This application proposes a core integral to the INIA-West Consortium tasked to identify target medications to treat alcoholism. Agents will be identified based on information obtained from projects within INIA-West. The agents will be examined to determine if they alter behaviors reflective of the various aspects of alcoholism including binge-intoxication, negative affect, and preoccupation-anticipation in a systematic manner using established behavioral methods with rats. Tests are conducted in an orderly manner with clearly defined decision points for continuation or cessation of studies with an agent. An agent's ability to alter behaviors indicative of binge-intoxication is examined using maintenance of operant self-administration of alcohol under progressive ratio schedules and promising results followed by place conditioning and 2-bottle preference procedures. Alleviation of negative affect is assessed by measuring withdrawal signs and anxiety- and depressive-like behaviors with elevated plus maze and forced swim tests. Preoccupation-anticipation (""""""""craving"""""""") is assessed with drug/cue-induced reinstatement of extinguished operant responding, conditioned approach, and sign-tracking. This set of """"""""craving"""""""" studies is a focal point of the grant given the importance of relapse prevention in alcoholism treatment and a reason rats are used as these procedures are more difficult to establish with mice. Further, because excessive alcohol can cause cognitive deficits that would likely interfere with psychological treatments (which are often combined with pharmacological treatments), we will also assess whether target agents alter cognitive function using standard learning and memory tasks (e.g., fear conditioning, object recognition, delayed alternation). Studies will be conducted in rats that have been chronically exposed to alcohol vapors. This project interacts closely with the Roberts and Bell projects to confirm or extend findings allowing greater confidence in results obtained. Finally, in collaboration with other projects and cores and using molecular genetic and neuropharmacological approaches, we will confirm the neurobiological effects of the target agents to alter chronic alcohol effects.

Public Health Relevance

The goal of this research program is to establish a behavioral testing core for the INIA-West Consortium aimed at testing potential pharmacotherapeutic agents for alcoholism. The main focus of this core is to conduct tests reflective of """"""""craving"""""""" although other aspects of alcoholism (intoxication, negative affect) will be addressed and results compared to those of the Bell and Roberts cores.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAA1-DD (50))
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Egli, Mark
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Baylor College of Medicine
Schools of Medicine
United States
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Nieto, Steven J; Quave, Cana B; Kosten, Therese A (2018) Naltrexone alters alcohol self-administration behaviors and hypothalamic-pituitary-adrenal axis activity in a sex-dependent manner in rats. Pharmacol Biochem Behav 167:50-59
Nieto, Steven J; Kosten, Therese A (2017) Female Sprague-Dawley rats display greater appetitive and consummatory responses to alcohol. Behav Brain Res 327:155-161
Haile, Colin N; Kosten, Therese A (2017) The peroxisome proliferator-activated receptor alpha agonist fenofibrate attenuates alcohol self-administration in rats. Neuropharmacology 116:364-370
Ohia-Nwoko, O; Kosten, T A; Haile, C N (2016) Animal Models and the Development of Vaccines to Treat Substance Use Disorders. Int Rev Neurobiol 126:263-91
Nieto, Steven J; Patriquin, Michelle A; Nielsen, David A et al. (2016) Don't worry; be informed about the epigenetics of anxiety. Pharmacol Biochem Behav 146-147:60-72
Gomez, Juan L; Cunningham, Christopher L; Finn, Deborah A et al. (2015) Differential effects of ghrelin antagonists on alcohol drinking and reinforcement in mouse and rat models of alcohol dependence. Neuropharmacology 97:182-93
Kosten, Therese A; Meisch, Richard A (2013) Predicting extinction and reinstatement of alcohol and sucrose self-administration in outbred rats. Exp Clin Psychopharmacol 21:245-51
Reilly, Matthew T; Faulkner, Geoffrey J; Dubnau, Joshua et al. (2013) The role of transposable elements in health and diseases of the central nervous system. J Neurosci 33:17577-86
Ponomarev, Igor; Wang, Shi; Zhang, Lingling et al. (2012) Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence. J Neurosci 32:1884-97
Kosten, Therese A (2011) Pharmacologically targeting the P2rx4 gene on maintenance and reinstatement of alcohol self-administration in rats. Pharmacol Biochem Behav 98:533-8

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