Drug addiction is characterized by a compulsiveness to seek and take drugs. This compulsion is triggered by environmental cues that become conditioned with drug exposure. The regulation of drug seeking is imperative to the prevention of relapse. The simplest form of regulation is extinction, in which conditioned responding to a stimulus decreases when the reinforcer is omitted. Thus, in the case of addiction, drug seeking is reduced when conditioned cues are presented in the absence of the drug reward. Extinction learning reduces drug-seeking behavior through the formation of an inhibitory memory. It is generally accepted that extinction is new learning that, like other forms of learning, proceeds through acquisition, consolidation and retrieval phases. Studies performed previously by the applicant and others have demonstrated that the infralimbic region of the medial prefrontal cortex (IL-mPFC) plays a key role in the consolidation and retrieval of extinction using a fear conditioning paradigm. Consolidation of fear extinction requires NMDA-receptor activity in IL-mPFC, both during and after extinction. Whether IL-mPFC also regulates drug seeking behavior after extinction is only beginning to be deciphered. Recent work has implicated a role for IL-mPFC in extinction of drug seeking, but these studies focused on expression of extinction. Nothing is known about IL-mPFC plasticity or its role in extinction of drug seeking. The overall goal of this grant is to determine whether NMDA-receptor mediated plasticity in IL-mPFC is necessary for the consolidation of extinction of cocaine seeking.
In Aim 1, we will evaluate the contribution of IL-mPFC to consolidation of extinction of cocaine seeking, using pre-training and post-training infusions of a NMDA receptor antagonist during the first three days of extinction.
In Aim 2, we will evaluate the effect of extinction training on glutamatergic synaptic transmission in IL-mPFC pyramidal neurons. This will be done using whole cell patch-clamp recording in prefrontal slices of rats given extinction training, to measure the response of IL-mPFC neurons to stimulation by a nearby stimulating electrode. We will assess extinction-induced changes in AMPA-receptor- and NMDA-receptor- mediated responses (EPSCs) by comparing the responses of IL-mPFC neurons taken from rats that received either extinction training, no extinction, or were naive. Understanding the neural mechanisms of extinction could lead to new treatments to increase the effectiveness of extinction-based therapies for drug addiction.

Public Health Relevance

Perhaps more than any other field in learning and memory, extinction is directly applicable to the treatment of various clinical disorders, which arise when conditioned responses are pathologically over-expressed. This research will explore the glutamatergic mechanisms of consolidation of extinction learning as it pertains to drug seeking. Understanding the mechanisms by which the prefrontal cortex consolidates extinction of drug seeking could lead to the development of pharmacotherapies to increase the effectiveness of extinction-based therapies for treatment of addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Small Research Grants (R03)
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Special Emphasis Panel (ZDA1-GXM-A (04))
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Sorensen, Roger
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University of Wisconsin Milwaukee
Schools of Arts and Sciences
United States
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Hafenbreidel, Madalyn; Rafa Todd, Carolynn; Mueller, Devin (2017) Infralimbic GluN2A-Containing NMDA Receptors Modulate Reconsolidation of Cocaine Self-Administration Memory. Neuropsychopharmacology 42:1113-1125
Otis, James M; Fitzgerald, Michael K; Mueller, Devin (2014) Infralimbic BDNF/TrkB enhancement of GluN2B currents facilitates extinction of a cocaine-conditioned place preference. J Neurosci 34:6057-64
Otis, James M; Fitzgerald, Michael K; Mueller, Devin (2014) Inhibition of hippocampal ?-adrenergic receptors impairs retrieval but not reconsolidation of cocaine-associated memory and prevents subsequent reinstatement. Neuropsychopharmacology 39:303-10
Hafenbreidel, Madalyn; Rafa Todd, Carolynn; Twining, Robert C et al. (2014) Bidirectional effects of inhibiting or potentiating NMDA receptors on extinction after cocaine self-administration in rats. Psychopharmacology (Berl) 231:4585-94
Otis, James M; Dashew, Kidane B; Mueller, Devin (2013) Neurobiological dissociation of retrieval and reconsolidation of cocaine-associated memory. J Neurosci 33:1271-81a
Twining, Robert C; Tuscher, Jennifer J; Doncheck, Elizabeth M et al. (2013) 17?-estradiol is necessary for extinction of cocaine seeking in female rats. Learn Mem 20:300-6
Otis, James M; Mueller, Devin (2011) Inhibition of ?-adrenergic receptors induces a persistent deficit in retrieval of a cocaine-associated memory providing protection against reinstatement. Neuropsychopharmacology 36:1912-20