Abstract
Alcohol consumption and the reinstatement of alcohol-seeking rely on glutamate and GABA transmission. Modulating these neurotransmitters may be a viable treatment strategy to prevent alcohol relapse. N-acetylcysteine (NAC) and the antibiotic ceftriaxone (CEF) alter the glial reuptake and release of glutamate while the antibiotic cefazolin (CEFAZ) modulates GABA signaling without affecting glutamate. Here, we used the extinction-reinstatement model of relapse to test the ability of these compounds to attenuate the reinstatement of alcohol-seeking. Male Sprague-Dawley rats were trained to self-administer 20% (v/v) alcohol in the home cage using an intermittent schedule (24 h on, 24 h off) for 12 sessions. Subsequently, animals self-administered alcohol during daily 45-min operant sessions for 26 sessions, followed by extinction training. We tested whether chronic administration of NAC, CEF, or CEFAZ attenuated the cue-primed reinstatement of alcohol-seeking. CEF and CEFAZ attenuated cue-primed reinstatement of alcohol-seeking while NAC had no effect. We subsequently investigated whether CEF and CEFAZ alter the self-administration of sucrose and chow pellets and if CEFAZ attenuates the reinstatement of cocaine-seeking. The operant self-administration of regular chow and sucrose was not altered by either CEF or CEFAZ. CEFAZ had no effect on cocaine reinstatement, a behavior that has been strongly tied to altered glutamate homeostasis in the nucleus accumbens. Thus the ability of CEFAZ to attenuate alcohol reinstatement likely does not involve the glial modulation of glutamate levels. The dampening of GABA transmission may be a common mechanism of action of cefazolin and ceftriaxone.
Highlights
Alcoholism or alcohol dependence is a chronic, progressive disease which results from an inability to regulate drug-seeking behavior
One method of inducing high amounts of unsweetened alcohol consumption in rodents is the intermittent access to alcohol (IAA) procedure in which rodents are provided 24 h access to alcohol followed by a 24 h period with no access (Wayner and Greenberg, 1972; Wise, 1973; Pinel and Huang, 1976)
We demonstrated that training Sprague-Dawley rodents to self-administer unsweetened alcohol in the operant chamber can be accomplished using daily training sessions without lengthy (14 h; e.g., Simms et al, 2010) operant sessions on alternating days
Summary
Alcoholism or alcohol dependence is a chronic, progressive disease which results from an inability to regulate drug-seeking behavior. Relapse is modeled in animals with the reinstatement paradigm, where animals are trained to self-administer drug in an operant chamber. Simms et al (2010) adapted the IAA paradigm to an operant self-administration model and engendered high levels of alcohol-seeking in the operant chamber after using 14 h operant sessions on intermittent days (MWF), followed by shorter (30–45 min) daily sessions in the operant chamber. We modified this method to eliminate the use of 14 h operant sessions and trained animals in the operant chamber only during daily 45-min sessions for 26 sessions (MTWRF)
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