There appears to be an inverse relationship between synaptic serotonergic throughput and alcohol consumption. A key piece of evidence for this is the effects of specific serotonin reuptake inhibitors (SSRIs) on ethanol consumption. However, because the mechanism(s) of these effects of SSRIs on ethanol consumption remains unknown, interpretation of these data remains ambiguous. Recently, we observed that the SSRI fluvoxamine reduces responding for ethanol at lower doses than those required to reduce responding for either food or sucrose solutions in rats. In this application, we propose to study the mechanism of these selective effects of fluvoxamine through three specific aims: I) extending our findings on fluvoxamine's selective effects; II) investigating the neurobiologic mechanisms of these selective effects; and III) investigating the behavioral mechanisms of the selective effects. We extend our findings by A) using a within-subject experimental design; B) showing clinically relevant ethanol consumption and C) determining if fluvoxamine and ethanol interact pharmacokinetically.
Aim I systematically replicates our earlier findings and extends these findings by examining three explanations of our results: i) that the potency of fluvoxamine increases with chronic exposure to ethanol; ii) self-administered ethanol has direct pharmacological effects that act synergistically with fluvoxamine to decrease response-rates; and iii) fluvoxamine and ethanol interact pharmacokinetically. We examine the neurobiologic mechanisms of fluvoxamine's selective effects by A) examining if other antidepressants have selective effects; B) examining whether these selective effects, previously observed in Lewis rats, are also observed in Fischer and Sprague Dawley rats; and C) examining if repeated fluvoxamine has selective effects. These experiments narrow the field of potential neurobiologic mechanisms. We investigate possible behavioral mechanisms of fluvoxamine's selective effects by examining A) whether fluvoxamine has effects consistent with the hypothesis that fluvoxamine produces its selective effects by attenuating ethanol reinforcement, and B) whether fluvoxamine has effects consistent with other alternative hypotheses for these selective effects. Only by conducting experiments such as these can we delineate what the behavioral actions of fluvoxamine are that result in selective decreases in ethanol-seeking behavior and thus, what these selective decreases mean with regards to 1) the role of serotonin in the control of alcohol consumption and alcoholism, and 2) the treatment of alcoholism with SSRIs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012337-05
Application #
6916221
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Egli, Mark
Project Start
2001-09-24
Project End
2007-05-09
Budget Start
2005-07-01
Budget End
2007-05-09
Support Year
5
Fiscal Year
2005
Total Cost
$216,750
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Psychiatry
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Ginsburg, Brett C; Levy, Simon A; Lamb, R J (2018) Nicotine as a discriminative stimulus for ethanol use. Drug Alcohol Depend 182:98-102
Lamb, R J; Ginsburg, Brett C (2018) Addiction as a BAD, a Behavioral Allocation Disorder. Pharmacol Biochem Behav 164:62-70
Lamb, Richard J; Ginsburg, Brett C; Schindler, Charles W (2017) Conditioned Stimulus Form Does Not Explain Failures to See Pavlovian-Instrumental-Transfer With Ethanol-Paired Conditioned Stimuli. Alcohol Clin Exp Res 41:1063-1071
Lamb, R J; Schindler, Charles W; Pinkston, Jonathan W (2016) Conditioned stimuli's role in relapse: preclinical research on Pavlovian-Instrumental-Transfer. Psychopharmacology (Berl) 233:1933-44
Lamb, R J; Ginsburg, Brett C; Schindler, Charles W (2016) Effects of an ethanol-paired CS on responding for ethanol and food: Comparisons with a stimulus in a Truly-Random-Control group and to a food-paired CS on responding for food. Alcohol 57:15-27
Lamb, R J; Maguire, David R; Ginsburg, Brett C et al. (2016) Determinants of choice, and vulnerability and recovery in addiction. Behav Processes 127:35-42
Lamb, Richard J; Pinkston, Jonathan W; Ginsburg, Brett C (2015) Ethanol self-administration in mice under a second-order schedule. Alcohol 49:561-70
Lamb, Richard J; Pinkston, Jonathan W; Daws, Lynette C (2014) Ethanol effects on multiple fixed-interval, fixed-ratio responding in mice with deletions of the serotonin transporter gene. Behav Pharmacol 25:92-5
Ginsburg, Brett C; Lamb, Richard J (2014) Relative potency of varenicline or fluvoxamine to reduce responding for ethanol versus food depends on the presence or absence of concurrently earned food. Alcohol Clin Exp Res 38:860-70
Ginsburg, B C; Lamb, R J (2014) Drug effects on multiple and concurrent schedules of ethanol- and food-maintained behaviour: context-dependent selectivity. Br J Pharmacol 171:3499-510

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