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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 |

REPOSITORIES: biostudies-literature

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Project description:IntroductionAlteration of ?-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 ?5-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 ?5 subunit-rich hippocampus is particularly reliable. The very low expression of the ?5 in the cerebellum (Fritschy and Mohler, 1995; Veronese et al., 2016) and the substantial ?1 subunit density in this region may hamper the application of reference tissue methods.

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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 [3H]-flumazenil and [3H]-Ro15-4513 GABAA receptor binding sites in the rat brain.

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OmicsDI is part of the ELIXIR infrastructure

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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.