PT - JOURNAL ARTICLE AU - Alba Peris-Yague AU - Amanda Kiemes AU - Diana Cash AU - Marie-Caroline Cotel AU - Nisha Singh AU - Anthony C. Vernon AU - Gemma Modinos TI - Region-specific and dose-specific effects of chronic haloperidol exposure on [<sup>3</sup>H]Flumazenil and [<sup>3</sup>H]Ro15-4513 GABA<sub>A</sub> receptor binding sites in the rat brain AID - 10.1101/869941 DP - 2019 Jan 01 TA - bioRxiv PG - 869941 4099 - http://biorxiv.org/content/early/2019/12/12/869941.short 4100 - http://biorxiv.org/content/early/2019/12/12/869941.full AB - Data from post-mortem studies suggest that schizophrenia is associated with abnormal expression of GABAA receptor (GABAAR) α subunits including α5GABAA. Positron emission tomography (PET) measures of GABAAR binding in schizophrenic patients, however, have not revealed consistent alterations in vivo. Animal studies using the GABAAR agonist [3H]muscimol have provided evidence that antipsychotic drugs used in schizophrenia can influence GABAAR 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 post-mortem using the GABAA selective radioligand [3H]Ro15-4513 and the non-subunit selective radioligand [3H]flumazenil. Chronic haloperidol exposure increased [3H]Ro15-4513 binding in the CA1 sub-field of the dorsal hippocampus (p&lt;0.01; q&lt;0.01). [3H]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 [3H]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 GABAAR in schizophrenic patients, specifically at the α1/5GABAAR.