (Gipson-Reichardt, PI; Bimonte-Nelson, Co-I)
6. Neuroinflammation and Addiction
Brain injury leads to pro-inflammatory signaling within the brain. For example, neuroinflammation occurs with chronic drug use and has been implicated across a number of neuropsychiatric and neurodegenerative pathologies. My research program is the first to systematically evaluate (1) neuroinflammation after nicotine addiction, during withdrawal, or during nicotine relapse; and (2) causal relations of neuroinflammation to rapid, transient, cue-induced synaptic plasticity in a nicotine addiction model. Given the limited clinical success of current smoking cessation treatments, novel treatment avenues are needed.
The central question driving my laboratory’s research is: does reducing neuroinflammation in the brain decrease aberrant glutamate signaling, and therefore decrease nicotine seeking motivation? Results from this line of research will power novel directions in therapeutic treatment strategies, as anti-inflammatory agents have shown some clinical efficacy in reducing smoking, such as bupropion. Related to this, we are examining the relationship between pro-inflammatory signaling within reward circuitry and composition of the gut microbiome. Preliminary results have been submitted to SRNT 2019 meeting, and provide the first evidence that gut microbes associated with chronic inflammatory diseases are induced by nicotine use, associated with pro-inflammatory signaling in the brain, and may serve as pathobionts (i.e., disease-causing organisms) to enhance nicotine addiction vulnerability.
In addition to the above project, we are interested in the link between neuroinflammation, hormones, and aging. Throughout the female reproductive life cycle, fluctuations in ovarian hormones impact neuronal physiology. Chronic use of nicotine is pro-inflammatory and smoking increases the risk for the development and progression of Alzheimer’s disease (AD). Thus, smoking is an important environmental risk factor for AD, possibly through neuroinflammatory mechanisms. In contrast to nicotine, estrogen acts as an anti-inflammatory agent, and thus when the precipitous loss of estrogen occurs during menopause, the neuroprotective effects of estrogen on dampening neuroimmune signaling are significantly diminished. Neuroinflammation may contribute to amyloid toxicity in AD. Given that aging is a major risk factor for the development of AD, and that many studies indicate that neuroinflammation may play a prominent role in its onset and progression, it is first important to understand if nicotine addiction exacerbates this process in a system undergoing aging processes which are not neurodegenerative. Importantly, nicotine is anti-estrogenic and smoking leads to premature aging by precipitating early onset of menopause. Thus, we seek to identify key neuroinflammatory targets such as markers of microglia activation and pro-inflammatory cytokines (which are associated with AD) in aged females. Importantly, these pro-inflammatory markers may be exacerbated due to nicotine addiction, which may highlight the need for more effective interventions to promote smoking cessation among aging female populations.
Funding Source: Arizona Alzheimer’s Consortium (Gipson-Reichardt, PI; Bimonte-Nelson, Co-I)
7. NMDA receptors and nicotine relapse
Addiction to nicotine has been associated with long lasting changes in brain synaptic physiology within the basal ganglia that might contribute to relapse. Specifically, initiation of cue-induced nicotine seeking produces rapid, transient synaptic potentiation (t-SP) in nucleus accumbens core (NAcore) medium spiny neurons (MSNs), defined as increases in spine head diameter and AMPA to NMDA current ratios (A/N). The neural mechanisms that gate nicotine relapse-associated t-SP, however, remain largely unknown. Ifenprodil, which we have shown to prevent reinstatement, antagonizes GluN2B-containing NMDA receptors and blocks serotonin transporters (SERT). Using a combination of behavior, in vivo pharmacotherapies, inhibitory siRNAs (for GluN2B NMDA receptors), and whole cell electrophysiology, the overarching goal of this project is to determine the therapeutic action of ifenprodil by investigating whether pharmacological blockade of SERT or GluN2B-specific knockdown directly into the NAcore would prevent cue-induced nicotine relapse as well as the associated structural and functional t-SP.
Funding Source: NIDA R00 DA036569 (Gipson-Reichardt, PI)
8. Compulsive cocaine seeking and prefrontal cortical neuronal physiology
Cocaine dependence affects nearly 1 million Americans and is a rapidly progressive disorder associated with detrimental neurological deficits. While the euphoric effects of cocaine are primarily reliant on its action at dopaminergic transporters, causing dopamine levels to rise, the neurophysiological effects of long-term use remain understudied. Like other substance abuse disorders, compulsivity, characterized by the pursuit of drug despite incurring significant negative consequences, is a major phenotype of cocaine dependence. Compulsivity has been heavily linked to deficits in prefrontal cortical (PFC) function, a brain area highly involved in mediating executive functioning tasks, including self-control. Using animal models, it has been demonstrated that a subset of rats will continue to self-administer intravenous cocaine despite paired delivery of foot shock, portraying the relationship to continue drug seeking despite negative consequences of use. These compulsive-prone animals displayed decreased ex vivo intrinsic excitability of layer V (LV) pyramidal neurons of the PFC, indicating hypofrontality induced by cocaine use. While these studies describe cocaine-induced hypofrontality contributing to compulsivity, the cellular mechanisms underlying hypofrontality as well as neural network-specific effects remain unexplored. For this project, we aim to explore the mechanisms underlying hypofrontality, specifically identifying single cell physiological alterations. This research has the potential to reveal novel pathways and neuronal subtypes contributing to the loss of inhibitory control commonly observed in substance abuse disorders, including cocaine. Given that treatment options for cocaine addiction targeting prefrontal hypofrontality have yet to be described, these data will provide a potential therapeutic target to reduce compulsivity and treat patients suffering from substance abuse disorders.
Funding Source: Arizona State University Institute for Social Science Research Seed Grant
If you're an ASU undergrad and would like to work in the lab as a volunteer or for PSY 399/499 course credit, please visit the Research Opportunites webpage and look for the lab name. Although priority will be given to Psychology majors, all science majors are encouraged to apply.
Dr. Gipson-Reichardt received her BS from the UC San Diego in 2004 and her PhD from the University of Kentucky in 2010. In 2015 she completed her post-doctoral fellowship in the lab of Dr. Peter Kalivas at the Medical University of South Carolina. Her primary research goal is to examine synaptic mechanisms underlying motivated behavioral processes that are perturbed in neuropsychiatric disorders such as nicotine addiction. The behavioral plasticity induced by drugs of abuse is an ideal model system in which to apply her interests with direct ties to public health and well-being. Her work focuses on the synaptic mechanisms that underlie drug relapse vulnerability. To accomplish this, multiple cutting-edge techniques are utilized including dendritic spine morphology, electrophysiology, self-administration, use of vivo morpholinos, in vivo microdialysis, and Western blotting. Curriculum Vitae
Jonna Jackson, PhD
Jonna received her undergraduate degree in Biomedical Sciences from the University of Northern Colorado in 2012. She then went on to earn her doctoral degree in Biological Education with research emphasis in neurophysiology. Her doctoral work studied the role of dopamine in synaptic plasticity and rhythmic dynamics of the prefrontal cortex. She has since joined the labs of Dr. Cassandra Gipson-Reichardt and Dr. Foster Olive and works on behavioral, electrophysiological and cell morphological components of substance use disorder, with particular interest in nicotine’s role in altering synaptic plasticity within the nucleus accumbens as well as the role of alcohol in mediating hypothalamic changes in POMC neurons.
Paula Overby, BS
Paula graduated from Barrett, The Honors College at Arizona State University with a B.S. in Psychology and Biological Sciences with a concentration in Neurobiology, Physiology and Behavior. As an undergraduate, she worked in Dr. Federico Sanabria’s lab studying basic behavioral processes in rats and
in Dr. Jon Harrison’s lab studying variation in anoxia tolerance in fruit flies. For her honors thesis, she investigated nicotine’s enhancement of incentive salience.
We are actively recruiting graduate students! Successful candidates will be interested in examining motivated behavior, specifically using the self-administration paradigm to study preclinical mechanisms of drug addiction. As well, students will be immersed in the field, where they will examine the links between neurobiology and motivation in addiction. Students will learn techniques such as whole cell patch clamp electrophysiology, spine morphology, Western blot, immunohistochemistry, chemogenetics, and optogenetics to answer complex questions regarding neural circuitry and cellular signaling mechanisms that drive motivated drug seeking behavior across different drugs of abuse. Using a multi-faceted approach, students will be able to answer questions from many complementary angles. As evidenced by the project descriptions, we have several lines of ongoing research, which allows students to increase breadth and depth of knowledge in the field.
Requirements for Undergraduates:
● Highly responsible and motivated
● Good communication skills
● Willing to work with rodents, including surgeries, animal handling, and animal testing
● Available for a minimum of 10 hr/week with longer blocks of availability preferred
● Able to commit 1+ year to the lab to insure enough time for thorough training
● Attend a biweekly lab meeting
Undergraduate research assistants can expect to receive hands-on experience in a research lab, including behavioral and wet lab techniques. Honors students will be required to become project lead of an independent research project, with oversight from graduate students and post-doctoral fellows, as well as Dr. Gipson-Reichardt.
If you're an ASU undergrad and would like to work in the lab as a volunteer or for PSY 399/499 course credit, please visit the Research Opportunites webpage and look for the lab name. You may also contact the lab manager, Paula Overby, at email@example.com.
Below are a sample of recent publications from Dr. Gipson-Reichardt’s research and lab. A more complete listing may be found in Dr. Gipson-Reichardt’s curriculum vitae.
Namba, M.D., Kupchik, Y.M., Spencer, S.M., Garcia-Keller, C., Goenaga, J.G., Powell, J.L., Vicino, I.A., Hogue, I.B., Gipson, C.D. (in press). Accumbens Neuroimmune Signaling and Dysregulation of Astrocytic Glutamate Transport Underlie Conditioned Nicotine Seeking Behavior. Addiction Biology.
Roberts-Wolfe, D.J., Heinsbroek, J.A., Spencer, S.M., Bobadilla, A.C., Smith, A.C.W., Gipson, C.D., Kalivas, P.W. (in press). Transient synaptic potentiation in nucleus accumbens shell during refraining from cocaine seeking. Addiction Biology.
Siemsen, B.M., Reichel, C.M., Leong, J.C., Garcia-Keller, C., Gipson, C.D., Spencer, S.M., McFaddin, J.A., Hooker, K.N., Kalivas, P.W., Scofield, M.D. (2019). Effects of methamphetamine self-administration and extinction on astrocyte structure and function in the nucleus accumbens core. Neuroscience, 406:528-541.
Powell, G.L., Namba, M.D., Cabrera-Brown, G., Neisewander, J.L., Marusich, J.A., Beckmann, J.S., Gipson, C.D. (in press). Analysis of economic demand for nicotine using an abbreviated behavioral economic protocol in rats. Drug and Alcohol Dependence.
Goenaga, J., Powell, G. L., Leyrer‐Jackson, J. M., Piña, J., Phan, S., Prakapenka, A. V., ... & Gipson, C. D. (2019). N‐acetylcysteine yields sex‐specific efficacy for cue‐induced reinstatement of nicotine seeking. Addiction biology.
Leyrer-Jackson, J. M., Olive, M. F., & Gipson, C. D. (2019). Whole-Cell Patch-Clamp Electrophysiology to Study Ionotropic Glutamatergic Receptors and Their Roles in Addiction. In Glutamate Receptors (pp. 107-135). Humana Press, New York, NY.
Namba, M. D., Powell, G. L., Del Franco, A. P., Goenaga, J. G., & Gipson, C. D. (2019). Brain Gene Expression in the Context of Nicotine Rewards: A Focus on Cholinergic Genes. In Neuroscience of Nicotine (pp. 321-328). Academic Press.
Powell, G. L., Leyrer‐Jackson, J. M., Goenaga, J., Namba, M. D., Piña, J., Spencer, S., ... & McClure, E. A. (2019). Chronic treatment with N‐acetylcysteine decreases extinction responding and reduces cue‐induced nicotine‐seeking. Physiological reports, 7(1), e13958.
Powell, G., McClure, E. A., Olive, M. F., & Gipson, C. D. (2019). Clinical Treatment of Addictive Disorders with N-Acetylcysteine. In The Therapeutic Use of N-Acetylcysteine (NAC) in Medicine (pp. 219-233). Adis, Singapore.
Piña, J. A., Namba, M. D., Leyrer-Jackson, J. M., Cabrera-Brown, G., & Gipson, C. D. (2018). Social Influences on Nicotine-Related Behaviors. International review of neurobiolog
Namba, M. D., Tomek, S. E., Olive, M. F., Beckmann, J. S., & Gipson, C. D. (2018). The winding road to relapse: forging a new understanding of cue-induced reinstatement models and their associated neural mechanisms. Frontiers in Behavioral Neuroscience, 12, 17.
Olive, M. F., Del Franco, A. P., & Gipson, C. D. (2018). Diolistic labeling and analysis of dendritic spines. In Neurotrophic Factors (pp. 179-200). Humana Press, New York, NY.
Overby, P. F., Daniels, C. W., Del Franco, A., Goenaga, J., Powell, G. L., Gipson, C. D., & Sanabria, F. (2018). Effects of nicotine self-administration on incentive salience in male Sprague Dawley rats. Psychopharmacology, 235(4), 1121-1130.
Romero, K., Daniels, C. W., Gipson, C. D., & Sanabria, F. (2018). Suppressive and enhancing effects of nicotine on food-seeking behavior. Behavioural brain research, 339, 130-139.
Gipson, C. D., & Olive, M. F. (2017). Structural and functional plasticity of dendritic spines–root or result of behavior?. Genes, Brain and Behavior, 16(1), 101-117.
Bobadilla, A.C., Heinsbroek, J.A., Gipson, C.D., Griffin, W., Fowler, C.D., Kenny, P., & Kalivas, P.W. (2017). Corticostriatal plasticity, neuronal ensembles, and regulation of drug-seeking behavior. Progress in Brain Research vol. “Addiction in Brain Research”, 235: 93-112.
Fowler, C.D.*, Gipson, C.D.*, Kleykamp, A., Rupprecht, L.E., Rees, V.W., Gould, T.J., Oliver, J., Bagdas, D., Damaj, I., Schmidt, H.D., Harrell, P.T., Duncan, A., De Biasi, M. (2017). Basic science and public policy: Informed regulation for nicotine and tobacco products. Nicotine and Tobacco Research. PMID: 29065200. *these authors contributed equally to this work.
Smith, A.C.W.*, Scofield, M.D.*, Heinsbroek, J.A.*, Gipson, C.D.*, Neuhofer, D., Roberts-Wolfe, D.J., Spencer, S., Stankeviciute, N.M., Smith, R., Allen, N.P., Lorang, M.R., Griffin III, W.C., Boger, H.A., & Kalivas, P.W. (2017). Accumbens nNOS interneurons regulate cocaine relapse. Journal of Neuroscience 37(4), 742-756. *These authors contributed equally to this work.
Garcia-Keller, C., Kupchik, Y. M., Gipson, C. D., Brown, R. M., Spencer, S., Bollati, F., ... & Cancela, L. M. (2016). Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration. Molecular psychiatry, 21(8), 1063.
Gipson, C. D. (2016). Treating addiction: unraveling the relationship between N-acetylcysteine, glial glutamate transport, and behavior. Biological psychiatry, 80(3), e11-e12.
Gipson, C. D., & Kalivas, P. W. (2016). Neural basis of drug addiction. In Drug Abuse in Adolescence (pp. 37-56). Springer, Cham.
Scofield, M. D., Heinsbroek, J. A., Gipson, C. D., Kupchik, Y. M., Spencer, S., Smith, A. C. W., ... & Kalivas, P. W. (2016). The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacological reviews, 68(3), 816-871.
Dr. Leyrer-Jackson and Dr. Gipson-Reichardt at CPDD 2019 in San Antonio, TX
Undergraduate Volunteer’s graduation party 2019. Pictured left to right: Paula Overby (lab manager), Ngoc Van Do (undergrad volunteer), Vincent Carfagno (graduating volunteer, B.S.), and Dr. Jonna Jackson (Post-doc).
Celebrating the lab’s March birthdays
Spring 2019 Lab Outing to Main Event.
Dr. Gipson-Reichardt (P.I.) at CPDD 2018 in San Diego, CA.
Celebrating the lab’s December birthdays.
Final stage of PCR genotyping for our transgenic rat colony.
Dr. Gipson-Reichardt (P.I.), Early Career Investigator Award at NIDA-NIAA Mini-Convention 2017 in Washington, D.C.
Honors and Awards to Dr. Gipson-Reichardt:
Undergraduate Honor’s Thesis Defenses:
Awards and Recognition to Lab Members: