Rapid communicationPhaclofen: a GABAB blocker reduces long-duration inhibition in the neocortex
References (3)
- D.I.B. Kerr et al.
Phaclofen: a peripheral and central baclofen antagonist
Brain Res.
(1987)
Cited by (43)
Phaclofen
2007, xPharm: The Comprehensive Pharmacology ReferencePhaclofen, a phosphonic acid analog of baclofen, is a selective, low-affinity (high μM), GABAB receptor antagonist. As one of the first antagonists for this site, phaclofen has been employed extensively for defining the physiological and pharmacological characteristics of this receptor system. In particular, it has been used widely for examining the electrophysiological properties of GABAB receptors and for in vitro studies. Its use as a research tool has diminished somewhat with the advent of higher affinity GABAB receptor antagonists, such as CGP 55845 and related phosphinic acid derivatives.
GABAergic characteristics of transcallosal activity of cat motor cortical neurons
1996, Neuroscience ResearchGABAergic characteristics of transcallosal activity of cat pyramidal tract neurons (PTNs) and non-PTNs (nPTNs) were studied with stressing on GABA, receptors. PTNs and nPTNs were further classified into group 1 ( < 10 ms) and group 2 ( > 10 ms) based on the latency upon transcallosal stimulation. However, mainly the results of group 1 neurons were presented here, due to the small number of group 2 neurons. GABA, bicuculline, CGP 35348 and phaclofen were iontophoretically applied. The spike number to 20 trials of transcallosal stimulation was 8.9 ± 4.3 (mean ± S.D.) for group 1 PTNs (n = 14) and 10.4 ± 4.5 for group 1 nPTNs (n = 38) under the control conditions. CGP 35348, phaclofen and bicuculline significantly increased the spike numbers in both cases. The increase was greater for nPTNs than for PTNs. GABA decreased them. The transcallosal latency was 3.9 ± 1.1 ms for PTNs under the control conditions. CGP 35348, phaclofen and bicuculline significantly shortened the latency, and GABA elongated it. The transcallosal latency for nPTNs under the control conditions was 2.7 ± 1.2 ms. This was significantly shortened by application of CGP 35348, phaclofen or bicuculline. GABA restored it. In conclusion, CGP 35348, phaclofen and bicuculline increased spike discharge and shortened the latency upon transcallosal stimulation for both group 1 PTNs and nPTNs.
The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism
1996, European Journal of PharmacologyThe present in vivo microdialysis study demonstrated that the subcutaneous injection of modafinil (diphenyl-methyl-sulfinyl-2-acetamide) in doses of 30–300 mg/kg dose dependently increased dopamine release from the intermediate level of the nucleus accumbens along the rostro-caudal axis of the halothane anaesthetized rat. The effect of modafinil in a dose of 100 mg/kg was counteracted by the local perfusion in the nucleus accumbens with the GABAB receptor antagonist phaclofen (β-p-chlorophenyl-γ-aminopropyl-phosphonic acid) (50 μM), the GABAA agonist muscimol (3-hydroxy-5-aminomethyl-isoxazolol) (10 μM) and the neuronal GABA reuptake inhibitor SKF89976A (4,4-diphenyl-3-butenyl-nipecotic acid) (0.1 μM), whereas it was increased by the GABAB receptor agonist (−)-baclofen [β-(p-chlorophenyl-γ-aminobutyric acid)] (10 μM). In addition, the modafinil-induced increase of dopamine release was associated with a significant reduction of accumbens GABA release. These results suggest that the dopamine releasing action of modafinil in the rat nucleus accumbens is secondary to its ability to reduce local GABAergic transmission, which leads to a reduction of GABAA receptor signaling on the dopamine terminals.
A physiological role for GABA<inf>B</inf> receptors and the effects of baclofen in the mammalian central nervous system
1995, Progress in NeurobiologyThe inhibitory neurotransmitter GABA acts in the mammalian brain through two different receptor classes: GABAA and GABAB receptors. GABAB receptors differ fundamentally from GABAA receptors in that they require a G-protein. GABAB receptors are located pre- and/or post-synaptically, and are coupled to various K+ and Ca2+ channels presumably through both a membrane delimited pathways and a pathway involving second messengers. Baclofen, a selective GABAB receptor agonist, as well as GABA itself have pre- and post-synaptic effects. Pre-synaptic effects comprise the reduction of the release of excitatory and inhibitory transmitters. GABAergic receptors on GABAergic terminals may regulate GABA release, however, in most instances spontaneous inhibitory synaptic activity is not modulated by endogenous GABA. Post-synaptic GABAB receptor-mediated inhibition is likely to occur through a membrane delimited pathway activating K+ channels, while baclofen, in some neurons, may activate K+ channels through a second messenger pathway involving arachidonic acid. Some, but not all GABAB receptor-gated K+ channels have the typical properties of those G-protein-activated K+ channels which are also gated by other endogenous ligands of the brain. New, high affinity GABAB antagonists are now available, and some pharmacological evidence points to a receptor heterogeneity. The pharmacological distinction of receptor subtypes, however, has to await final support from a characterization of the molecular structure. The functional importance of post-synaptic GABAB receptors is highlighted by a segregation of GABAA and GABAB synapses in the mammalian brain.
GABA<inf>B</inf> receptors
1995, Pharmacology and TherapeuticsGABAB receptors are a distinct subclass of receptors for the major inhibitory transmitter 4-aminobutanoic acid (GABA) that mediate depression of synaptic transmission and contribute to the inhibition controlling neuronal excitability. The development of specific agonists and antagonists for these receptors has led to a better understanding of their physiology and pharmacology, highlighting their diverse coupling to different intracellular effectors through proteins. This review emphasises our current knowledge of the neurophysiology and neurochemistry of GABAB receptors, including their heterogeneity, as well as the therapeutic potential of drugs acting at these sites.
The Pharmacology and Function of Central Gaba<inf>B</inf> Receptors
1994, International Review of NeurobiologyThis chapter focuses on the pharmacological properties of GABAB receptors, the intracellular signaling systems to which these receptors are coupled, and their role in regulating synaptic transmission in the central nervous system. GABAB receptors enable GABA to modulate neuronal function in a manner not possible through GABAB receptors alone. These receptors are present at both pre- and postsynaptic sites and can exert both inhibitory and disinhibitory effects. In particular, GABAB receptors are important in regulating NMDA receptor-mediated responses, including the induction of long-term potentiation (LTP). They also can regulate the filtering properties of neural networks, allowing peak transmission in the frequency range of theta rhythm. GABAB receptors are G protein-coupled to a variety of intracellular effector systems, and thereby, have the potential to produce long-term changes in the state of neuronal activity, through actions such as protein phosphorylation. Although the majority of the effects of GABAB receptors have been reported in vitro, recent studies demonstrate that GABAB receptors exert electrophysiological actions in vivo. For example, GABAB receptor antagonists reduce the late inhibitory postsynaptic potential (IPSP) in vivo and consequently, can decrease inhibition of spontaneous neuronal firing following a stimulus. In addition, blockade of GABAB receptors can increase spontaneous activity of central neurons, suggesting the presence of GABAB receptor-mediated tonic inhibition.