This proposal requests support for a comprehensive training plan that will enable Noelle C. Anastasio, Ph.D., to broaden, enhance, and refine technical skills that are necessary for a productive independent research career. My long-term career goal is to obtain a tenure-track faculty position at a research-intensive academic institution and build a research program focused upon the ultimate scientific goal to understand the psychopharmacology of the impulsivity trait to advance prevention and treatment of addiction. Various aspects of drug abuse, including the initiation of drug-taking, the transition from casual to compulsive drug use, the maintenance of drug-seeking behaviors as well as the penchant to reinstate drug-seeking correlate with high levels of inherent impulsivity. Dysregulation in serotonin (5-HT) 2C receptor (5-HT2CR) function within the mesocorticolimbic circuit has been implicated in these stages of the addiction cycle as well as the manifestation of the impulsive phenotype. There is evidence that both serotonin (5-HT) neurotransmission through its cognate 5-HT2C receptor (5-HT2CR) and glutamate neurotransmission through the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR) play key roles in the cognitive and/or behavioral dimensions of impulsivity and addictive behaviors, especially in the mPFC, a region integral to decision-making and goal-directed behavior. Thus, the interaction between 5-HT and glutamate systems in the mPFC may contribute to the cognitive impairments seen in cocaine addiction. I will receive multifaceted training during the K99 mentored phase (Years 1-2;
Aims 1 -2) from a team of collaborating mentors that includes training in molecular techniques (e.g., protein crosslinking, creation of cell lines, bioresponsive assays) to analyze receptor subcellular localization and signal transduction regulation, as well as sophisticated behavioral neuroscience/pharmacology/molecular genetics techniques (e.g., immunohistochemistry, intracranial microinfusion, viral-mediated gene transfer). I will also receive mentoring in career development, grantsmanship, laboratory staff and student management and fiscal and planning responsibilities critical to running an independent laboratory. The research plan that is proposed during the R00 independent phase (Years 3-5;
Aims 3 -4) builds on this training to focus more specifically on the neurobiology of the mPFC NMDAR and the 5-HT2CR:NMDAR heteromeric complex as functional rheostats in expression of inherent impulsivity and cocaine-associated relapse events. The central hypothesis is that a balance of 5-HT2CR and NMDAR function drives mPFC output and that the loss of this balance contributes to inherent impulsivity, leading to vulnerability for the development of addictive disorders and associated relapse events. We will test this hypothesis and uncover neuromolecular drivers responsible for inherent impulsivity as well as the cocaine- evoked impulsivity in relation to cocaine-associated relapse events (e.g., cue reactivity). To address this hypothesis, four specific aims have been formulated:
Aim 1) establish the role for mPFC 5-HT2CR in inherent impulsivity;
Aim 2) establish the role for mPFC 5-HT2CR in aggregate impulsivity/cue reactivity;
Aim 3) elucidate the role for mPFC NMDAR in inherent impulsivity and aggregate impulsivity/cue reactivity;
Aim 4) explore the biology of the 5-HT2CR: NMDAR complex in vitro and ex vivo. We will determine that neuronal 5-HT2CR and NMDAR systems govern impulsivity and that rebalancing these systems may ultimately support behavioral recovery in disorders marked by impulsivity. Together, these innovative translational studies will be the first to systemically explore the contribution and interaction of 5-HT2CR- and NMDAR-mediated function in addiction- relevant phenotypes, ultimately allowing for the design of targeted pharmacotherapeutics to promote abstinence and prevent relapse in addictive disorders.
Impulsivity is a hallmark phenotype across a spectrum of chronic pathological maladies (e.g., drug addiction, attention deficit disorders, autism, and obesity/binge eating disorder). We propose that a balance of serotonin 5-HT2C receptor and glutamate N-methyl-D-aspartate receptor function in the medial prefrontal cortex exists and that the loss of this balance contributes to inherent impulsivity, leading to vulnerability for the development of addictive disorders and associated relapse events. A clear appreciation of the neuromolecular biology of impulsivity is necessary to significantly advance prevention and treatment of addictive disorders as well as related maladies linked to impulsivity.
|Neelakantan, Harshini; Holliday, Erica D; Fox, Robert G et al. (2017) Lorcaserin Suppresses Oxycodone Self-Administration and Relapse Vulnerability in Rats. ACS Chem Neurosci 8:1065-1073|
|Swinford-Jackson, S E; Anastasio, N C; Fox, R G et al. (2016) Incubation of cocaine cue reactivity associates with neuroadaptations in the cortical serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system. Neuroscience 324:50-61|
|Anastasio, Noelle C; Stutz, Sonja J; Fink, Latham H L et al. (2015) Serotonin (5-HT) 5-HT2A Receptor (5-HT2AR):5-HT2CR Imbalance in Medial Prefrontal Cortex Associates with Motor Impulsivity. ACS Chem Neurosci 6:1248-58|
|Fink, Latham H L; Anastasio, Noelle C; Fox, Robert G et al. (2015) Individual Differences in Impulsive Action Reflect Variation in the Cortical Serotonin 5-HT2A Receptor System. Neuropsychopharmacology 40:1957-68|
|Anastasio, N C; Liu, S; Maili, L et al. (2014) Variation within the serotonin (5-HT) 5-HT?C receptor system aligns with vulnerability to cocaine cue reactivity. Transl Psychiatry 4:e369|
|Anastasio, Noelle C; Stutz, Sonja J; Fox, Robert G et al. (2014) Functional status of the serotonin 5-HT2C receptor (5-HT2CR) drives interlocked phenotypes that precipitate relapse-like behaviors in cocaine dependence. Neuropsychopharmacology 39:370-82|
|Cunningham, Kathryn A; Anastasio, Noelle C (2014) Serotonin at the nexus of impulsivity and cue reactivity in cocaine addiction. Neuropharmacology 76 Pt B:460-78|
|Anastasio, Noelle C; Gilbertson, Scott R; Bubar, Marcy J et al. (2013) Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior. J Neurosci 33:1615-30|