Depressive-like behavior and high alcohol drinking co-occur in the FH/WJD rat but appear to be under independent genetic control
Department of Psychiatry and Center for Alcohol Studies, University of North Carolina, CB #7178, Chapel Hill, NC 27599-7178, USA. Neuroscience & Biobehavioral Reviews
(Impact Factor: 8.8).
02/2007; 31(1):103-14. DOI: 10.1016/j.neubiorev.2006.07.002
This review will consider the evidence supporting the view that a specific substrain of Fawn-Hooded rat (FH/Wjd) exhibits co-occurring depressive-like behavior and high alcohol intake independently. First, the FH/Wjd rat is compared with other Fawn-Hooded substrains (FH/Har, FHH/Eur, FHL/Eur) and it is concluded that only the FH/Wjd rat is both highly immobile in the forced swim test and drinks substantial amounts of 5-10% alcohol voluntarily. Next it is demonstrated that the FH/Wjd rat fulfils many of the criteria proposed for an animal model of alcoholism (becomes tolerant, becomes dependent and expresses withdrawal symptoms, bar-presses for alcohol). Other literature in addition to the high swim test immobility suggests that the FH/Wjd rat may also be an animal model of depression (high basal corticosterone levels, blunted hormonal responses to serotonergic agonists). To study the phenotypes more closely an inbred strain (ACI/N) of rat that drank little alcohol voluntarily and exhibited considerable swimming in the forced swim test (i.e., low immobility) was obtained. A systematic intercrossing of the parental strains and the resulting F1 progeny was carried out to generate more than 800 F2s. Swim test immobility, alcohol intake and preference and saccharin intake are four of the 7 variables assessed in each of these rats. Using classical quantitative genetics methods, it was determined that these four phenotypes exhibited modest heritability and were influenced by multiple genes. Correlation coefficients between immobility and the other measures were near zero, whereas alcohol intake and preference were highly correlated (r=0.9) and alcohol and saccharin intakes were modestly correlated (r=0.3). A final study showed that chronic fluoxetine treatment counteracted the high immobility but did not affect alcohol intake, similar to human studies. These findings suggest that although depressive-like behavior and high alcohol intake co-occur in the FH/Wjd rat, they are independently regulated.
Available from: Andrew J Lawrence
- "Tolerance also develops to acamprosate for voluntary ethanol intake and ethanol-seeking behaviors with repeated treatments36. The development of tolerance to the effects of these drugs in pre-clinical models has raised questions about their clinical utility37. In the course of a 10-d BRU treatment, no tolerance was observed. "
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Brucine (BRU) extracted from the seeds of Strychnos nux-vomica L is glycine receptor antagonist. We hypothesize that BRU may modify alcohol consumption by acting at glycine receptors, and evaluated the pharmacodynamic profiles and adverse effects of BRU in rat models of alcohol abuse.
Alcohol-preferring Fawn-Hooded (FH/Wjd) rats were administered BRU (10, 20 or 30 mg/kg, sc). The effects of BRU on alcohol consumption were examined in ethanol 2-bottle-choice drinking paradigm, ethanol/sucrose operant self-administration paradigm and 5-d ethanol deprivation test. In addition, open field test was used to assess the general locomotor activity of FH/Wjd rats, and conditioned place preference (CPP) was conducted to assess conditioned reinforcing effect.
In ethanol 2-bottle-choice drinking paradigm, treatment with BRU for 10 consecutive days dose-dependently decreased the ethanol intake associated with a compensatory increase of water intake, but unchanged the daily total fluid intake and body weight. In ethanol/sucrose operant self-administration paradigms, BRU (30 mg/kg) administered before each testing session significantly decreased the number of lever presses for ethanol and the ethanol intake, without affecting the number of sucrose (10%) responses, total sucrose intake, and the number of lever presses for water. Acute treatment with BRU (30 mg/kg) completely suppressed the deprivation-induced elevation of ethanol consumption. Treatment with BRU (10, 20, and 30 mg/kg) did not alter locomotion of FH/Wjd rats, nor did it produce place preference or aversion.
BRU selectively decreases ethanol consumption with minimal adverse effects. Therefore, BRU may represent a new pharmacotherapy for alcoholism.
Acta Pharmacologica Sinica 06/2014; 35(7). DOI:10.1038/aps.2014.28 · 2.91 Impact Factor
Available from: Andrew J Lawrence
- "In the present study, we expanded the existing findings by investigating the role of PDE4 in EtOH-mediated behaviors in FH/Wjd rats, a reliable rodent model of alcoholism (Overstreet et al., 2007; Rezvani et al., 2002). First, with the use of operant self-administration procedures, we tested the influence of rolipram on EtOH-seeking behavior and determined the selectivity of rolipram effect via similar assessment of nature reward seeking (sucrose reinforcement). "
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ABSTRACT: Alcohol dependence is a complex psychiatric disorder demanding development of novel pharmacotherapies. Because the cyclic adenosine monophosphate (cAMP) signaling cascade has been implicated in mediating behavioral responses to alcohol, key components in this cascade may serve as potential treatment targets. Phosphodiesterase-4 (PDE4), an enzyme that specifically catalyzes the hydrolysis of cAMP, represents a key point in regulating intracellular cAMP levels. Thus, it was of interest to determine whether PDE4 was involved in the regulation of alcohol use and abuse.
Male Fawn-Hooded (FH/Wjd) rats were tested for 5% (v/v) ethanol (EtOH) and 10% (w/v) sucrose operant oral self-administration following treatment with the selective PDE4 inhibitor rolipram (0.0125, 0.025, or 0.05 mg/kg, subcutaneous [s.c.]); rolipram at higher doses (0.05, 0.1, and 0.2 mg/kg, s.c.) was tested to determine its impact on the intake of EtOH, sucrose, or water using the 2-bottle choice drinking paradigm. Subsequent open-field testing was performed to evaluate the influence of higher doses of rolipram on locomotor activity.
Acute administration of rolipram dose-dependently reduced operant self-administration of 5% EtOH, but had no effect on 10% sucrose responding. Time-course assessment revealed significant decreases in EtOH consumption after rolipram (0.1, 0.2 mg/kg) treatment in continuous- and intermittent access to EtOH at 5% or 10%, respectively. Moreover, chronic rolipram treatment time-dependently decreased 5% EtOH consumption and preference during treatment days and after the termination of rolipram administration. Rolipram at the highest doses (0.1 and 0.2 mg/kg) did decrease locomotor activity, but the effect lasted only 10 and 20 minutes, respectively, which did not likely alter long-term EtOH drinking.
These results suggest that PDE4 plays a role in alcohol seeking and consumption behavior. Drugs interfering with PDE4 may be a potential pharmacotherapy for alcohol dependence.
Alcoholism Clinical and Experimental Research 06/2012; 36(12). DOI:10.1111/j.1530-0277.2012.01845.x · 3.21 Impact Factor
Available from: ncbi.nlm.nih.gov
- "Given MSG's substantial salty taste component, it is difficult to reconcile this finding with the Brown Norway's reputation as a sodium-avoiding strain. With respect to Fawn Hooded rats, the FH/Wjd strain has strong preferences for ethanol and saccharin (e.g., Daoust et al. 1991; Overstreet et al. 1999, 2007; Goodwin et al. 2000; Rezvani et al. 2007), and it is insensitive to the bitter compounds cycloheximide, phenylthiocarbamide, and quinine relative to Long Evans or Wistar strains (Tobach et al. 1974; Goodwin and Amit 2000). However, the FH/ Wjd strain appears to be unique in this regard; the FHH strain used here does not have such high preferences for ethanol or saccharin (Overstreet et al. 1999, reviewed in Overstreet et al. 2007), and its sensitivity to bitter compounds is untested. "
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ABSTRACT: There has been extensive work to elucidate the behavioral and physiological mechanisms responsible for taste preferences of the rat but little attempt to delineate the underlying genetic architecture. Here, we exploit the FHH-Chr nBN/Mcwi consomic rat strain set to identify chromosomes carrying genes responsible for taste preferences. We screened the parental Fawn Hooded Hypertensive (FHH) and Brown Norway (BN) strains and 22 FHH-Chr nBN consomic strains, with 96-h 2-bottle tests, involving a choice between water and each of the following 16 solutions: 10 mM NaCl, 237 mM NaCl, 32 mM CaCl2, 1 mM saccharin, 100 mM NH4Cl, 32 mM sucrose, 100 mM KCl, 4% ethanol, 1 mM HCl, 10 mM monosodium glutamate, 1 mM citric acid, 32 μM quinine hydrochloride, 1% corn oil, 32 μM denatonium, 1% Polycose, and 1 μM capsaicin. Depending on the taste solution involved, between 1 and 16 chromosomes were implicated in the response. Few of these chromosomes carried genes believed to mediate taste transduction in the mouse, and many chromosomes with no candidate taste genes were revealed. The genetic architecture of taste preferences is considerably more complex than has heretofore been acknowledged. © The Author 2010. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected]
Chemical Senses 07/2010; 35(6):473-89. DOI:10.1093/chemse/bjq038 · 3.16 Impact Factor
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