Effects of fenfluramine, 8-OH-DPAT, and tryptophan-enriched diet on the high-ethanol intake by rats bred for susceptibility to stress

Abstract

The swim-test susceptible (SUS) line of rats has been bred in our laboratory for the characteristic of reduced motor activity in the swim test following exposure to an acute stressor. Testing of multiple generations of SUS rats has also revealed that they consume large amounts of ethanol voluntarily. As reported for lines of rats that show a propensity for high-ethanol intake, the SUS rats show evidence of low serotonergic function. Because serotonergic function has often been shown to be involved in the regulation of alcohol consumption, here we examined the effects of manipulations of serotonin transmission on intake of ethanol by SUS rats. Fenfluramine, a serotonin-releasing drug, was injected at various doses (0.625, 1.25, 2.5, and 5.0 mg/kg) twice per day and ethanol intake was measured using a two-bottle free-choice method. The 8-OH-DPAT, a 5‑HT 1A agonist, was injected at various doses (0.03125, 0.0625, 0.125, 0.25, 0.5, and 1.0 mg/kg) before a 1-h session of exposure to ethanol (single-bottle test, water available the other 23 h per day). A diet enriched with 3% tryptophan (TRP), the amino acid precursor for serotonin synthesis, was administered in a restricted feeding schedule (5 h per day) with ethanol intake measured the last 4 h. Fenfluramine decreased ethanol intake at all doses tested. The 8-OH-DPAT increased ethanol intake at lower doses, presumably acting at autoreceptors, which inhibit serotonergic neurons, and decreased intake at higher doses, presumably acting at postsynaptic 5-HT 1A receptors. TRP-enriched diet also significantly decreased ethanol intake. Food and water intake were less or unaffected by these three manipulations. With all three manipulations, ethanol intake remained suppressed one or more days after the day of tests that decreased ethanol intake. These data suggest that SUS rats, like many other lines/strains of rodents that consume large amounts of alcohol, show an inverse relationship between serotonin transmission and voluntary intake of ethanol.