GABA(B) receptor modulators potentiate baclofen-induced depression of dopamine neuron activity in the rat ventral tegmental area

2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) is a recently reported positive allosteric modulator of gamma-aminobutyric acid (GABA)(B) receptors. In this study, we assessed the ability of CGP7930 to modulate the baclofen-induced depression of dopamine (DA) neuron activity via...

Full description

Saved in:
Bibliographic Details
Published in:British journal of pharmacology 2005-04, Vol.144 (7), p.926
Main Authors: Chen, Ying, Phillips, Keith, Minton, Gareth, Sher, Emanuele
Format: Article
Language:English
Subjects:
Animals
Baclofen - pharmacology
Dopamine - physiology
Dose-Response Relationship, Drug
Drug Synergism
GABA Modulators - pharmacology
In Vitro Techniques
Long-Term Synaptic Depression - drug effects
Long-Term Synaptic Depression - physiology
Male
Neurons - drug effects
Neurons - physiology
Rats
Rats, Sprague-Dawley
Receptors, GABA-B - physiology
Ventral Tegmental Area - drug effects
Ventral Tegmental Area - physiology
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) is a recently reported positive allosteric modulator of gamma-aminobutyric acid (GABA)(B) receptors. In this study, we assessed the ability of CGP7930 to modulate the baclofen-induced depression of dopamine (DA) neuron activity via the activation of GABA(B) receptors in the ventral tegmental area in rat midbrain slices. The selective GABA(B) receptor agonist, baclofen, depressed the spontaneous firing rate of DA neurons in a concentration-dependent manner (EC50 = 0.27 microM, n = 11). CGP7930 (30 microM) significantly (P < 0.05) shifted the baclofen concentration-response curve to the left (EC50 = 0.15 microM, n = 5). The effects of baclofen alone or baclofen coapplied with CGP7930 were fully blocked by 1 microM (2S)-3-[[(1S)-1-(3,4-dichloropheny)ethyl]amino-2-hydroxypropyl] (phenylmethyl) phosphinic acid (CGP55845), a potent and selective GABA(B) receptor antagonist. In similar experiments, N-[3,3-diphenylpropyl]-alpha-methylbenzylamine (fendiline) (30 or 50 microM), a compound shown to potentiate GABA(B) receptor-mediated cortical hyperpolarisation, also significantly enhanced the inhibitory effect of baclofen. It is therefore concluded that the recently reported GABA(B) receptor modulators, CGP7930 and fendiline, can enhance GABA(B) receptor-mediated depression of DA neuronal activity. This finding suggests a therapeutic potential for GABA(B) potentiators for the treatment of diseases associated with a hyperfunctional mesocorticolimbic system.
ISSN:0007-1188
DOI:10.1038/sj.bjp.0706100