Abstract
N-[(4-trifluoromethyl)benzyl]4-methoxybutyramide (GET73) is a newly synthesized compound structurally related to the clinically used, alcohol-substituting agent, gamma-hydroxybutyric acid (GHB). The present study was designed to assess whether GET73 may share with GHB the capacity to reduce alcohol intake in rats. Additionally, the effect of treatment with GET73 on anxiety-related behaviors and cognitive tasks in rats was investigated. A series of in vitro binding assays investigated the capacity of GET73 to bind to the GHB binding site and multiple other receptors. GET73 (10−9–10−3 M) failed to inhibit [3H]GHB binding at both high- and low-affinity GHB recognition sites in rat cortical membranes. GET73 displayed minimal, if any, binding at dopamine, serotonin, GABA, and glutamate receptors in membranes from different rat brain areas. Acute treatment with low-to-moderate, non-sedative doses of GET73 (5–50 mg/kg, i.g. or i.p.) (a) reduced alcohol intake and suppressed “alcohol deprivation effect” (a model of alcohol relapse) in selectively bred, Sardinian alcohol-preferring (sP) rats, (b) exerted anxiolytic effects in Sprague-Dawley (SD) and sP rats exposed to the Elevated Plus Maze test, and (c) tended to induce promnestic effects in SD rats exposed to a modified water version of the Hebb–Williams maze test. Although the mechanism of GET73 action is currently unknown, the results of the present study suggest that GET73 has a multifaceted pharmacological profile, including the capacity to reduce alcohol drinking and anxiety-related behaviors in rats.
Highlights
In spite of the increasing emphasis placed on alcohol use disorders (AUDs) worldwide, to date only a few therapeutic options have been approved and are currently available for clinical use
EXPERIMENT 1: [3H]gamma-hydroxybutyric acid (GHB) BINDING ASSAY As expected from previous studies (Carai et al, 2002; Castelli et al, 2003), GHB – used as reference compound – inhibited [3H]GHB binding with IC50 equal to 108 ± 30 nM and 3.5 ± 1.0 μM
GET73 – tested at concentrations ranging from 10−9 to 10−3 M – failed to inhibit [3H]GHB binding at both GHB recognition sites
Summary
In spite of the increasing emphasis placed on alcohol use disorders (AUDs) worldwide, to date only a few therapeutic options (namely disulfiram, naltrexone, and acamprosate) have been approved and are currently available for clinical use. In recent years research studies have focused on investigating multiple alternative molecular targets potentially involved in AUDs, and testing drugs capable of modulating these neural systems and affecting different alcohol-related behaviors. Open and double-blind clinical trials, as well as several case reports, have demonstrated the capacity of GHB to (a) reduce alcohol craving and consumption, (b) promote and maintain abstinence from alcohol, and (c) ameliorate signs and symptoms of alcohol withdrawal syndrome in alcoholics (e.g., Gallimberti et al, 1989, 1992; Addolorato et al, 1996, 1998a,b, 1999; Moncini et al, 2000; Glisson and Norton, 2002; Nimmerrichter et al, 2002; for review, see Agabio and Gessa, 2002; Addolorato et al, 2009; Caputo et al, 2010; Chick and Nutt, 2012) These data have led to GHB obtaining approval as a pharmacotherapy for alcohol dependence in Italy and other European Countries. Bind to the GHB binding site (Experiment 1) as well as other receptor systems (Experiment 2); (b) evaluation of GET73 effects on spontaneous locomotor activity (Experiment 3), cognitive functions (Experiments 4–6), and anxiety-related behaviors (Experiment 7) in Sprague-Dawley (SD) and sP rats; (c) investigation on the capacity of GET73 to affect alcohol drinking behavior and relapse-like drinking in sP rats (Experiments 8 and 9)
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