2010 |
Mueller, Devin |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Glutamate and Prefrontal Regulation of Cocaine Seeking After Extinction @ University of Wisconsin Milwaukee
DESCRIPTION (provided by applicant): 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.
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0.948 |
2014 — 2018 |
Mueller, Devin |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neural Mechanisms Underlying Estradiol-Enhanced Extinction of Cocaine Seeking @ University of Wisconsin Milwaukee
DESCRIPTION (provided by applicant): Women are more susceptible than men to developing compulsive patterns of psychostimulant use, but paradoxically, are more responsive to treatment. Natural fluctuations in levels of estrogens, such as 17?- estradiol (E2), may account for the increased abuse liability, but little is known about the role of E2 during treatment of addiction. Treatment is modeled by extinction learning, which results in the formation of a new inhibitory memory that suppresses drug seeking. E2 enhances learning in female rodents, and therefore, may facilitate extinction of cocaine seeking, as extinction requires new learning. However, virtually nothing is known about the effects of E2 on extinction of cocaine seeking in females. This oversight is a major gap in the drug abuse literature, chiefly because E2 has been implicated in the expression of drug seeking without regard to its potential therapeutic benefit. Our long-term goal is to understand how sex hormones impact treatment for addictive disorders. Our preliminary data show that systemic E2 administration in female rats enhances expression and extinction of cocaine seeking, and the absence of E2 results in a persistent extinction deficit (Twining et al., 2013). Thus, the objective of this proposal is to determine the neural mechanisms through which E2 facilitates extinction of cocaine seeking in female rats. To achieve this objective, we will use microinfusions of E2 to target brain regions known to be involved in extinction in males, including the infralimbic medial prefrontal cortex, dorsal hippocampus, and nucleus accumbens shell. Our central hypothesis is that E2 facilitates extinction in females by epigenetically altering the expression of neurotrophins, thereby regulating synaptic plasticity, in these brain regions. The rationale for the proposed research is that identifying the neural mechanisms through which E2 enhances extinction learning will result in new and innovative approaches to individualized treatment for women with addictive disorders. Guided by our strong preliminary data, our hypothesis will be tested in three specific aims designed to: 1) determine the neuroanatomical loci of E2-induced facilitation of extinction of cocaine seeking, 2) define the key neurotrophic mechanisms mediating E2-induced facilitation of extinction of cocaine seeking, and 3) determine synaptic and intrinsic mechanisms underlying E2-induced facilitation of extinction of cocaine seeking. This research is innovative because it represents a substantial paradigm shift from the conventional focus on acquisition and expression of drug seeking to an emphasis on extinction. The proposed research is significant because understanding the neural basis of E2-induced enhancement of extinction could lead to new treatments to increase the effectiveness of therapies for drug addiction in women. This contribution will enable subsequent development of treatments that maintain optimal levels of E2 to improve therapeutic outcomes in cocaine- addicted women. Reducing drug abuse among women will greatly improve the quality of life for millions of women and their families.
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