Accumulating evidence points to an intersection between binge drinking behavior, smoking, and the ongoing development of the medial prefrontal cortex, during adolescence. The concurrence of these events may have lasting detrimental effects on neurotransmission, drug use, and reckless and impulsive behaviors in adulthood. Glutamate is an amino acid neurotransmitter known to influence neuronal activity in mesolimbic and cortical areas and has been implicated in both ethanol and nicotine abuse. The prefrontal cortex both receives glutamate inputs and has glutamatergic projections to key sites involved in ethanol and nicotine self- administration. The current approach will test the hypothesis that concommittant voluntary ethanol and nicotine intake during peri-adolescence leads to profound effects on both ethanol and nicotine self-administration behavior, and mesocorticolimbic glutamate neurotransmission, in adulthood. The selectively bred alcohol- preferring (P) rat will be used in this part of the project because individual and concurrent voluntary intake of ethanol and nicotine has been demonstrated in this line. Control groups drinking ethanol, nicotine, or water alone will also be used to assess the impact of concurrent intake as compared to intake of each drug alone. Importantly, both male and female rats will be tested to identify sex differences in outcomes for all experiments in this application, and rats with initial ethanol and nicotine exposure as adults will be also be studied to identify changes specific to peri-adolescent initiation of drug taking. To assess the long-term consequences of concurrent ethanol and nicotine exposure during peri-adolescence, ethanol and nicotine self-administration (including measures of craving and relapse) will be examined after voluntary ethanol and nicotine intake in peri-adolescence. Concurrently, microdialysis-HPLC procedures will also be conducted in adult animals to measure how peri-adolescent ethanol and nicotine intake affects extracellular levels of glutamate in critical mesocorticolimbic brain circuits which have been implicated in alcohol and drug abuse. Together, these studies represent a novel approach to examine the impact of the co-use of ethanol and nicotine in the peri- adolescent period on neurobiology and the susceptibility to ethanol and nicotine in adulthood. It is anticipated that this application will provide important information for the development of early (adolescent) and late (adult) treatment and/or prevention strategies targeting the critical public health problems of alcoholism and nicotine addiction.

Public Health Relevance

The long-range goals of this project are to better understand the behavioral and neurobiological consequences that occur when adolescents co-abuse ethanol and nicotine. The knowledge gained from this project is expected to lead to interventions and treatment strategies to prevent or reduce the maladaptive effects of combined drinking and smoking during adolescence and into adulthood.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Grakalic, Ivana
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Bell, Richard L; Hauser, Sheketha R; Liang, Tiebing et al. (2017) Rat animal models for screening medications to treat alcohol use disorders. Neuropharmacology 122:201-243
Chambers, R Andrew; Wallingford, Sue C (2017) On Mourning and Recovery: Integrating Stages of Grief and Change Toward a Neuroscience-Based Model of Attachment Adaptation in Addiction Treatment. Psychodyn Psychiatry 45:451-473
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Bell, R L; Hauser, S; Rodd, Z A et al. (2016) A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction. Int Rev Neurobiol 126:179-261
Rahman, Shafiqur; Engleman, Eric A; Bell, Richard L (2016) Recent Advances in Nicotinic Receptor Signaling in Alcohol Abuse and Alcoholism. Prog Mol Biol Transl Sci 137:183-201
Katner, Simon N; Toalston, Jamie E; Smoker, Michael P et al. (2015) Time-course of extracellular nicotine and cotinine levels in rat brain following administration of nicotine: effects of route and ethanol coadministration. Psychopharmacology (Berl) 232:551-60
Toalston, Jamie E; Deehan Jr, Gerald A; Hauser, Sheketha R et al. (2015) The reinforcing properties of ethanol are quantitatively enhanced in adulthood by peri-adolescent ethanol, but not saccharin, consumption in female alcohol-preferring (P) rats. Alcohol 49:513-8
Greene, Marion S; Chambers, R Andrew (2015) Pseudoaddiction: Fact or Fiction? An Investigation of the Medical Literature. Curr Addict Rep 2:310-317

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