Electrophysiologic Analysis of Antidepressant Drug Effects on the GABA&lt;sub&gt;A&lt;/sub&gt; Receptor Complex Based upon Antagonist-Induced Encephalographic Power Spectrum Changes

Matsubara, Momoyo; Suzuki, Sigeru; Miura, Kazuya; Terashima, Minoru; Sugita, Sotaro; Kimura, Hitoshi; Hatsuda, Satoshi; Mori, Takao; Murakami, Hirosuke; Hayashi, Takuji; Ohta, Tatsuro; O’Hara, Maureen

doi:10.1159/000026685

Cited by 10 publications

(6 citation statements)

References 26 publications

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“…56,57 Recent studies in rats that examined the effects of antidepressants on GABA A receptors based on antagonist-induced EEG power spectrum changes suggest that imipramine may enhance the function of the GABA A receptor complex. 58 It is thus likely that some of the EEG effects of imipramine may be related to its GABA-ergic effects. Whether such properties are shared by amitriptyline as well remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Relative Contribution of CYP3A to Amitriptyline Clearance in Humans: In Vitro and In Vivo Studies

Venkatakrishnan

Schmider

Harmatz

et al. 2001

The Journal of Clinical Pharma

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The relative contribution of cytochrome P450 3A (CYP3A) to the oral clearance of amitriptyline in humans has been assessed using a combination of in vitro approaches together with a clinical pharmacokinetic interaction study using the CYP3A-selective inhibitor ketoconazole. Lymphoblast-expressed CYPs were used to study amitriptyline N-demethylation and E-10 hydroxylation in vitro. The relative activity factor (RAF) approach was used to predict the relative contribution of each CYP isoform to the net hepatic intrinsic clearance (sum of N-demethylation and E-10 hydroxylation). Assuming no extrahepatic metabolism, the model-predicted contribution of CYP3A to net intrinsic clearance should equal the fractional decrement in apparent oral clearance of amitriptyline upon complete inhibition of the enzyme. This hypothesis was tested in a clinical study of amitriptyline (50 mg, p.o.) with ketoconazole (three 200 mg doses spaced 12 hours apart) in 8 healthy volunteers. The RAF approach predicted CYP2C19 to be the dominant contributor (34%), with a mean 21% contribution of CYP3A (range: 8%-42% in a panel of 12 human livers). The mean apparent oral clearance of amitriptyline in 8 human volunteers was decreased from 2791 ml/min in the control condition to 2069 ml/min with ketoconazole. The average 21% decrement (range: 2%-40%) was identical to the mean value predicted in vitro using the RAF approach. The central nervous system (CNS) sedative effects of amitriptyline were slightly greater when ketoconazole was coadministered, but the differences were not statistically significant. In conclusion, CYP3A plays a relatively minor role in amitriptyline clearance in vivo, which is consistent with in vitro predictions using the RAF approach.

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Section: Discussionmentioning

confidence: 99%

Relative Contribution of CYP3A to Amitriptyline Clearance in Humans: In Vitro and In Vivo Studies

Venkatakrishnan

Schmider

Harmatz

et al. 2001

The Journal of Clinical Pharma

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“…Increased GABA synthesis in amygdala, hippocampus, lateral septum after selective NE reuptake inhibitors [Herman et al, 2003]. Reduced pentylenetetrazoleactivated hippocampal electroencephalogram power in rats after AD treatment [Matsubara et al, 2000]. Recovery from depression increases plasma level of GABA-active steroid agonists allopregnanolone and pregnanolone but decreases concentration of steroid antagonist 3b-hydroxy5a-pregnan-20-one [Rupprecht, 2003].…”

Section: Historical Background and Recent Findingsmentioning

confidence: 99%

Role of GABA in anxiety and depression

2007

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This review assesses the parallel data on the role of gamma-aminobutyric acid (GABA) in depression and anxiety. We review historical and new data from both animal and human experimentation which have helped define the key role for this transmitter in both these mental pathologies. By exploring the overlap in these conditions in terms of GABAergic neurochemistry, neurogenetics, brain circuitry, and pharmacology, we develop a theory that the two conditions are intrinsically interrelated. The role of GABAergic agents in demonstrating this interrelationship and in pointing the way to future research is discussed.

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“…The pharmacological properties of GABARs are determined in large part by their subunit composition (Korpi et al, 2002). Previous studies have suggested both positive and negative regulation of GABAR activity by fluoxetine (Tunnicliff et al, 1999;Matsubara et al, 2000). However, there is little current evidence of a direct effect on the GABAR by fluoxetine or of the possible role of GABAR subunit composition in this modulation.…”

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confidence: 99%

Fluoxetine Increases GABA_AReceptor Activity through a Novel Modulatory Site

Robinson

Drafts²,

Fisher

2002

J Pharmacol Exp Ther

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Fluoxetine is a selective serotonin reuptake inhibitor used widely in the treatment of depression. In contrast to the proconvulsant effect of many antidepressants, fluoxetine has anticonvulsant activity. This property may be due in part to positive modulation of the GABA A receptors (GABARs), which mediate most fast inhibitory neurotransmission in the mammalian brain. We examined the effect of fluoxetine on the activity of recombinant GABARs transiently expressed in mammalian cells. Fluoxetine increased the response of the receptor to submaximal GABA concentrations but did not alter the maximum current amplitude. Sensitivity did not depend upon the ␤-or ␥-subtype composition of the receptor when coexpressed with the ␣ 1 subunit. Among the six ␣ subtypes, only the ␣ 5 subunit conferred reduced sensitivity to fluoxetine. The metabolite norfluoxetine was even more potent than fluoxetine. Mutations at residues in the ␣ 5 subunit that alter its sensitivity to zinc or selective benzodiazepine derivatives did not affect potentiation by fluoxetine. This suggests that fluoxetine acts through a novel modulatory site on the GABAR. The direct positive modulation of GABARs by fluoxetine may be a factor in its anticonvulsant activity.

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Electrophysiologic Analysis of Antidepressant Drug Effects on the GABA<sub>A</sub> Receptor Complex Based upon Antagonist-Induced Encephalographic Power Spectrum Changes

Cited by 10 publications

References 26 publications

Relative Contribution of CYP3A to Amitriptyline Clearance in Humans: In Vitro and In Vivo Studies

Relative Contribution of CYP3A to Amitriptyline Clearance in Humans: In Vitro and In Vivo Studies

Role of GABA in anxiety and depression

Fluoxetine Increases GABA_AReceptor Activity through a Novel Modulatory Site

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Electrophysiologic Analysis of Antidepressant Drug Effects on the GABA<sub>A</sub> Receptor Complex Based upon Antagonist-Induced Encephalographic Power Spectrum Changes

Cited by 10 publications

References 26 publications

Relative Contribution of CYP3A to Amitriptyline Clearance in Humans: In Vitro and In Vivo Studies

Relative Contribution of CYP3A to Amitriptyline Clearance in Humans: In Vitro and In Vivo Studies

Role of GABA in anxiety and depression

Fluoxetine Increases GABAAReceptor Activity through a Novel Modulatory Site

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Product

Resources

About

Fluoxetine Increases GABA_AReceptor Activity through a Novel Modulatory Site