Electrophysiological characterization of potent agonists and antagonists at pre‐ and postsynaptic GABA_B receptors on neurones in rat brain slices

Abstract

1 Intracellular recordings were made from neurones in striatum (caudate-putamen) and substantia nigra pars compacta in rat brain slices. Three GABAB agonists, baclofen, 3-aminopropylphosphinic acid (3-APPA) and 3-aminopropyl(methyl) 3-APHPA and phaclofen with estimated equilibrium dissociation constants (KB) of 11.2 + 1.7#UM (n = 4), 13.3 + 0.4,M (n = 3), and 405 + 43,pM (n = 3) respectively. CGP 35348 and 3-APHPA appeared to act competitively (Schild plot slopes of 0.99 and 1.01 respectively). 4 Nigral neurones were hyperpolarized by up to 25mV by SK&F 97541 and baclofen with EC50s of 0.15#UM and 3.6#M respectively. The maximum hyperpolarization by 3-APPA was only 84% that of the other agonists, with an EC50 of 9.0,gM. Agonist concentration-effect data fitted a single-site logistic model. 5 The SK&F 97541-induced hyperpolarization was reversibly antagonized by CGP 35348, 3-APHPA and phaclofen with estimated KBS of 17.6 + 4.4 (n = 3), 14.0 + 1.5 (n = 4), and >400 gM (n = 1) respectively. CGP 35348 appeared competitive (Schild plot slope of 0.99). Antagonists were also tested with baclofen as agonist, yielding similar KB estimates as for SK&F 97541. 6 It is concluded that at both the presynaptic and postsynaptic sites examined, SK&F 97541 was about 10 fold more potent than baclofen or 3-APPA. The antagonists CGP 35348 and 3-APHPA (KB 1O-20gM) were about 20 fold more potent than phaclofen. The similarities in relative agonist potency and estimated antagonist affinity between these two functionally distinct GABAB receptors renders them pharmacologically indistinguishable at present.

The effect of centrally acting myorelaxants on NMDA receptor‐mediated synaptic transmission in the immature rat spinal cord in vitro

“…The apparent Kd of 10.6 pM reported here for the GABAB antagonist, CGP35348, in reversing the action of baclofen is not significantly different from the value of 11.2 gM for depression of e.p.s.ps of striatal neurones (Seabrook et al, 1990).…”

Cataleptic effects of γ-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABAB receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists

“…There is evidence for functional GABA B receptor subtypes (Seabrook et al 1990;Bonanno and Raiteri 1992;Lanza et al 1993;Fassio et al 1994;Yamada et al 1999). Conceivably, differential activity of GHB and baclofen at GABA B autoreceptors and heteroreceptors could account for the differential ability of CGP35348 to antagonize GHB and baclofen.…”

Different roles for GABAA and GABAB receptors in visual processing in the rat superior colliculus

“…Effects of GABAA and GABAB agonists and antagonists on SGS visual responses Both GABA and the GABAB agonist baclofen (Seabrook, Howson & Lacey, 1990) reduced the visual responses of SGS neurones. GABA was most effective when ejected for short (4-6 s) periods just prior to and during stimulus presentation, and reduced the visual response to 44 ± 5 % (n = 14) of the control within the same cycle.…”