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Updated: Oct 11, 2026
A Method for Evaluating the Reinforcing Properties of Ethanol in Rats without Water Deprivation, Saccharin Fading or Extended Access Training
Published on: January 29, 2017
Effects of MDL 72222, a serotonin3 antagonist, on operant responding for ethanol by alcohol-preferring P rats
D L McKinzie1, W J McBride, J M Murphy
1Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis 46202-4887, USA.
Background:
Previous studies indicated that, under continuous access conditions, the 5-HT3 antagonist MDL 72222 (MDL) effectively reduced ethanol drinking of alcohol-preferring P rats. However, MDL was without effect when similar doses were tested under scheduled access conditions, unless the ethanol access period was randomly presented. This study examined the effects of MDL on operant responding for ethanol and water by adult male alcohol-preferring P rats.
Methods:
During the dark cycle, subjects in the first experiment were trained to respond concurrently for 15% ethanol and water on a fixed-ratio 5 (FR-5) and FR-1 schedule of reinforcement, respectively. Approximately 30 min before the 4-hr operant session, rats were injected subcutaneously (sc) with saline or MDL (1, 3, or 5 mg/kg). A second experiment tested the effects of 1 mg/kg MDL on operant responding for 15% ethanol in 1-hr sessions when operant access was given at a fixed time each day (fixed scheduled access, FSA group) or at variable time periods throughout the dark cycle (variable scheduled access, VSA group).
Results:
In the first experiment, only the 5 mg/kg dose of MDL decreased responding for ethanol (approximately 20%) during the first 30 min of the 4-hr session. This dose also reduced total 4-hr responding for ethanol and water. In the second experiment, the 1 mg/kg dose of MDL had no effect on operant responding by the FSA group, but significantly reduced ethanol responding by the VSA group.
Conclusions:
These results suggest that 5-HT3 receptors may be involved in mediating the reinforcing effects of ethanol, and that temporal-environmental cues associated with the presentation of ethanol may be one factor involved in reducing the effectiveness of 5-HT3 antagonists to attenuate ethanol intake.
Insights
The 5-HT3 antagonist MDL 72222 (MDL) reduced ethanol intake in rats only when access was unpredictable. Temporal cues influence how this drug affects alcohol consumption, suggesting a role for 5-HT3 receptors in ethanol reinforcement.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Previous research showed the 5-HT3 antagonist MDL 72222 (MDL) reduced ethanol intake in P rats under continuous access.
- MDL was ineffective under scheduled access unless ethanol presentation was randomized.
Purpose of the Study:
- To investigate the effects of MDL on operant responding for ethanol and water in alcohol-preferring P rats.
- To explore the role of temporal-environmental cues in modulating the efficacy of 5-HT3 antagonists on ethanol intake.
Main Methods:
- Rats were trained on concurrent fixed-ratio schedules for ethanol and water.
- MDL (1, 3, or 5 mg/kg) was administered subcutaneously before operant sessions.
- A second experiment compared MDL's effects under fixed versus variable scheduled access conditions.
Main Results:
- The 5 mg/kg dose of MDL decreased ethanol responding during the initial 30 minutes of a 4-hour session and reduced overall intake.
- In a separate experiment, 1 mg/kg MDL did not affect responding under fixed scheduled access but significantly reduced ethanol intake under variable scheduled access.
Conclusions:
- 5-HT3 receptors appear to mediate ethanol's reinforcing effects.
- Temporal-environmental cues associated with ethanol availability can influence the effectiveness of 5-HT3 antagonists in reducing ethanol intake.
