One of the defining characteristics of drug addiction is compulsive drug seeking when it is ineffective or detrimental for the individual to do so. Animal models investigating the neural basis of drug seeking have, until recently, focused little attention on characterizing addiction-related endophenotypes that differentially manifest across individuals. The development of treatments for addiction is dependent on understanding what changes occur in the brains of addicted vs. non-addicted individuals. The goal of the proposed project is to investigate the neural basis of individual differences in compulsive drug seeking. Along with cocaine self-administration, we will employ recently-described behavioral models that use clusters of addiction-related endophenotypes to identify individuals as addict-like or non-addict. In these models, such rats are reliably identified based on how strongly they persist in seeking cocaine under different types of conflict introduced in a battery of tests. The tests and the endophenotypes measured include: progressive ratio (willingness to expend effort), seeking in the presence of a paired aversive stimulus (resistance to negative outcomes), and seeking during a non-drug period (persistence despite known absence of drug). We will focus on differential neuronal adaptations in the prefrontal cortex (PFC). The PFC is consistently implicated in both driving and inhibiting drug seeking in humans and animals, and dysregulation of PFC function is thought to be a major factor in the development of addiction. It is not clear, however, how different regions of this heterogeneous structure (e.g., cingulate, prelimbic, infralimbic, and orbitofrontal cortices in the rat) interact to regulate drug seeking in addicted individuals. To address this issue, we will record the activity of multiple single neurons in each of these four PFC regions simultaneously in rats during both self-administration and performance of the addiction-characterizing tests described above. Rats will be tested and recorded during an early (~2 weeks) and late (~7 weeks) session in order to monitor PFC neural activity related to the onset of addiction endophenotypes. We hypothesize that PFC areas more directly involved in driving drug-seeking behavior (prelimbic and orbitofrontal) will have amplified seeking-related activity in addict-like individuals that strengthens over time. We also hypothesize that PFC regions more involved in inhibiting drug seeking behavior (infralimbic and cingulate) will display a gradual weakening of activity over time in addict-like rats. The dual nature of this plasticity: the strengthening of seeking-related circuits and weakening of inhibition-related circuits is proposed to be a key component of the compulsive drive to obtain drugs in addicts. These studies constitute a novel way to investigate the neural plasticity related to addiction and will produce valuable data addressing potential targets for addiction-specific treatments. .

Public Health Relevance

Addiction to cocaine and other drugs of abuse is a serious public health concern. Addiction develops through changes in the neural circuitry that controls motivation and decision-making, ultimately leading to compulsive drug seeking irrespective of the consequences. The proposed experiments will investigate what changes occur in the prefrontal cortex over the development of addiction with the goal of identifying targets for treatment of this disease.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory/Developmental Grants (R21)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Volman, Susan
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Medical University of South Carolina
Schools of Medicine
United States
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Moorman, David E; James, Morgan H; Kilroy, Elisabeth A et al. (2017) Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats. Brain Res 1654:34-42
Lopez, Marcelo F; Moorman, David E; Aston-Jones, Gary et al. (2016) The highly selective orexin/hypocretin 1 receptor antagonist GSK1059865 potently reduces ethanol drinking in ethanol dependent mice. Brain Res 1636:74-80
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Moorman, David E; James, Morgan H; Kilroy, Elisabeth A et al. (2016) Orexin/hypocretin neuron activation is correlated with alcohol seeking and preference in a topographically specific manner. Eur J Neurosci 43:710-20
Moorman, David E; Aston-Jones, Gary (2015) Prefrontal neurons encode context-based response execution and inhibition in reward seeking and extinction. Proc Natl Acad Sci U S A 112:9472-7
Orsini, Caitlin A; Moorman, David E; Young, Jared W et al. (2015) Neural mechanisms regulating different forms of risk-related decision-making: Insights from animal models. Neurosci Biobehav Rev 58:147-67
Moorman, David E; James, Morgan H; McGlinchey, Ellen M et al. (2015) Differential roles of medial prefrontal subregions in the regulation of drug seeking. Brain Res 1628:130-46
Mahler, Stephen V; Moorman, David E; Smith, Rachel J et al. (2014) Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nat Neurosci 17:1298-303
Moorman, David E; Aston-Jones, Gary (2014) Orbitofrontal cortical neurons encode expectation-driven initiation of reward-seeking. J Neurosci 34:10234-46
Shahbaba, Babak; Zhou, Bo; Lan, Shiwei et al. (2014) A semiparametric Bayesian model for detecting synchrony among multiple neurons. Neural Comput 26:2025-51

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