Differential modulation by the GABAB receptor allosteric potentiator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)-phenol (CGP7930) of synaptic transmission in the rat hippocampal CA1 area.
The recently discovered GABAB receptor-positive allosteric modulators enhanced the potency and efficacy of GABAB receptor agonists in in vitro experiments. These GABAB modulators also attenuated reward and anxiety in behavioral experiments without causing the untoward side effects associated with GABAB receptor activation by agonist administration and hence exhibited potential therapeutic utility. However, the underlying molecular mechanisms enabling the GABAB allosteric modulators to dissociate from the GABAB agonistic side effects remain elusive. To address this question, we have examined the effects of a typical GABAB modulator, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)-phenol (CGP7930), on GABAB receptor-mediated modulations of both the excitatory and the delayed inhibitory components of hippocampal CA1 synaptic transmission. Using baclofen as an agonist and a multielectrode recording system, we recorded GABAB receptor-mediated modulations of both the field excitatory postsynaptic potentials and the population spikes simultaneously, as well as the paired-pulse inhibition of the population spike. We found that CGP7930 selectively enhanced the baclofen-induced modulation of synaptic inhibition without having any significant effects on the synaptic excitation. Our experiments have therefore revealed a pathway-selective differential modulation of synaptic transmission by CGP7930. This finding provides a synaptic mechanism to support the hypothesis that GABAB potentiators may be a better therapeutic alternative than GABAB agonists for central nervous system disorders.
Chen
Ying
Y
School of Biomedical and Molecular Sciences, University of Surrey, Guildford, UK GU2 7XH. ying.chen@surrey.ac.uk
Menendez-Roche
Nicole
N
Sher
Emanuele
E
D000200:Action Potentials / Q000187:drug effects; D000494:Allosteric Regulation; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*
C438607:2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol; D018757:GABA Modulators; D010636:Phenols; D018080:Receptors, GABA-B; D001418:Baclofen