L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for α5-containing GABAA receptors

Atack, John; Bayley, Peter J.; Seabrook, Guy R.; Wafford, Keith A.; McKernan, Ruth M.; Dawson, Gerard R.

doi:10.1016/j.neuropharm.2006.04.018

Cited by 170 publications

(155 citation statements)

References 33 publications

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“…Standard tests of locomotor activity were not usually employed in reported studies with α5 subunit-selective ligands (Atack et al, 2006a;Chambers et al, 2003;Collinson et al, 2006;Dawson et al, 2006). Based on the results with three novel BZ site agonists functionally silent at the α1 subunit, we recently set out the hypothesis that positive modulation at the GABA A receptors containing α5 subunits may contribute to sedative properties of BZ site agonists (Savić et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…It is notable that GABA A receptors containing the α5 subunit are abundantly expressed in the hippocampus (Pirker et al, 2000;Sieghart and Sperk, 2002), the structure substantially involved in memory formation (Izquierdo and Medina, 1997). Recent evidence from animal studies with affinity-selective (Atack et al, 2006a) or efficacy-selective ligands (Chambers et al, 2003;Dawson et al, 2006 has confirmed that the α 5 subunit was significantly involved in cognition enhancement mediated by the negative modulation of GABA A receptor functions. Moreover, it was shown in humans that pre-treatment with an α 5 efficacy-selective inverse agonist significantly reduces the amnesic effect of alcohol on learning a word list (Nutt et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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PWZ-029, a compound with moderate inverse agonist functional selectivity at GABAA receptors containing α5 subunits, improves passive, but not active, avoidance learning in rats

Savić¹,

Clayton²,

Furtmüller³

et al. 2008

Brain Research

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Benzodiazepine (BZ) site ligands affect vigilance, anxiety, memory processes, muscle tone and epileptogenic propensity through modulation of neurotransmission at GABA A receptors containing α 1 , α 2 , α 3 or α 5 subunits, and may have numerous experimental and clinical applications. The ability of nonselective BZ site inverse agonists to enhance cognition, documented in animal models and human studies, is clinically not feasible due to potentially unacceptable psychomotor effects. Most investigations to date have proposed the α 1 and/or α 5 subunit-containing GABA A receptors as comprising the memory-modulating population of these receptors. The novel ligand PWZ-029, which we synthesised and characterized electrophysiologically, possesses in vitro binding selectivity and moderate inverse agonist functional selectivity at α 5 -containing GABA A receptors. This ligand has also been examined in rats in the passive and active avoidance, spontaneous locomotor activity, elevated plus maze and grip strength tests, primarily predictive of the effects on the memory acquisition, basal locomotor activity, anxiety level and muscle tone, respectively. The improvement of task learning was detected at the dose of 5 mg/kg in the passive, but not active avoidance test. The inverse agonist PWZ-029 had no effect on anxiety or muscle tone, whereas at higher doses (10 and 20 mg/kg) it decreased locomotor activity. This effect was antagonized by flumazenil and also by the lower (but not the higher) dose of an agonist (SH-053-R-CH3-2'F) selective for GABA A receptors containing the α 5 subunit. The hypolocomotor effect of PWZ-029 was not antagonized by the

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PWZ-029, a compound with moderate inverse agonist functional selectivity at GABAA receptors containing α5 subunits, improves passive, but not active, avoidance learning in rats

Savić¹,

Clayton²,

Furtmüller³

et al. 2008

Brain Research

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“…An increase in tonic inhibition would increase the threshold of the input before the pyramidal cell would start firing, yet would maintain the sensitivity of the I-O relationship to a change in input. Consequently, the increased rate of spatial learning observed in animals in which CA1 pyramidal cell tonic inhibition is genetically or pharmacologically reduced (Collinson et al, 2002;Caraiscos et al, 2004;Atack et al, 2006;Dawson et al, 2006) may be at the expense of output saturation and so may result in paradoxical loss of input discrimination.…”

Section: Effects Of Rectification Of the Tonic Conductance On Noise Amentioning

confidence: 99%

“…Tonic conductances in the hippocampus modulate cognitive function: genetic deletion or pharmacological inhibition of ␣5 subunit-containing GABA A Rs, which contribute to tonic inhibition in CA1 pyramidal cells (Caraiscos et al, 2004;Scimemi et al, 2005;Prenosil et al, 2006;Glykys et al, 2008), improves spatial learning and memory (Collinson et al, 2002;Atack et al, 2006;Dawson et al, 2006). A possible mechanism linking tonically active GABA A Rs to cognition is the modulation of long-term potentiation (Cheng et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Outwardly Rectifying Tonically Active GABA_AReceptors in Pyramidal Cells Modulate Neuronal Offset, Not Gain

Pavlov

Savtchenko²,

Kullmann³

et al. 2009

J. Neurosci.

112

124

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Hippocampal pyramidal cell excitability is regulated both by fast synaptic inhibition and by tonically active high-affinity extrasynaptic GABA A receptors. The impact of tonic inhibition on neuronal gain and offset, and thus on information processing, is unclear. Offset is altered by shunting inhibition, and the gain of a neuronal response to an excitatory input can be modified by changing the level of "background" synaptic noise. Therefore, tonic activation of GABA A receptors would be expected to modulate offset and, in addition, to alter gain through a shunting effect on synaptic noise. Here we show that tonically active GABA A receptors in CA1 pyramidal cells show marked outward rectification, while the peaks of IPSCs exhibit a linear current-voltage relationship. As a result, tonic GABA A receptormediated currents have a minimal effect upon subthreshold membrane potential variation due to synaptic noise, but predominantly affect neurons at spiking threshold. Consistent with this, tonic GABA A receptor-mediated currents in pyramidal cells exclusively affect offset and not gain. Modulation of tonically active GABA A receptors by fluctuations in extracellular GABA concentrations or neuromodulators acting on high-affinity receptors potentially provides a powerful mechanism to alter neuronal offset independently of neuronal gain.

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“…3 Additional studies have shown that blocking tonic GABA A receptors improved learning and memory in mice, thereby suggesting a role for that subtype in brain plasticity. 4,5 Collectively, these findings led the UCLA team to hypothesize that signaling between GABA and tonic GABA A receptors plays a role in the brain's response to loss of motor function and thus might be targeted therapeutically to recover that function after stroke. The group's electrophysiological studies showed that wild-type mouse models of cortical stroke had higher levels of tonic Gaba A receptor activity than normal controls.…”

Section: By Michael J Haas Senior Writermentioning

confidence: 99%

GABAA: better late

Haas¹

2010

Science-Business eXchange

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L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for α5-containing GABAA receptors

Cited by 170 publications

References 33 publications

PWZ-029, a compound with moderate inverse agonist functional selectivity at GABAA receptors containing α5 subunits, improves passive, but not active, avoidance learning in rats

PWZ-029, a compound with moderate inverse agonist functional selectivity at GABAA receptors containing α5 subunits, improves passive, but not active, avoidance learning in rats

Outwardly Rectifying Tonically Active GABA_AReceptors in Pyramidal Cells Modulate Neuronal Offset, Not Gain

GABAA: better late

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L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for α5-containing GABAA receptors

Cited by 170 publications

References 33 publications

PWZ-029, a compound with moderate inverse agonist functional selectivity at GABAA receptors containing α5 subunits, improves passive, but not active, avoidance learning in rats

PWZ-029, a compound with moderate inverse agonist functional selectivity at GABAA receptors containing α5 subunits, improves passive, but not active, avoidance learning in rats

Outwardly Rectifying Tonically Active GABAAReceptors in Pyramidal Cells Modulate Neuronal Offset, Not Gain

GABAA: better late

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Outwardly Rectifying Tonically Active GABA_AReceptors in Pyramidal Cells Modulate Neuronal Offset, Not Gain