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Research

Animal Core

The animal core trains rats to self-administer cocaine or heroin, making them available to the various primary and pilot projects to evaluate addiction-related changes in brain biochemistry and physiology, as well as to behaviorally evaluate new drugs as pharmacotherapy for treating addiction. In addition, the animal core is conducting studies to extend and evaluate advances in animal models of addiction. For example, we are investigating the value of short versus long access of the rats to drug. Recent studies point to the possibility that giving rats longer access to drug each day more accurately mimics human addiction. We are examining changes in brain biochemistry and physiology after long access to help determine if this is true

Project 1: Addictive Drugs Change Glutamate Transmission in the Nucleus Accumbens Making Drug Cues Intrusive & Hard to Control

Principle Investigator: Peter Kalivas, Ph.D.

The inability of addicts to prevent drug cues and contexts from leading to relapse to drug use is a primary behavioral pathology that characterizes addiction. Thus, akin to many other neuropsychiatric disorders where a primary endophenotype of the disease is rumination and intrusive thinking, the uncontrollable desire to obtain drug is intrusive and controls behavior. As our work has progressed over the last decade to uncover the neurobiology of why drug-associated cues and contexts are intrusive and drive behavior in a manner that is difficult to control, we have focused on changes in how the prefrontal cortex communicates with the nucleus accumbens. We use the animal model of cue-induced relapse provided by the NARC Animal Core, and rely in part on a simple principle that while each addictive drug has its own molecular targets, changes produced in the brain that are shared between drugs are most likely to represent the neurobiology of addiction and relapse. Accordingly, we use animal models of cocaine, heroin, nicotine and, most recently, marijuana (THC plus CBD) self-administration and withdrawal. Using this model, and cutting edge neurobiological approaches, we have discovered a ‘microcircuit’ within the core subcompartment of the accumbens (NAcore) that is outlined in the figure below. While drug-associated cues activate this circuit that reduces the capacity of an animal to regulate cue-induced lever pressing, similar activation does not occur when an animal presses for sucrose. Each of the steps in the microcircuit has been characterized in our recent publications or in our recently submitted manuscripts as indicated below.

For the immediate future, we are asking the question: Does the nucleus accumbens microcircuit also control adaptive intrusive thinking? For example, when a person is running from danger, they will not likely notice that they have stepped on a nail and keep running, only to notice the injury once they reach safety. This type of focus on a single goal is akin to the intrusive craving that an addict experiences in the process of relapsing to drug use. As a first step, we are trying to decrease an animals control over sucrose seeking by potentiating the microcircuit in the figure below. This involves using genetically altered mice and viral introduction of transgenes to selectively manipulate individual steps in the microcircuit shown in the figure.

Figure 1. When a drug cue is recognized, synaptic activity is initiated from the prefrontal cortex (PFC) into the nucleus accumbens (1). Because glial glutamate transport is down-regulated by most addictive drugs, synaptic glutamate spills into the nonsynaptic extracellular space (2), which stimulates mGluR5 receptors on nNOS-expressing interneurons (3). mGluR5 activation stimulates release of internal calcium that activates nNOS to produce nitric oxide NO. NO freely diffuses into the extracellular space where it activates matrix metalloproteases (MMP) (2). MMP activation catalytically signals through the extracellular matrix via integrins to induce transient synaptic potentiation (t-SP) in the accumbens medium spiny neurons (4). Our current thinking is that the induction of t-SP causes compulsive drug-seeking behavior. Below are key papers describing this model.

Project 1 Figure detailing drug cue microcircuit

Image Key:

  1. Kalivas, PW. 2009. The glutamate homeostasis hypothesis of addiction. Nature Rev Neuroscience, 10: 561-572. PMID: 19571793
  2. Smith ACW, YM Kupchik, MD Scofield, CD Gipson and PW Kalivas. 2014. Synaptic plasticity mediating cocaine relapse requires matrix metalloproteinases. Nature Neuroscience, 17: 1655-1657, 2014. PMC4241163
  3. Manuscript submitted for publication
  4. Gipson CD, YM Kupchik, H Shen, KJ Reissner, CA Thomas and PW Kalivas. 2013. Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron, 77: 867-872. PMC3619421

Project 2: BDNF Prevents Cocaine Abstinence-Induced Neuroadaptations

Principle Investigator: Jacqueline McGinty, Ph.D.

In this project, we are investigating the neurobiological mechanisms underlying the ability of BDNF/TrkB stimulation in the prelimbic cortex (PLC) during early withdrawal from cocaine self-administration to suppress persistent cocaine-seeking and the underlying neuroadaptations. We have demonstrated that BDNF infusion into the PLC of rats immediately after the last cocaine self-administration session suppresses conditioned cue-induced or drug-primed cocaine-seeking after forced abstinence or extinction. Such a single intra-PLC BDNF infusion during early withdrawal normalized basal, and prevented a cocaine prime-induced increase in, extracellular glutamate levels in the NAc three weeks later. Further, local inhibition of the ERK MAP kinase cascade blocked the ability of intra-PLC BDNF to suppress cocaine-seeking. The latter study also demonstrated that BDNF infusion immediately after the last cocaine SA exposure reversed a marked cocaine-induced dephosphorylation of ERK and CREB in the PLC 2 hr later. In contrast, after 7 days of forced abstinence, phospho-ERK is normal but phospho-CREB and phospho-Ser845-GluR1 in the PLC are elevated in a PKA-dependent manner. Thus, BDNF-induced reversal of cocaine-induced ERK dephosphorylation (or ERK “shutoff”) in the PLC during early withdrawal appears to be a critical step in restoring homeostatic regulation of the PFC-accumbens pathway that leads to lasting suppression of cocaine-seeking. Recent data implicate a reduction in GluN2B receptors and increased activation of the striatal-enriched tyrosine phosphatase (STEP) in cocaine self-administration-induced ERK dephosphorylation in the PLC during early withdrawal. The role of synaptic activity and kinase-phosphatase balance in the ability of intra-PFC BDNF to normalize ERK phosphorylation in PLC during early withdrawal and suppress cocaine-seeking in rats with a cocaine SA history is under investigation.

Project 3: Selective Cortical Networks in Cocaine Seeking

Principle Investigator: Gary Aston-Jones, Ph.D.

Relapse is a persistent problem in cocaine addiction, and many important aspects of the brain mechanisms involved remain unknown. One key area for cocaine relapse is the medial prefrontal cortex (mPFC); in particular, mPFC interactions with the nucleus accumbens (NA) and ventral tegmental area (VTA) are critical for reinstatement of extinguished cocaine seeking. Projects 1 and 2 in this center focus on molecular and cellular mechanisms involved in the mPFC-to-NA pathway during extinction and reinstatement. Little is known about the activities of neurons in mPFC that project to NA, or that receive dopamine (DA) from VTA, during these cocaine behaviors. Here, we will use Fos labeling and unit recording during extinction and reinstatement to measure impulse activity of mPFC neurons identified as projecting to NA core or shell. We also will capitalize on TH::Cre rats and optogenetics methods recently implemented in our lab to determine the influence of endogenous DA release on impulse activity of prelimbic cortex neurons that project to NA core during extinction and reinstatement. Together, these studies will provide an overall map of NA-projecting mPFC neurons that are activated during cocaine behaviors, and also measure their impulse activities with respect to specific task stimuli and behaviors during exinction or reinstatement of cocaine seeking. These findings will provide a detailed circuit analysis of behavior-related activities in these key mPFC neurons that will be important information to extend results of molecular- and cellular-level studies in other projects of this center.

Shared Resources

The Aston-Jones lab received Th-Cre progenitor female rats from Karl Deisseroth in 2011, and has established a robust breeding colony that produces TH-Cre offspring. These TH-Cre rats are now being used by NARC personnel and others at MUSC to study selectively the role of catecholamine brain systems in addiction and other behaviors. DREADD designer receptor expression (red) in ventral VTA of a TH-Cre rat. Mahler unpublished.

Fos-activated afferents to VTA following cue-ionduced reinstatement of cocaine seeking. Mahler SV, Aston-Jones GS (2012) Fos Activation of Selective Afferents to Ventral Tegmental Area during Cue-Induced Reinstatement of Cocaine Seeking in Rats. Journal of Neuroscience 32:13309–13325.

Project 4: Preclinical Evaluation of Anti-Relapse Medications

Principle Investigator: Ronald E. See, Ph.D.

In this project, we take intervention strategies identified through the NARC aimed at reducing relapse to cocaine seeking. Our project uses standardized procedures through the NARC Animal Core of self-administration, withdrawal, and reinstatement to assess acute and chronic pharmacotherapy treatments that inhibit cocaine seeking. This data is then used in other NARC projects to assess the validity of cocaine-induced neuroplasticity for drug target development and as a transition to future clinical assessment of promising pharmacotherapies. We have primarily focused on selected strategies of drug intervention by targeting dopaminergic activity via a partial DA receptor agonist, enhancement of glutamate homeostasis, antagonism of the orexin-1 receptor, and the novel attention-enhancing agent, modafinil. Since our focus is to assess compounds that can be readily applied in a clinical environment, we have generally concentrated on systemically available, approved drugs for use in humans. However, we also take identified compounds from the NARC projects for systematic examination of their anti-relapse potential.

Pilot Project Proposals

A Pilot Project Core is part of the National Institutes of Health (NIH)-funded Neurobiology of Addiction Research Center (NARC). The NARC Pilot Core will oversee the execution and development of basic science, translational and clinical pilot projects that will bring new technologies and new investigators into the field of addiction research. The goals of the Pilot Core are to provide a mechanism primarily to attract young faculty, and secondarily to recruit senior investigators, into the field of addiction and to identify novel technologies that will augment ongoing NARC investigations of the long-term neuroadaptations produced by cocaine self-administration.

The NARC has funds available annually to fund pilot projects related to addiction issues. The project may be either a clinical or basic science study. The purpose of the pilot funding provided by the NARC is to provide an opportunity to collect preliminary data that will ultimately support an R01 application.

Projects will be funded for one year with an opportunity for a one-year competitive renewal.

Pilot Project Submission Guidelines

  • Submit a 3 to 5 page description of your project using the following format:
    • Abstract
    • Specific Aims/ Significance of Problem
    • Preliminary Data
    • Experimental Design and Methods
  • Submit biosketches for each investigator
  • Submit a budget (up to $25,000 preclinical; $50K clinical) and a brief budget justification (no travel or computers; up to 5 percent salary plus benefits per investigator/technical staff member).

Submit proposals by email and address inquiries to Jacqueline McGinty, Ph.D., Program Coordinator, Neurobiology of Addiction Research Center.

Funding for the Neurobiology of Addiction Research Center is provided by NIDA 1 P50 DA015369 in partnership with MUSC.