Ethanol has reinforcing properties in man that are thought to contribute to alcohol abuse and alcoholism. In rats ethanol is readily self-administered orally when taste factors are minimized by preexposing the rats to sweetened solutions. Non-dependent and non- fluid or non-food deprived rats will choose ethanol over water in limited access situations and will lever press to ingest sufficient quantities to produce meaningful blood ethanol levels. Work in the previous funding period was directed at examining the role of a limbic-nucleus accumbens-extrapyramidal circuit in ethanol reinforcement. Results show that while dopamine in the nucleus accumbens may modulate ethanol reinforcement, other systems such as GABA and glutamate may have important if not crucial roles. The purpose of the present proposal will be to extend these earlier results in non-dependent rats to other brain sites such as the amygdala and to other neurotransmitter systems. A further purpose will be to examine the neuropharmacological basis of ethanol reinforcement in dependent rats. Finally, possible sex differences in ethanol reinforcement and the neuropharmacological modulation of ethanol reinforcement will be explored. Non-food or non-fluid deprived male and female rats will be trained to self-administer ethanol in daily 30 minute sessions using a saccharin fade out procedure. The rats then will be implanted with bilateral cannulas aimed at specific brain sites implicated by previous work on ethanol reinforcement. Following establishment of stable ethanol self-administration, the rats will be microinjected with neurotransmitter antagonists and agonists prior to ethanol self-administration sessions. Dose effect functions will be generated using Latin square within subjects designs for dopamine, serotonin, opioid peptide, GABA and glutamate antagonists, and in some cases agonists. Experiments yielding significant results will be repeated in control experiments where rats are trained to self-administer saccharin (without ethanol). Following establishment of critical sites and neuropharmacological effects in non-dependent rats, similar experiments will be repeated in dependent animals and in female rats. The hypothesis under test is that chronic ethanol may result in adaptive changes in those brain mechanisms critical for ethanol reinforcement in the non-dependent animal and that this adaptation may be a crucial motivational part of the dependence process. Knowledge of the neurobiological basis of the motivational aspects of ethanol dependence will provide key information for the development of diagnosis, treatment, and prevention strategies for alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AA008459-05
Application #
2044543
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1990-04-01
Project End
1998-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Aoun, E G; Jimenez, V A; Vendruscolo, L F et al. (2018) A relationship between the aldosterone-mineralocorticoid receptor pathway and alcohol drinking: preliminary translational findings across rats, monkeys and humans. Mol Psychiatry 23:1466-1473
Cui, Changhai; Noronha, Antonio; Warren, Kenneth R et al. (2015) Brain pathways to recovery from alcohol dependence. Alcohol 49:435-52
Leão, Rodrigo M; Cruz, Fábio C; Vendruscolo, Leandro F et al. (2015) Chronic nicotine activates stress/reward-related brain regions and facilitates the transition to compulsive alcohol drinking. J Neurosci 35:6241-53
Koob, George F; Buck, Cara L; Cohen, Ami et al. (2014) Addiction as a stress surfeit disorder. Neuropharmacology 76 Pt B:370-82
Buck, Cara L; Malavar, Jordan C; George, Olivier et al. (2014) Anticipatory 50 kHz ultrasonic vocalizations are associated with escalated alcohol intake in dependent rats. Behav Brain Res 271:171-6
Logrip, Marian L; Vendruscolo, Leandro F; Schlosburg, Joel E et al. (2014) Phosphodiesterase 10A regulates alcohol and saccharin self-administration in rats. Neuropsychopharmacology 39:1722-31
Buck, Cara L; Vendruscolo, Leandro F; Koob, George F et al. (2014) Dopamine D1 and ?-opioid receptor antagonism blocks anticipatory 50 kHz ultrasonic vocalizations induced by palatable food cues in Wistar rats. Psychopharmacology (Berl) 231:929-37
Kallupi, Marsida; Vendruscolo, Leandro F; Carmichael, Casey Y et al. (2014) Neuropeptide YY(2)R blockade in the central amygdala reduces anxiety-like behavior but not alcohol drinking in alcohol-dependent rats. Addict Biol 19:755-7
Koob, George F (2013) Addiction is a Reward Deficit and Stress Surfeit Disorder. Front Psychiatry 4:72
Park, Paula E; Vendruscolo, Leandro F; Schlosburg, Joel E et al. (2013) Corticotropin-releasing factor (CRF) and ? 2 adrenergic receptors mediate heroin withdrawal-potentiated startle in rats. Int J Neuropsychopharmacol 16:1867-75

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