title: Ethanol withdrawal-induced brain metabolites and the pharmacological effects of acamprosate in mice lacking ENT1.
abstract: Acamprosate is clinically used to treat alcohol-dependent patients. While the molecular and pharmacological mechanisms of acamprosate remain unclear, it has been shown to regulate γ-aminobutyric acid (GABA) or glutamate levels in the cortex and striatum. To investigate the effect of acamprosate on brain metabolites in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), we employed in vivo 16.4 T proton magnetic resonance spectroscopy. We utilized type 1 equilibrative nucleoside transporter (ENT1) null mice since acamprosate attenuates ethanol drinking in these mice. Our findings demonstrated that ethanol withdrawal reduced GABA levels and increased phosphorylated choline compounds in the mPFC of both wild-type and ENT1 null mice. Notably, acamprosate normalized these withdrawal-induced changes only in ENT1 null mice. In the NAc, ethanol withdrawal increased glutamate and glutamine (Glx) levels only in wild-type mice. Interestingly, acamprosate reduced Glx levels in the NAc compared to the withdrawal state in both genotypes. These results provide a molecular basis for the pharmacological effect of acamprosate in the cortical-striatal circuit.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hinton
authors.forename: Moonnoh R
authors.initials: MR
authors.lastname: Lee
authors.forename: Taylor L
authors.initials: TL
authors.lastname: Jacobson
authors.forename: Prasanna K
authors.initials: PK
authors.lastname: Mishra
authors.forename: Mark A
authors.initials: MA
authors.lastname: Frye
authors.forename: David A
authors.initials: DA
authors.lastname: Mrazek
authors.forename: Slobodan I
authors.initials: SI
authors.lastname: Macura
authors.forename: Doo-Sup
authors.initials: DS
authors.lastname: Choi
mesh_terms: D000077443:Acamprosate; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics / Q000378:metabolism*; D000431:Ethanol / Q000009:adverse effects*; D018698:Glutamic Acid / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D033721:Equilibrative Nucleoside Transporter 1; C498476:SLC29A1 protein, mouse; D013654:Taurine; D000431:Ethanol; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000077443:Acamprosate