Evidence of Acamprosate Penetration Into the Rat Brain

Durbin, Philippe; Belleville, M; Chabac, S.

doi:10.1097/00008877-199508000-00039

Cited by 3 publications

(2 citation statements)

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“…These findings are consistent with earlier studies showing that plasma levels of the drug in rats peak at approximately 30–40 minutes following oral administration (Zornoza et al . 2006), and peak brain levels of the drug are observed at 30 minutes following oral administration (Durbin & Belleville 1995; Durbin et al . 1995).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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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.

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Section: Discussionmentioning

confidence: 99%

“…Studies with radiolabeled analogues of acamprosate and naltrexone have shown that both drugs penetrate the blood‐brain barrier (BBB) in rodents after systemic administration (Misra et al . 1976; Durbin & Belleville 1995; Durbin, Belleville & Chabac 1995; Courtyn et al . 2004).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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Effects of acute acamprosate and homotaurine on ethanol intake and ethanol-stimulated mesolimbic dopamine release

Olive

Nannini

et al. 2002

European Journal of Pharmacology

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Mechanism of Action of Acamprosate. Part I. Characterization of Spermidine‐Sensitive Acamprosate Binding Site in Rat Brain

Naassïla

Hammoumi

Legrand

et al. 1998

Alcoholism Clin & Exp Res

145

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It has been suggested that the anticraving drug, acamprosate, acts via the glutamatergic system, but the exact mechanism of action is still unknown. The aim of this study was to characterize [3H]acamprosate binding and establish whether this showed any relation to sites on the NMDA receptor complex. We found saturable specific binding of [3H]acamprosate to rat brain membranes with a KD of 120 microM and a Bmax of 450 pmol/mg of protein. This acamprosate binding site was sensitive to inhibition by spermidine (IC50: 13.32 +/- 1.1 microM; Hill coefficient = 1.04), and arcaine and glutamate both potentiated the inhibitory effect of spermidine. Acamprosate binding to the acamprosate binding site was also sensitive to inhibition by divalent cations (Ca2+, Mg2+, and Sr2+). Conversely, acamprosate displaced [14C]spermidine binding from rat brain membranes with an IC50 of 645 microM and a Hill coefficient = 1.74. This inhibitory effect of acamprosate was not affected by arcaine, and was associated with a significant reduction in Bmax and binding affinity for spermidine, suggesting an allosteric interaction between acamprosate and a spermidine binding site. These data are consistent with an effect of acamprosate on the NMDA receptor protein complex, and acamprosate was also found to alter binding of [3H]dizocilpine to rat brain membranes. When no agonists were present in vitro (minimal NMDA receptor activation), acamprosate markedly potentiated [3H]dizocilpine binding at concentrations in the 5 to 200 microM range. However, under conditions of maximal receptor activation (100 microM glutamate, 30 microM glycine), acamprosate only inhibited [3H]dizocilpine binding (at concentrations concentrations >100 microM). When these binding studies were performed in the presence of 1 microM spermidine, the enhancing effects of acamprosate on [3H]dizocilpine binding were inhibited. The results show that acamprosate binds to a specific spermidine-sensitive site that modulates the NMDA receptor in a complex way. Together, with data from al Quatari et al. (see next paper), this work suggests that acamprosate acts as "partial co-agonist" at the NMDA receptor, so that low concentrations enhance activation when receptor activity is low, whereas higher concentrations are inhibitory to high levels of receptor activation. This may be relevant to the clinical effects of acamprosate in alcohol-dependent patients during abstinence.

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Evidence of Acamprosate Penetration Into the Rat Brain

Cited by 3 publications

References 0 publications

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

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

Effects of acute acamprosate and homotaurine on ethanol intake and ethanol-stimulated mesolimbic dopamine release

Mechanism of Action of Acamprosate. Part I. Characterization of Spermidine‐Sensitive Acamprosate Binding Site in Rat Brain

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