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. 2008 Feb;32(2):188-96.
doi: 10.1111/j.1530-0277.2007.00569.x.

Effects of acamprosate on neuronal receptors and ion channels expressed in Xenopus oocytes

Matthew T Reilly  1 , Ingrid A Lobo, Lindsay M McCracken, Cecilia M Borghese, Diane Gong, Takafumi Horishita, R Adron Harris
Affiliations

Affiliation

  • 1 Waggoner Center for Alcohol & Addiction Research, The University of Texas at Austin, Austin, Texas 78712-1095, USA. reillym@mail.utexas.edu

Effects of acamprosate on neuronal receptors and ion channels expressed in Xenopus oocytes

Matthew T Reilly et al. Alcohol Clin Exp Res. 2008 Feb.
. 2008 Feb;32(2):188-96.
doi: 10.1111/j.1530-0277.2007.00569.x.

Authors

Matthew T Reilly  1 , Ingrid A Lobo, Lindsay M McCracken, Cecilia M Borghese, Diane Gong, Takafumi Horishita, R Adron Harris

Affiliation

  • 1 Waggoner Center for Alcohol & Addiction Research, The University of Texas at Austin, Austin, Texas 78712-1095, USA. reillym@mail.utexas.edu

Abstract

Background: Acamprosate (calcium acetylhomotaurinate) has proven to be a moderately effective pharmacological adjunct for the treatment of alcoholism. However, the central nervous system mechanism by which acamprosate reduces alcohol relapse remains unclear. Here we survey a number of metabotropic receptors, ligand-gated ion channels, and voltage-gated ion channels, to determine if acamprosate has actions at these sites in the central nervous system.

Methods: Xenopus oocytes were injected with cDNAs or cRNAs encoding metabotropic glutamate receptors 1 and 5, M1 muscarinic receptors, glycine alpha1 homomeric and alpha1beta1 heteromeric receptors, gamma-aminobutyric acid A (GABA(A)alpha4beta3delta, alpha4beta3gamma2s, and alpha1beta2gamma2s) receptors, vanilloid receptor 1, and various combinations of alpha and beta subunits of voltage-gated Na+ channels. Electrophysiological responses were measured using two-electrode voltage clamp parameters after activation with agonists or voltage steps (for the voltage-gated channels). Acamprosate (0.1 to 100 microM) was pre-applied for 1 minute, followed by co-application with agonist. Acamprosate was also applied with ethanol to determine if it altered ethanol responses at some of these receptors and channels.

Results: None of the receptors or ion channels responded to acamprosate alone. Acamprosate also failed to alter the activation of receptors or channels by agonists or after activation of voltage-gated channels. There was no effect of acamprosate on ethanol responses at GABA(A)alpha1beta2gamma2s receptors or Na+ channels.

Conclusions: Acamprosate does not significantly modulate the function of these receptors and ion channels at clinically relevant concentrations. Thus, the clinical effectiveness of acamprosate in the treatment of alcoholism is not likely due to direct effects on these receptors or ion channels.

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Figures

Fig. 1

Fig. 1

Acamprosate does not modulate metabotropic…

Fig. 1

Acamprosate does not modulate metabotropic glutamate receptor (mGluR5) function. Xenopus oocytes were injected…

Fig. 1
Acamprosate does not modulate metabotropic glutamate receptor (mGluR5) function. Xenopus oocytes were injected with (mGluR5) cRNA, and calcium-activated chloride currents were measured after application of glutamate and co-application with acamprosate. (A) Representative current tracings after application of 100 μM glutamate or acamprosate (1 and 100 μM) are shown. (B) Summary data showing mean ± SEM of the percent of the glutamate response in 5–6 oocytes per bar.
Fig. 2

Fig. 2

Acamprosate does not modulate metabotropic…

Fig. 2

Acamprosate does not modulate metabotropic glutamate receptor (mGluR1) function. Xenopus oocytes were injected…

Fig. 2
Acamprosate does not modulate metabotropic glutamate receptor (mGluR1) function. Xenopus oocytes were injected with mGluR1 cRNA, and calcium-activated chloride currents were measured after application of glutamate and co-application with acamprosate. (A) Representative current tracings after application of 100 μM glutamate or acamprosate (1 and 100 μM) are shown. (B) Summary data showing mean ± SEM of the percent of the glutamate response from 5 to 7 oocytes per bar.
Fig. 3

Fig. 3

Acamprosate does not modulate muscarinic…

Fig. 3

Acamprosate does not modulate muscarinic receptor (M1) function. Xenopus oocytes were injected with…

Fig. 3
Acamprosate does not modulate muscarinic receptor (M1) function. Xenopus oocytes were injected with M1 cRNA, and calcium-activated chloride currents were measured after application of acetylcholine and co-application with acamprosate. (A) Representative current tracings after application of 100 μM acetylcholine or acamprosate (1 and 10 μM) are shown. (B) Summary data showing mean ± SEM of the percent of the acetylcholine response from 4 to 6 oocytes per bar.
Fig. 4

Fig. 4

Acamprosate does not modulate vanilloid…

Fig. 4

Acamprosate does not modulate vanilloid receptor function. (A) Representative current tracings after application…

Fig. 4
Acamprosate does not modulate vanilloid receptor function. (A) Representative current tracings after application of 3 μM capsaicin alone or with acamprosate (1, 10 and 100 μM). (B) Summary data showing the mean ± SEM of the percent of the capsaicin response from 5 oocytes.
Fig. 5

Fig. 5

Acamprosate does not modulate glycine…

Fig. 5

Acamprosate does not modulate glycine receptor function. (A) Glycine α 1 receptor current…

Fig. 5
Acamprosate does not modulate glycine receptor function. (A) Glycine α1 receptor current tracing during application of acamprosate and co-application with EC5–10 glycine. (B) Summary data from A showing mean ± SEM of the percent of the glycine response from 8 oocytes per bar. (C) Glycine α1β receptor current tracing during application of acamprosate and co-application with EC5–10 glycine. (D) Summary data from C showing mean ± SEM of the percent of the glycine response in 8 oocytes per bar. (E) Glycine α1 receptor current tracing during application of acamprosate and co-application with EC5–10 taurine. (F) Summary data from E showing mean ± SEM of the percent of the taurine response in 8 oocytes per bar. (G) Glycine α1β receptor current tracing during application of acamprosate and co-application with EC5–10 taurine. (H) Summary data from G showing mean ± SEM of the percent of the taurine response in 6 oocytes per bar.
Fig. 6

Fig. 6

Acamprosate does not modulate γ …

Fig. 6

Acamprosate does not modulate γ -aminobutyric acid type A receptor (GABA A )…

Fig. 6
Acamprosate does not modulate γ-aminobutyric acid type A receptor (GABAA) function. (A) GABAA (α4β3δ) receptor current tracing during application of acamprosate and co-application with EC20 GABA. (B) Summary data from A showing mean ± SEM of the percent of the GABA response in 6 oocytes per bar. (C) GABAA (α4β3γ2s) receptor current tracing during application of acamprosate and co-application with EC20 GABA. (D) Summary data from C showing mean ± SEM of the percent of the GABA response in 6 oocytes per bar. (E) GABAA (α1β2γ2s) receptor current tracing during application of acamprosate and co-application with EC5–10 GABA. (F) Summary data from E showing mean ± SEM of the percent of the GABA response in 7 to 10 oocytes per bar.
Fig. 7

Fig. 7

Acamprosate does not modulate voltage-gated…

Fig. 7

Acamprosate does not modulate voltage-gated Na + channel (Nav) function. (A) Representative current…

Fig. 7
Acamprosate does not modulate voltage-gated Na+ channel (Nav) function. (A) Representative current tracing at Vmax (−90 mV) and V1/2 before, during and after application of acamprosate (1 μM) is shown in an oocyte expressing Nav 1.2 and β1 subunits. (B) Summary data showing the mean ± SEM of the percent of the control responses in 4–5 oocytes per bar. (C) Na+ channel current tracings in the presence and absence (control) of acamprosate elicited by depolarizing steps from −80 to 60 mV from a holding potential of −90 mV (D) Current-voltage plots in the presence and absence of acamprosate.
Fig. 8

Fig. 8

Acamprosate does not alter ethanol…

Fig. 8

Acamprosate does not alter ethanol responses at γ -aminobutyric acid type A [(GABA …

Fig. 8
Acamprosate does not alter ethanol responses at γ-aminobutyric acid type A [(GABAA) α1β2γ2s] receptors or voltage-gated Na+ channels (Nav). (A) Ethanol potentiation of GABAA receptors expressed as a percent of the GABA response in the presence and absence of acamprosate. Bars represent the mean ± SEM from 8 oocytes per bar. (B) Ethanol inhibition of Nav expressed as a percent of the control response in the presence and absence of acamprosate. Bars represent the mean ± SEM from 7 oocytes per bar.
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