Welcome to Dr. McGinty's Laboratory
The goal of research in the McGinty Lab is to understand the neurobiology of, and develop therapies for, substance use disorders. Our research has demonstrated that brain-derived neurotrophic factor (BDNF) and the neuropeptide, oxytocin, suppress drug-seeking in preclinical models of stress and addiction.
Our current research is driven by three main questions.
- What mechanisms underlie cocaine-induced phospho-protein disturbances in the prefrontal cortex during early withdrawal that leads to drug-seeking?
- How does BDNF suppress drug-seeking when it is infused into the prefrontal cortex during early withdrawal from cocaine?
- How does stimulating the endogenous oxytocin receptor system attenuate methamphetamine-seeking in a preclinical model of traumatic stress?
We are members of MUSC’s NIH-funded Neurobiology of Addiction Research Center. Our research is also supported by individual RO1 and training grant awards from NIH.
We welcome you to explore this site to learn more about us.
Cocaine Self-Administration Causes Signaling Dysfunction in the Prefrontal Cortex that Triggers Relapse
In this project, we are investigating the mechanisms underlying a profound dysfunction of the prefrontal cortex at the end of cocaine self-administration that triggers cocaine-seeking. Repeated, daily self-administration of cocaine dephosphorylates (inactivates) many signaling proteins (ERK MAP kinase, CREB, NMDA receptor subunits) that mediate excitatory neurotransmission in the prefrontal cortex. These dephosphorylation events are preceded by a suppression of neuronal activity in prefrontal neurons recorded in vivo during cocaine self-administration.
Preventing the Signaling Dysfunction in the Prefrontal Cortex Decreases Relapse to Drug-Seeking
A single infusion of brain-derived neurotrophic factor (BDNF) into the prefrontal cortex re-phosphorylates proteins inactivated by cocaine and normalizes glutamate transmission in the nucleus accumbens. As a consequence, cocaine-seeking decreases for several weeks. However, BDNF is not a therapeutically useful medication because it is a neuropeptide that does not effectively cross the blood-brain barrier. Therefore, it is necessary to identify alternative targets for medication development. Accordingly, we have discovered that pharmacological inhibition of the striatal-enriched protein tyrosine phosphatase, STEP, prevents the dephosphorylation of key signaling proteins and decreases cocaine-seeking like BDNF does. Similarly, activation of an inhibitory Designer Receptor Exclusively Activated by a Designer Drug (DREADD) during early abstinence inhibits relapse to cocaine-seeking. Ongoing studies are probing the mechanisms underlying these promising discoveries.
These studies impact the field of drug abuse research by advancing our understanding of the key neurobiological substrates that mediate cocaine-induced neuroadaptations and relapse to drug-seeking with the potential of leading to novel preventive interventions during early abstinence.
Oxytocin Prevents Methamphetamine-seeking & Neuroadaptations Associated With Chronic Stress
Many individuals try drugs of abuse but only 16percent of the population becomes addicted. This is true even among individuals who have experienced stressful events, although prior stress increases vulnerability for substance use disorders. What makes some individuals resilient? We have discovered that the repeated, systemic administration of oxytocin (OXT) increases resilience by counteracting stress-induced reinstatement of methamphetamine (METH)–-seeking exacerbated by pre-exposure to a predator odor in a sex-dependent manner. OXT is an endogenous neurohormone that enhances positive social reward and protects against social anxiety. In preclinical and clinical experiments, local, intra-nasal, or systemic OXT administration decreases stress reactivity in response to visual fearful/threatening stimuli and ameliorates the response to a variety of stressful events. Further, preclinical studies have demonstrated OXT’s suppressive effects on drug-taking and seeking behavior. However, little attention has been focused on whether OXT plays a role in promoting resilience, thereby decreasing substance abuse vulnerability. When male and female rats are exposed to a stressful predator odor, TMT, before acquisition of METH self-administration, reinstatement of TMT-induced METH-seeking is exacerbated. Repeated OXT injections for 5 or 10 days after TMT and before METH self-administration selectively decreased METH-seeking in male rats that were pre-exposed to TMT. METH-seeking in female rats was decreased by OXT whether or not they were pre-exposed to TMT. Preliminary data in female rats indicate that OXT prevents a TMT-induced decrease in Oxt mRNA in the hypothalamus and an increase in Crh mRNA in the BNST of rats with a METH treatment history. These data suggest that enhanced OXT in the CNS promotes resilience that protects against stress-induced METH-seeking. We are investigating genes and proteins in key nodes of stress/reward circuitry that mediate OXT-induced resilience in response to TMT-induced exacerbation of METH-seeking in male and female rats. In addition, we are investigating the effects of selective DREADD activation of OXT neurons in the paraventricular hypothalamus on stress-exacerbated METH seeking. These aims provide an opportunity to explore CNS mediation of OXT-mediated resilience and establish a foundation for development of OXT as a novel therapeutic to treat stress-induced and -exacerbated substance use disorders.
Ferland CL, Reichel CM, McGinty JF (2016) Effects of oxytocin on methamphetamine-seeking exacerbated by predator odor pre-exposure in rats. Psychopharmacology 233(6):1015-24.
Go BS, Barry SM, McGinty JF (2016) Glutamatergic neurotransmission in the prefrontal cortex mediates the suppressive effect of intra-prelimbic cortical infusion of BDNF on cocaine-seeking. Eur Neuropsychopharmacology 26:1989-1999.
Siemsen BM, Lombroso PJ, McGinty JF (2017) Intra-prelimbic cortical inhibition of striatal-enriched tyrosine phosphatase suppresses cocaine-seeking in rats. Addiction Biol DOI:10.1111/adb.12504.
King C, Griffin WC, Luderman L, Kates M, McGinty JF, Becker HC (2017) Oxytocin reduces ethanol self-administration in mice. Alcoholism: Clinical and Experimental Research DOI:10.1111/acer.13359.
Sun WL, Zelek-Molik A, McGinty JF. Short and long access to cocaine self-administration attenuates the tyrosine phosphatase STEP and GluN2B phosphorylation but differentially regulates AMPA subunit expression in the prefrontal cortex. Psychopharmacol. 229:603-613, 2013.
Sun WL, Coleman NT, Zelek-Molik A, Barry SM, Whitfield, Jr., TW, McGinty JF. Relapse to cocaine-seeking after abstinence Is regulated by cAMP-dependent protein kinase A in the prefrontal cortex. Addiction Biology 19:77-86, 2014.
Sun WL, Eisenstein EA, Zelek-Molik A, McGinty JF. A single BDNF infusion into the dorsomedial prefrontal cortex attenuates cocaine self-administration-induced phosphorylation of synapsin in the nucleus accumbens during early withdrawal. Intl J Neuropsychopharmacology 2014 Dec 5 doi: 10.1093/ijnp/pyu049.
Zhou L, Sun WL, Young AB, Lee K, McGinty JF. Oxytocin reduces cocaine seeking and reverses chronic cocaine-induced changes in glutamate receptor function. Intl J Neuropsychopharmacology 2014 Oct 31 18(1). doi: 10.1093/ijnp/pyu009
Jacqueline F. McGinty, Ph.D.
Ph.D. in Neuroanatomy
Downstate Medical Center SUNY
Torry Dennis, Ph.D.
Ph.D. in Psychology: Health & Neuroscience
University of Texas at Arlington
Casey O'Neill, Ph.D.
University of Colorado
B.S in Neuroscience
Furman University, Greenville, SC
BA in Psychology
Nebraska Wesleyan University, Lincoln, NE
MS, the Citadel
Howard Becker, Ph.D.
William Griffin III, Ph.D.
Sudie Back, Ph.D.