No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia

Abi‐Dargham, Anissa; Laruelle, Marc; Krystal, John H.; D’Souza, Cyril; Zoghbi, Sami S.; Baldwin, Ronald M.; Seibyl, John; Mawlawi, Osama; Erasquin, Gabriel de; Charney, Dennis S.; Innis, Robert B.

doi:10.1016/s0893-133x(98)00107-9

Cited by 53 publications

(21 citation statements)

References 45 publications

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“…A three-dimensional affine transformation, similar to that used for spatial normalization in SPM, has been applied successfully to perfusion SPECT images of healthy subjects (34), and SPM has been applied to a BZR SPECT study comparing schizophrenic patients with controls (35). However, given the fact that some of the epileptogenic foci may have consisted of small anatomic lesions in our patient group, there may have been slight inaccuracies with spatial normalization of the SPECT images.…”

Section: Discussionmentioning

confidence: 99%

Effects of Vigabatrin on the GABAergic System as Determined by [¹²³I]Iomazenil SPECT and GABA MRS

et al. 1999

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Summary:Purpose: To evaluate effects of vigabatrin (VGB) by using [1231)iomazenil single-photon emission computed tomography (SPECT) to estimate central y-aminobutyric acid (GABA,)/benzodiazepine receptors (BZRs), and magnetic resonance spectroscopy (MRS) to assess tissue GABA levels.Methods: Six patients with partial seizures had both SPECT and MRS before and 25-84 days after starting VGB (3 g P.o., q.d.). SPECT was acquired by using the constant-infusion method and, after nonuniform attenuation correction, coregistered with T,-weighted MR Imaging (MRI) A volume of interest (VOI) of 3 x 2 x 2 cc over the occipital cortex, used for MRS acquisition, was positioned on both MRI and coregistered SPECT. Occipital activity was divided by either total plasma activity or plasma [1231]iomazenil concentration to estimate BZR distribution volume (V,-p and Vk, respectively). Wilcoxon's test was used for VOI differences in GABA levels, BZR V,-p or V;. SPM96 (either no global normalization or proportional scaling) was used to compare BZR V,-p changes in the patients with and without VGB with test-retest data in eight healthy age-matched controls.Results: Occipital GABA levels were increased threefold (without VGB, 1.1 -t 0.1 pmol/g; with VGB, 2.9 & 0.5 pmol/g; p = 0.027). BZR distribution volumes showed no change, when estimated by either V,-p (without VGB, 6.00 2 0.91 mllg; with VGB, 5.86 k 0.44 ml/g; p = 0.92) or V; (without VGB, 41.1 2 11.2 ml/g; with VGB, 41.2 _t 9.9 ml/g; p = 0.75). No significant changes were detected by SPM96.Conclusions: A clinically effective dose of VGB caused a threefold increase in tissue GABA levels but was not associated with a substantial BZR downregulation. Key Words: Vigabatrin-Benzodiazepine receptor-SPECT-GAB A-MRS .y-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in human cerebral cortex. Animal models show that GABA plays a pivotal role in suppressing the origin and spread of seizure activity. The antiepileptic drug (AED) vigabatrin (VGB; y-vinyl GABA, or 4-amino-hex-5-enoic acid) irreversibly inhibits GABA transaminase, preferentially in neurons but also in astrocytes, markedly increasing GABA concentrations in vitro and in vivo (1). VGB may in addition compete with GABA for the neuronal GABA transporter (2). A previous study using 'H nuclear magnetic resonance spectroscopy (MRS) showed a twofold elevation of occipital cor- (3). The vast majority of tissue GABA measured by MRS is intracellular. Nevertheless, the increased tissue GABA levels induced by VGB probably also reflect the extracellular pool of GABA, which interacts with and may modulate GABA*ibenzodiazepine receptors (BZR) levels. That is, lumbar cerebrospinal fluid (CSF) GABA concentrations also are increased threefold with daily VGB therapy, and the increased CSF GABA concentrations correlate with improved seizure control (4)(5)(6)(7)(8). Therefore the increase in GABA levels appears to be critical to the efficacy of VGB .Alterations in BZR may modulate the effect of increased GABA levels. For example, incr...

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Section: Discussionmentioning

confidence: 99%

Effects of Vigabatrin on the GABAergic System as Determined by [¹²³I]Iomazenil SPECT and GABA MRS

et al. 1999

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“…SPECT studies with [ 123 I]iomazenil reported no group differences in comparison with control subjects (Abi-Dargham et al, 1999; Ball et al, 1998; Busatto et al, 1997; Verhoeff et al, 1999), as did a PET study with [ 11 C]Ro15-4513 (Asai et al, 2008). One group found that medial frontal cortex binding was positively associated with total symptoms, but negatively associated with outcome measures across the brain after displacement of the ligand following a diazepam infusion (Schroder et al, 1997).…”

Section: 0 In Vivo Measurement Of Gaba and Gabarsmentioning

confidence: 94%

“…One group found that medial frontal cortex binding was positively associated with total symptoms, but negatively associated with outcome measures across the brain after displacement of the ligand following a diazepam infusion (Schroder et al, 1997). While other groups also found symptom correlations with binding (Ball et al, 1998; Busatto et al, 1997), another group failed to replicate these symptom correlations using a quantitative measurement of binding not sensitive to cerebral blood flow (Abi-Dargham et al, 1999). Considering what is now known from the post-mortem findings, these essentially negative findings should not be too surprising.…”

Section: 0 In Vivo Measurement Of Gaba and Gabarsmentioning

confidence: 98%

GABA abnormalities in schizophrenia: A methodological review of in vivo studies

Taylor

Tso

2015

Schizophrenia Research

104

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Abnormalities of GABAergic interneurons are some of the most consistent findings from post-mortem studies of schizophrenia. However, linking these molecular deficits with in vivo observations in patients – a critical goal in order to evaluate interventions that would target GABAergic deficits – presents a challenge. Explanatory models have been developed based on animal work and the emerging experimental literature in schizophrenia patients. This literature includes: neuroimaging ligands to GABA receptors, magnetic resonance spectroscopy (MRS) of GABA concentration, transcranial magnetic stimulation of cortical inhibitory circuits and pharmacologic probes of GABA receptors to dynamically challenge the GABA system, usually in combination with neuroimaging studies. Pharmacologic challenges have elicited behavioral changes, and preliminary studies of therapeutic GABAergic interventions have been conducted. This article critically reviews the evidence for GABAergic dysfunction from each of these areas. These methods remain indirect measures of GABAergic function, and a broad array of dysfunction is linked with the putative GABAergic measures, including positive symptoms, cognition, emotion, motor processing and sensory processing, covering diverse brain areas. Measures of receptor binding have not shown replicable group differences in binding, and MRS assays of GABA concentration have yielded equivocal evidence of large-scale alteration in GABA concentration. Overall, the experimental base remains sparse, and much remains to be learned about the role of GABAergic interneurons in healthy brains. Challenges with pharmacologic and functional probes show promise, and may yet enable a better characterization of GABAergic deficits in schizophrenia.

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“…Consistent with these postmortem findings, pairedpulse transcranial magnetic stimulation has revealed reduced cortical inhibition (Daskalakis et al, 2002). However, functional imaging studies using ligands for the benzodiazepine receptor (Abi-Dargham et al, 1999) have failed to show altered GABAR densities, whereas magnetic resonance spectroscopy studies of GABA concentrations have reported mixed results (Kegeles et al, 2012;Yoon et al, 2010). Thus, the functional significance of GABA alterations remains to be elucidated.…”

Section: Introductionmentioning

confidence: 91%

Abnormal GABAergic Function and Negative Affect in Schizophrenia

Taylor

Demeter

Phan

et al. 2013

Neuropsychopharmacol

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Deficits in the g-aminobutyric acid (GABA) system have been reported in postmortem studies of schizophrenia, and therapeutic interventions in schizophrenia often involve potentiation of GABA receptors (GABAR) to augment antipsychotic therapy and treat negative affect such as anxiety. To map GABAergic mechanisms associated with processing affect, we used a benzodiazepine challenge while subjects viewed salient visual stimuli. Fourteen stable, medicated schizophrenia/schizoaffective patients and 13 healthy comparison subjects underwent functional magnetic resonance imaging using the blood oxygenation level-dependent (BOLD) technique while they viewed salient emotional images. Subjects received intravenous lorazepam (LRZ; 0.01 mg/kg) or saline in a single-blinded, cross-over design (two sessions separated by 1-3 weeks). A predicted group by drug interaction was noted in the dorsal medial prefrontal cortex (dmPFC) as well as right superior frontal gyrus and left and right occipital regions, such that psychosis patients showed an increased BOLD signal to LRZ challenge, rather than the decreased signal exhibited by the comparison group. A main effect of reduced BOLD signal in bilateral occipital areas was noted across groups. Consistent with the role of the dmPFC in processing emotion, state negative affect positively correlated with the response to the LRZ challenge in the dmPFC for the patients and comparison subjects. The altered response to LRZ challenge is consistent with altered inhibition predicted by postmortem findings of altered GABAR in schizophrenia. These results also suggest that negative affect in schizophrenia/schizoaffective disorder is associated-directly or indirectly-with GABAergic function on a continuum with normal behavior.

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No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia

Abstract: Deficits in gamma-amino-butyric acid (GABA) neurotransmitter systems have been implicated in the

Cited by 53 publications

References 45 publications

Effects of Vigabatrin on the GABAergic System as Determined by [¹²³I]Iomazenil SPECT and GABA MRS

Effects of Vigabatrin on the GABAergic System as Determined by [¹²³I]Iomazenil SPECT and GABA MRS

GABA abnormalities in schizophrenia: A methodological review of in vivo studies

Abnormal GABAergic Function and Negative Affect in Schizophrenia

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No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia

Abstract: Deficits in gamma-amino-butyric acid (GABA) neurotransmitter systems have been implicated in the

Cited by 53 publications

References 45 publications

Effects of Vigabatrin on the GABAergic System as Determined by [123I]Iomazenil SPECT and GABA MRS

Effects of Vigabatrin on the GABAergic System as Determined by [123I]Iomazenil SPECT and GABA MRS

GABA abnormalities in schizophrenia: A methodological review of in vivo studies

Abnormal GABAergic Function and Negative Affect in Schizophrenia

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Product

Resources

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Effects of Vigabatrin on the GABAergic System as Determined by [¹²³I]Iomazenil SPECT and GABA MRS

Effects of Vigabatrin on the GABAergic System as Determined by [¹²³I]Iomazenil SPECT and GABA MRS