TY - JOUR
T1 - Region-specific and dose-specific effects of chronic haloperidol exposure on [3H]-flumazenil and [3H]-Ro15-4513 GABAA receptor binding sites in the rat brain
AU - Peris-Yague, Alba
AU - Kiemes, Amanda
AU - Cash, Diana
AU - Cotel, Marie-Caroline
AU - Singh, Nisha
AU - Vernon, Anthony C
AU - Modinos, Gemma
N1 - Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
PY - 2020/12
Y1 - 2020/12
N2 - Postmortem studies suggest that schizophrenia is associated with abnormal expression of specific GABA
A receptor (GABA
AR) α subunits, including α5GABA
AR. Positron emission tomography (PET) measures of GABA
AR availability in schizophrenia, however, have not revealed consistent alterations in vivo. Animal studies using the GABA
AR agonist [
3H]-muscimol provide evidence that antipsychotic drugs influence GABA
AR availability, in a region-specific manner, suggesting a potential confounding effect of these drugs. No such data, however, are available for more recently developed subunit-selective GABA
AR radioligands. To address this, we combined a rat model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or drug vehicle were administered continuously to adult male Sprague-Dawley rats via osmotic mini-pumps for 28 days. Quantitative receptor autoradiography was then performed postmortem using the GABA
AR subunit-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 rat dorsal hippocampus (p<0.01; q<0.01; d=+1.3), which was not dose-dependent. [
3H]-flumazenil binding also increased in most rat brain regions (p<0.05; main effect of treatment), irrespective of the haloperidol dose. These data confirm previous findings that chronic haloperidol exposure influences the specific binding of non-subtype selective GABA
AR radioligands and is the first to demonstrate a potential effect of haloperidol on the binding of a α1/5GABA
AR-selective radioligand. Although caution should be exerted when extrapolating results from animals to patients, our data support a view that exposure to antipsychotics may be a confounding factor in PET studies of GABA
AR in the context of schizophrenia.
AB - Postmortem studies suggest that schizophrenia is associated with abnormal expression of specific GABA
A receptor (GABA
AR) α subunits, including α5GABA
AR. Positron emission tomography (PET) measures of GABA
AR availability in schizophrenia, however, have not revealed consistent alterations in vivo. Animal studies using the GABA
AR agonist [
3H]-muscimol provide evidence that antipsychotic drugs influence GABA
AR availability, in a region-specific manner, suggesting a potential confounding effect of these drugs. No such data, however, are available for more recently developed subunit-selective GABA
AR radioligands. To address this, we combined a rat model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or drug vehicle were administered continuously to adult male Sprague-Dawley rats via osmotic mini-pumps for 28 days. Quantitative receptor autoradiography was then performed postmortem using the GABA
AR subunit-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 rat dorsal hippocampus (p<0.01; q<0.01; d=+1.3), which was not dose-dependent. [
3H]-flumazenil binding also increased in most rat brain regions (p<0.05; main effect of treatment), irrespective of the haloperidol dose. These data confirm previous findings that chronic haloperidol exposure influences the specific binding of non-subtype selective GABA
AR radioligands and is the first to demonstrate a potential effect of haloperidol on the binding of a α1/5GABA
AR-selective radioligand. Although caution should be exerted when extrapolating results from animals to patients, our data support a view that exposure to antipsychotics may be a confounding factor in PET studies of GABA
AR in the context of schizophrenia.
KW - Autoradiography
KW - GABA
KW - Haloperidol
KW - Schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=85095757076&partnerID=8YFLogxK
U2 - 10.1016/j.euroneuro.2020.10.004
DO - 10.1016/j.euroneuro.2020.10.004
M3 - Article
C2 - 33153853
SN - 0924-977X
VL - 41
SP - 106
EP - 117
JO - European Neuropsychopharmacology
JF - European Neuropsychopharmacology
ER -
