PRECLINICAL STUDY: A microdialysis study of extracellular levels of acamprosate and naltrexone in the rat brain following acute and repeated administration

Abstract

Acamprosate and naltrexone are widely used in the treatment of alcoholism. However, numerous studies in rodents have shown differential effects of these compounds on alcohol consumption and/or relapse-like behavior following acute versus repeated administration. In order to determine if these differential behavioral effects could be attributable to changes in extracellular levels of these compounds, we used in vivo microdialysis to monitor extracellular levels of acamprosate and naltrexone in the rat medial prefrontal cortex following acute and repeated intraperitoneal administration. For acute treatment, animals received a single administration of acamprosate (100 or 300 mg/kg) or naltrexone (1 or 3 mg/kg). For repeated treatment, animals received once daily treatment with saline, acamprosate (300 mg/kg) or naltrexone (3 mg/kg) for 10 days before a subsequent challenge with the compound according to their respective pretreatment group. Dialysate levels of acamprosate and naltrexone were analyzed by liquid chromatography-tandem mass spectrometry and high performance liquid chromatography, respectively. Following acute administration, peak dialysate concentrations of each compound were dose-dependent, observed within 1 hour of administration, and were found to be in the low micromolar range for acamprosate and in the low to mid-nanomolar range for naltrexone. Pretreatment with acamprosate, but not naltrexone, for 10 days resulted in higher dialysate concentrations of the compound relative to saline-pretreated controls. Thus, repeated administration of acamprosate, but not naltrexone, results in augmented extracellular levels of the compound in the brain relative to saline-pretreated controls, which may explain the need for repeated administration of acamprosate in order to observe effects on alcohol consumption and/or relapse.

The effects of acamprosate on alcohol-cue reactivity and alcohol priming in dependent patients: a randomized controlled trial

“…This is in agreement with previous clinical trials indicating a dose-response effect of acamprosate (e.g., Mason et al 2006;Pelc et al 1997). Further, the results are in agreement with recent preclinical data suggesting that the modulation of drinking behavior by acamprosate is correlated with its extracellular concentration in brain (Burattini et al 2008). However, alternative explanations must be noted.…”

Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety

“…Therefore, the timing of the behavioral tests (1 h following treatment) was chosen to allow mice to recover from the treatment injection while still assessing behavior prior to drug elimination. Furthermore, chronic administration of acamprosate in rodents has been shown to result in increased extracellular brain concentrations of the drug relative to a single treatment suggesting that repeated administration may be needed to achieve clinical efficacy and supports the chronic treatment paradigm used in the current in vivo tests [121]. …”

Glutamatergic targets for new alcohol medications

“…However, although acamprosate was initially thought to act in part by inhibiting N -methyl-D-aspartate receptors (NMDAR) and metabotropic glutamate (mGluR5) receptors (Dahchour and De Witte 2003; Popp and Lovinger 2000), actions on these receptors remain unclear (Brasser et al 2004; Spanagel et al 1996), especially at the plasma levels typically achieved in humans with oral administration (Johnson et al 2003b) (c.f. Burattini et al 2008). Topiramate is often used, off-label, as a treatment for alcoholism, and inhibits glutamate release and blocks L-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid ionotropic (AMPAR)/ kainate receptors (KAR) as part of a complex pharmacological profile.…”