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

Abstract

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.

Rat animal models for screening medications to treat alcohol use disorders

“…Preclinical and clinical research indicates the following endophenotypes are directly related to the development of ethanol dependence (a) lower initial sensitivity to ethanol's aversive effects (c.f., Bell et al, 2006b, 2012; Colombo et al, 2006; Draski and Deitrich, 1996; Le et al, 2001b; Schuckit and Gold, 1988), (b) greater levels and/or quicker development of ethanol-induced tolerance (c.f., Costin and Miles, 2014; Lê and Mayer, 1996), (c) anxiety-like and/or depressive behavior including during ethanol withdrawal (c.f., Ciccocioppo et al, 2006; Heilig et al, 2010; Kirby et al, 2011; Overstreet et al, 2006; Pautassi et al, 2010; Sjoerds et al, 2014; Thorsell, 2010), (d) stress reactivity (c.f., Barr and Goldman, 2006), and (e) sweet liking/preference (c.f., de Wit and Richards, 2004; Kampov-Polevoy et al, 2014; Lange et al, 2010; Pepino and Mennella, 2007; Perry and Carroll et al, 2008). …”

Neuropharmacology of alcohol addiction

“…In particular, a number of neurochemical differences were found in genetically selected alcohol‐preferring rat lines as compared with non‐preferring lines. The most commonly used lines are the Finnish alcohol‐preferring (AA), the Sardinian‐preferring (SP), the Indiana University alcohol‐preferring (P) and the HAD rat lines ( Bell et al ., 2006 ; Ciccocioppo et al ., 2006 ; Overstreet et al ., 2006 ; Sommer et al ., 2006 ). As an example, low levels of DA and 5‐HT in several limbic structures were seen in alcohol‐preferring P and HAD rat lines in comparison to their alcohol non‐preferring counterparts.…”

Pre-Clinical Studies with D-Penicillamine as a Novel Pharmacological Strategy to Treat Alcoholism: Updated Evidences

“…Specifically, we explored whether the combination of DP with NTX could suppress the delayed ADE, i.e., the rebound in alcohol consumption detected in animal laboratory models after continuous blockade of the opioid receptor with antagonists such as NTX (Heyser et al, 2003) or naloxone (Hölter and Spanagel, 1999). In this sense, in several strains of rats using free choice paradigms it has been demonstrated that NTX decreases ethanol consumption (Overstreet et al, 2006), however, tolerance to this effect was demonstrated after repeated drug administration, leading to an increase in alcohol consumption (Cowen et al, 1999; Juárez and Eliana, 2007). This fact is probably due to the MORs up-regulation associated with its continuous blockade (Hyytiä et al, 1999; Overstreet et al, 1999; Orrico et al, 2014).…”