Modulation of high alcohol drinking in the inbred Fawn-Hooded (FH/Wjd) rat strain: implications for treatment.

The Fawn-Hooded rat (FH/Wjd) is an inbred alcohol-preferring rat strain, unlike most of the other strains that were selectively bred for high alcohol intake and preference. It was chosen for study some 16 years ago because of a reported mutation that disrupted platelet serotonin function. Although the FH/Wjd rat has high alcohol intake (>5 g/kg/day) and preference (>65%), interbreeding with an alcohol-non-preferring inbred strain suggested that these measures are unrelated to the serotonin abnormality. Similarly, the exaggerated immobility of the FH/Wjd rats in the forced swim test did not correlate with the high alcohol intake. Many compounds have been tested in the FH/Wjd rats after both acute and chronic treatment and a substantial number of them have proved effective. However, as the case with opiate antagonists, tolerance to the effects of the drug can develop. An up-regulation of opioid receptors accompanied the chronic treatment and this mechanism may account for the development of tolerance. Tolerance to opiate antagonists has also been demonstrated in two of the selectively bred alcohol-preferring rat lines, but it is unknown whether this process may contribute to the relapses seen in individuals being treated with naltrexone. Other drugs that reliably decrease alcohol intake in the FH/Wjd rats include the 5-hydroxytryptamine-2A receptor antagonist, amperozide, the mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and herbal derivatives such as ibogaine, St. John's wort and kudzu extract. Thus, studies in the FH/Wjd rat have led to the discovery of a wide variety of targets for the development of novel agents to treat alcoholism. The fact that several of these drugs were shown to reduce alcohol intake in some of the selectively bred alcohol-preferring rat lines and/or alcohol-preferring vervet monkeys increases our confidence that they are good candidates for further development.