Evidence for a significant role of α3-containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines

被引：199

作者：

Dias, R ^{[1
]}

Sheppard, WFA ^{[1
]}

Fradley, RL ^{[1
]}

Garrett, EM ^{[1
]}

Stanley, JL ^{[1
]}

Tye, SJ ^{[1
]}

Goodacre, S ^{[1
]}

Lincoln, RJ ^{[1
]}

Cook, SM ^{[1
]}

Conley, R ^{[1
]}

Hallett, D ^{[1
]}

Humphries, AC ^{[1
]}

Thompson, SA ^{[1
]}

Wafford, KA ^{[1
]}

Street, LJ ^{[1
]}

Castro, JL ^{[1
]}

Whiting, PJ ^{[1
]}

Rosahl, TW ^{[1
]}

Atack, JR ^{[1
]}

McKernan, RM ^{[1
]}

Dawson, GR ^{[1
]}

Reynolds, DS ^{[1
]}

机构：

[1] Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Harlow CM20 2QR, Essex, England

来源：

JOURNAL OF NEUROSCIENCE | 2005年 / 25卷 / 46期

关键词：

GABA(A); benzodiazepine; anxiety; alpha; 3; subunit; agonist; stress-induced hyperthermia;

D O I：

10.1523/JNEUROSCI.1166-05.2005

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

The GABA(A) receptor subtypes responsible for the anxiolytic effects of nonselective benzodiazepines (BZs) such as chlordiazepoxide (CDP) and diazepam remain controversial. Hence, molecular genetic data suggest that alpha 2-rather than alpha 3-containing GABAA receptors are responsible for the anxiolytic effects of diazepam, whereas the anxiogenic effects of an alpha 3-selective inverse agonist suggest that an agonist selective for this subtype should be anxiolytic. We have extended this latter pharmacological approach to identify a compound, 4,2'- difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyridin-3-yl] biphenyl-2-carbonitrile (TP003), that is an alpha 3 subtype selective agonist that produced a robust anxiolytic-like effect in both rodent and non-human primate behavioral models of anxiety. Moreover, in mice containing a point mutation that renders alpha 2-containing receptors BZ insensitive (alpha 2H101R mice), TP003 as well as the nonselective agonist CDP retained efficacy in a stress-induced hyperthermia model. Together, these data show that potentiation of alpha 3-containing GABAA receptors is sufficient to produce the anxiolytic effects of BZs and that alpha 2 potentiation may not be necessary.

引用

页码：10682 / 10688

页数：7

共 33 条

[1] The benzodiazepine binding site of GABAA receptors as a target for the development of novel anxiolytics [J].

Atack, JR .

EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2005, 14 (05) :601-618

[2] Anxiogenic properties of an inverse agonist selective for α3 subunit-containing GABAA receptors [J].

Atack, JR ;

Hutson, PH ;

Collinson, N ;

Marshall, G ;

Bentley, G ;

Moyes, C ;

Cook, SM ;

Collins, I ;

Wafford, K ;

McKernan, RM ;

Dawson, GR .

BRITISH JOURNAL OF PHARMACOLOGY, 2005, 144 (03) :357-366

[3] Regional differences in the inhibition of mouse in vivo [3H]Ro 15-1788 binding reflect selectivity for α1 versus α2 and α3 subunit-containing GABAA receptors [J].

Atack, JR ;

Smith, AJ ;

Emms, F ;

McKernan, RM .

NEUROPSYCHOPHARMACOLOGY, 1999, 20 (03) :255-262

[4] Pharmacological characterization of a novel cell line expressing human α4β3δ GABAA receptors [J].

Brown, N ;

Kerby, J ;

Bonnert, TP ;

Whiting, PJ ;

Wafford, KA .

BRITISH JOURNAL OF PHARMACOLOGY, 2002, 136 (07) :965-974

[5]

Collinson N, 2002, J NEUROSCI, V22, P5572

[6] Anxiolytic-like action of diazepam:: mediated by GABAA receptors containing the α2 subunit -: Response from Crestani et al [J].

Crestani, F ;

Möhler, H ;

Rudolph, U .

TRENDS IN PHARMACOLOGICAL SCIENCES, 2001, 22 (08) :403-403

[7] Trace fear conditioning involves hippocampal α5 GABAA receptors [J].

Crestani, F ;

Keist, R ;

Fritschy, JM ;

Benke, D ;

Vogt, K ;

Prut, L ;

Blüthmann, H ;

Möhler, H ;

Rudolph, U .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (13) :8980-8985

[8]

Davis M., 2000, The Amygdala, V2, P213, DOI 10.1146/annurev.ne.15.030192.002033

[9]

FACKLAM M, 1992, J PHARMACOL EXP THER, V261, P1113

[10] The neuroanatomical and neurochemical basis of conditioned fear [J].

Fendt, M ;

Fanselow, MS .

NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS, 1999, 23 (05) :743-760

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