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<jats:title>Abstract</jats:title><jats:p>Data from <jats:italic>post-mortem</jats:italic> studies suggest that schizophrenia is associated with abnormal expression of GABA<jats:sub>A</jats:sub> receptor (GABA<jats:sub>A</jats:sub>R) α subunits including α5GABA<jats:sub>A</jats:sub>. Positron emission tomography (PET) measures of GABA<jats:sub>A</jats:sub>R binding in schizophrenic patients, however, have not revealed consistent alterations <jats:italic>in vivo</jats:italic>. Animal studies using the GABA<jats:sub>A</jats:sub>R agonist [<jats:sup>3</jats:sup>H]muscimol have provided evidence that antipsychotic drugs used in schizophrenia can influence GABA<jats:sub>A</jats:sub>R binding, in a region-specific manner, complicating the interpretation of the PET GABA signal in medicated patients. No binding data, however, are available for more subunit-selective ligands. To address this, we combined a rodent model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or vehicle were continuously administered to adult male Sprague-Dawley rats via osmotic pumps to maintain a clinically relevant, steady-state levels of drug exposure for 28 days. Quantitative receptor autoradiography was then performed <jats:italic>post-mortem</jats:italic> using the GABA<jats:sub>A</jats:sub> selective radioligand [<jats:sup>3</jats:sup>H]Ro15-4513 and the non-subunit selective radioligand [<jats:sup>3</jats:sup>H]flumazenil. Chronic haloperidol exposure increased [<jats:sup>3</jats:sup>H]Ro15-4513 binding in the CA1 sub-field of the dorsal hippocampus (p&lt;0.01; q&lt;0.01). [<jats:sup>3</jats:sup>H]flumazenil binding was also increased in most of the explored regions (p&lt;0.05), independently of the dose of haloperidol used. This is the first study to demonstrate a region/dose-specific effect of haloperidol on [<jats:sup>3</jats:sup>H]Ro15-4513 binding. Although caution needs to be exerted when extrapolating results from animals to patients, collectively these data confirm previous findings that antipsychotic treatment contributes to the heterogeneity observed in PET studies of GABA<jats:sub>A</jats:sub>R in schizophrenic patients, specifically at the α1/5GABA<jats:sub>A</jats:sub>R.</jats:p>

Original publication

DOI

10.1101/869941

Type

Journal article

Publisher

Cold Spring Harbor Laboratory

Publication Date

11/12/2019