Effects of a Specific Benzodiazepine Antagonist (RO 15???1788) on Cerebral Blood Flow

Forster, A.; Juge, O; Louis, Martine A.; Nahory, A.

doi:10.1213/00000539-198704000-00003

Cited by 43 publications

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“…Studies in humans, using the xenon-inhalation technique (26)(27)(28), have demonstrated benzodiazepine-induced changes in rCBF, although this method lacks the spatial resolution of…”

Section: Discussionmentioning

confidence: 99%

Benzodiazepine receptors mediate regional blood flow changes in the living human brain.

Matthew

Andreason

Pettigrew

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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We studied the effects of a high-affinity 'y-aminobutyric acid (GABA)-benzodiazepine-receptor agonist (lorazepam) and an antagonist (flumazenil) in humans, using H2150 positron-emission tomography. Administration of lorazepam to healthy volunteers caused time-and dosedependent reductions in regional cerebral blood flow and self-reported alterations in behavioral/mood parameters. Flumazenil administration reversed these changes. These observations indicated that benzodiazepine-induced effects on regional cerebral blood flow and mood/behavior are mediated at some level through GABA-benzodiazepine receptors, although the specific mechanism remains unclear. The approach described here provides a method for quantifying GABA-benzodiazepine-receptor-mediated neurotransmission in the living human brain and may be useful for studying the role of these receptors in a variety of neuropsychiatric disorders.Benzodiazepines (diazepam and related compounds) have been widely used as antianxiety, sedative-hypnotic, anticonvulsant, and muscle-relaxant agents for over three decades. Their neural effects are mediated through specific receptors that modulate the effects of the major inhibitory neurotransmitter in brain, y-aminobutyric acid (GABA) (1-3). These benzodiazepine receptors are part of a heterooligomeric receptor complex composed of membrane-spanning polypeptide subunits that form intrinsic chloride ion channels (4) and contain distinct binding sites for GABA as well as a number of sedative-hypnotic drugs. When benzodiazepines interact with their receptors, GABA-mediated chloride ion conductance is potentiated, and the net result is enhancement of GABAmediated inhibitory synaptic events (5). While the binding of benzodiazepines to their receptors is clearly the initial step in the chain of events that culminates in the pharmacological actions of these drugs, little is known about the brain regions or neural circuits and neurotransmitters that may be involved in producing these effects.Changes in the activity of neurons in a given brain region, whether excitatory or inhibitory, result in altered regional cerebral blood flow (rCBF) and substrate utilization (6). We reasoned that, given the widespread distribution of GABAergic neurons and their corresponding receptors, it would be possible to observe changes in rCBF by increasing or decreasing GABA-mediated inhibitory events. The structural association between benzodiazepine receptors and the GABA receptor itself, coupled with the relative safety of benzodiazepines, suggested an alternative way of studying GABAergic neurotransmission. In fact, previous work indicates that administration of benzodiazepines is associated with decreases in rCBF (7, 8) and glucose utilization (9, 10), similar to the reported effects of GABA or GABA-receptor agonists in laboratory animals (11,12).Benzodiazepine receptors have been implicated in a number of neuropsychiatric disorders, including anxiety and panic disorder (11) and epilepsy (12). Their pathophysiologic role, however, remains ...

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“…Studies in humans, using the xenon-inhalation technique (26)(27)(28), have demonstrated benzodiazepine-induced changes in rCBF, although this method lacks the spatial resolution of…”

Section: Discussionmentioning

confidence: 99%

Benzodiazepine receptors mediate regional blood flow changes in the living human brain.

Matthew

Andreason

Pettigrew

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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“…14,15 However, the antagonistic effects on CBF of flumazenil administered after midazolam are controversial. 3,4 As mentioned in the introduction, this discrepancy between previous studies may be explained by the differences in the level of sedation/awareness and/or the sequence of administration of the 2 drugs. Therefore, the present study investigated the changes in steady-state MCBFV after midazolam sedation followed by flumazenil administration, with assessment of sedation/awareness levels.…”

Section: Discussionmentioning

confidence: 92%

“…However, the antagonistic effects of flumazenil administered after midazolam on CBF are controversial. 3,4 A previous study reported that flumazenil administration following midazolam anesthesia with fentanyl and nitrous oxide did not antagonize reductions in CBF, 4 whereas another report states that simultaneous administration of flumazenil and midazolam antagonized the midazolam-induced reductions in CBF. 3 Several factors, such as the level of awareness, subsequent resedation due to midazolam, influence of other drugs, and/or the sequence of midazolam and flumazenil administrations, could have led to these discrepancies in the changes in CBF.…”

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confidence: 99%

“…3,4 A previous study reported that flumazenil administration following midazolam anesthesia with fentanyl and nitrous oxide did not antagonize reductions in CBF, 4 whereas another report states that simultaneous administration of flumazenil and midazolam antagonized the midazolam-induced reductions in CBF. 3 Several factors, such as the level of awareness, subsequent resedation due to midazolam, influence of other drugs, and/or the sequence of midazolam and flumazenil administrations, could have led to these discrepancies in the changes in CBF. 3,4 Moreover, our previous study showed that midazolam sedation alters dynamic cerebral autoregulation, which reflects responses of CBF to rapid changes in cerebral perfusion pressure.…”

mentioning

confidence: 99%

“…3 Several factors, such as the level of awareness, subsequent resedation due to midazolam, influence of other drugs, and/or the sequence of midazolam and flumazenil administrations, could have led to these discrepancies in the changes in CBF. 3,4 Moreover, our previous study showed that midazolam sedation alters dynamic cerebral autoregulation, which reflects responses of CBF to rapid changes in cerebral perfusion pressure. 5 However, it remains unclear whether flumazenil antagonizes the alteration in dynamic cerebral autoregulation induced by midazolam.…”

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confidence: 99%

See 2 more Smart Citations

The Effects of Flumazenil After Midazolam Sedation on Cerebral Blood Flow and Dynamic Cerebral Autoregulation in Healthy Young Males

Ogawa¹,

Iwasaki²,

Aoki³

et al. 2015

Journal of Neurosurgical Anesthesiology

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Midazolams Cardiac Depressant Effects and Their Lack of Reversal by Flumazenil in Isolated Rabbit Hearts

Öztürk¹,

Tunçok

Kalkan

et al. 1999

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Effects of a Specific Benzodiazepine Antagonist (RO 15???1788) on Cerebral Blood Flow

Cited by 43 publications

References 0 publications

Benzodiazepine receptors mediate regional blood flow changes in the living human brain.

Benzodiazepine receptors mediate regional blood flow changes in the living human brain.

The Effects of Flumazenil After Midazolam Sedation on Cerebral Blood Flow and Dynamic Cerebral Autoregulation in Healthy Young Males

Midazolams Cardiac Depressant Effects and Their Lack of Reversal by Flumazenil in Isolated Rabbit Hearts

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