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Region-specific and dose-specific effects of chronic haloperidol exposure on [³H]-flumazenil and [³H]-Ro15-4513 GABA_A receptor binding sites in the rat brain.

ABSTRACT: 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.

SUBMITTER: Peris-Yague A

PROVIDER: S-EPMC7731940 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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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.

Peris-Yague Alba A Kiemes Amanda A Cash Diana D Cotel Marie-Caroline MC Singh Nisha N Vernon Anthony C AC Modinos Gemma G

European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 20201102

Postmortem studies suggest that schizophrenia is associated with abnormal expression of specific GABAA receptor (GABAAR) α subunits, including α5GABAAR. Positron emission tomography (PET) measures of GABAAR availability in schizophrenia, however, have not revealed consistent alterations in vivo. Animal studies using the GABAAR agonist [3H]-muscimol provide evidence that antipsychotic drugs influence GABAAR availability, ...[more]

PMID: 33153853

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Project description:IntroductionAlteration of γ-aminobutyric acid "A" (GABAA) receptor-mediated neurotransmission has been associated with various neurological and psychiatric disorders. [11C]Ro15-4513 is a PET ligand with high affinity for α5-subunit-containing GABAA receptors, which are highly expressed in limbic regions of the human brain (Sur et al., 1998). We quantified the test-retest reproducibility of measures of [11C]Ro15-4513 binding derived from six different quantification methods (12 variants).MethodsFive healthy males (median age 40 years, range 38-49 years) had a 90-min PET scan on two occasions (median interval 12 days, range 11-30 days), after injection of a median dose of 441 MegaBequerels of [11C]Ro15-4513. Metabolite-corrected arterial plasma input functions (parent plasma input functions, ppIFs) were generated for all scans. We quantified regional binding using six methods (12 variants), some of which were region-based (applied to the average time-activity curve within a region) and others were voxel-based: 1) Models requiring arterial ppIFs - regional reversible compartmental models with one and two tissue compartments (2kbv and 4kbv); 2) Regional and voxelwise Logan's graphical analyses (Logan et al., 1990), which required arterial ppIFs; 3) Model-free regional and voxelwise (exponential) spectral analyses (SA; (Cunningham and Jones, 1993)), which also required arterial ppIFs; 4) methods not requiring arterial ppIFs - voxelwise standardised uptake values (Kenney et al., 1941), and regional and voxelwise simplified reference tissue models (SRTM/SRTM2) using brainstem or alternatively cerebellum as pseudo-reference regions (Lammertsma and Hume, 1996; Gunn et al., 1997). To compare the variants, we sampled the mean values of the outcome parameters within six bilateral, non-reference grey matter regions-of-interest. Reliability was quantified in terms of median absolute percentage test-retest differences (MA-TDs; preferentially low) and between-subject coefficient of variation (BS-CV, preferentially high), both compounded by the intraclass correlation coefficient (ICC). These measures were compared between variants, with particular interest in the hippocampus.ResultsTwo of the six methods (5/12 variants) yielded reproducible data (i.e. MA-TD <10%): regional SRTMs and voxelwise SRTM2s, both using either the brainstem or the cerebellum; and voxelwise SA. However, the SRTMs using the brainstem yielded a lower median BS-CV (7% for regional, 7% voxelwise) than the other variants (8-11%), resulting in lower ICCs. The median ICCs across six regions were 0.89 (interquartile range 0.75-0.90) for voxelwise SA, 0.71 (0.64-0.84) for regional SRTM-cerebellum and 0.83 (0.70-0.86) for voxelwise SRTM-cerebellum. The ICCs for the hippocampus were 0.89 for voxelwise SA, 0.95 for regional SRTM-cerebellum and 0.93 for voxelwise SRTM-cerebellum.ConclusionQuantification of [11C]Ro15-4513 binding shows very good to excellent reproducibility with SRTM and with voxelwise SA which, however, requires an arterial ppIF. Quantification in the α5 subunit-rich hippocampus is particularly reliable. The very low expression of the α5 in the cerebellum (Fritschy and Mohler, 1995; Veronese et al., 2016) and the substantial α1 subunit density in this region may hamper the application of reference tissue methods.

Project description:BackgroundType 1 diabetes (T1D) is an autoimmune disease characterized by a progressive β-cell destruction. There are no clinically established methods for quantifying endocrine cells of the pancreas and current knowledge is almost exclusively based on autopsy material and functional measurements. Based on the expression of the γ-aminobutyric acid A receptors (GABAARs) in pancreatic islets and the fact that GABAAR agonists are being explored as treatment for T1D, we hypothesized that the positron emission tomography (PET) tracer [11C]flumazenil ([11C]FMZ) could serve as a marker of the endocrine mass of the pancreas. The in vivo uptake of [11C]FMZ in pig pancreas was evaluated by PET/CT, either tracer alone or after blockade of GABAAR by unlabeled flumazenil. The pancreatic binding of [11C]FMZ was investigated in vitro with frozen sections of pig pancreas as well as human organ donors, in addition to isolated mouse and human islets and exocrine preparations. The expression of GABAAR subunits in pig, human and mouse pancreas was explored by immunohistochemistry.ResultsStrong specific in vivo uptake of [11C]FMZ was observed in the pig brain as expected, but in the pancreas the signal was moderate and only partially reduced by blockade. In vitro experiments revealed a positive but weak and variable binding of [11C]FMZ in islets compared to exocrine tissue in the mouse, pig and human pancreas. In pig and mouse pancreatic islets we identified the GABAAR subunits β2 and γ2 but not α2. In the human pancreas from non-diabetic donors, we have identified the α2, β2 (although weak) and γ2 subunits, whereas from a T2D donor the α2 subunit was missing.ConclusionsOur findings suggest that [11C]FMZ bind to GABAARs in the islets, but not with a sufficient contrast or magnitude to be implemented as an in vivo PET marker for the endocrine mass of the pancreas. However, GABAARs with different subunits are widely expressed in the endocrine cells within the pancreas in pig, human and mouse. Hence, the GABAAR could still be a potential imaging target for the endocrine cells of the pancreas but would require tracers with higher affinity and selectivity for individual GABAAR subunits.

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Region-specific and dose-specific effects of chronic haloperidol exposure on [³H]-flumazenil and [³H]-Ro15-4513 GABA_A receptor binding sites in the rat brain.

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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.

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Dataset Information

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.

Publications

Region-specific and dose-specific effects of chronic haloperidol exposure on [&lt;sup&gt;3&lt;/sup&gt;H]-flumazenil and [&lt;sup&gt;3&lt;/sup&gt;H]-Ro15-4513 GABA&lt;sub&gt;A&lt;/sub&gt; receptor binding sites in the rat brain.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Region-specific and dose-specific effects of chronic haloperidol exposure on [³H]-flumazenil and [³H]-Ro15-4513 GABA_A receptor binding sites in the rat brain.

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.