3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABAB sites in rat brain

Hill, David R.; Bowery, Norman G.

doi:10.1038/290149a0

Cited by 1,038 publications

(318 citation statements)

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“…11 Although both GABA-A and GABA-B receptor activation cause increased GABA neuronal output, the GABA-A receptor is rendered relatively less sensitive by chronic exposure to alcohol. Baclofen is a pure GABA-B receptor agonist, 12 and its GABA-B stimulatory effect is maintained even in habituated alcoholics. 13,14 The absence of cross-tolerance between baclofen and ethanol suggests that low doses of baclofen may be helpful in the management of AWS.…”

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confidence: 99%

Treating alcohol withdrawal with oral baclofen: A randomized, double‐blind, placebo‐controlled trial

Lyon

Khan

Gessert

et al. 2011

Journal of Hospital Medicine

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BACKGROUND:Abrupt cessation of alcohol intake causes habituated drinkers to experience symptoms of alcohol withdrawal syndrome (AWS).OBJECTIVE:To determine the effect of the gamma‐aminobutyric acid (GABA)‐B agonist baclofen on the course of acute symptomatic AWS.DESIGN:Prospective, randomized, double‐blind, placebo‐controlled clinical study.SETTING:Two tertiary‐care hospitals in Duluth, Minnesota.PATIENTS:Inpatient adults admitted for any reason (including AWS) judged to be at high risk for AWS.INTERVENTION:Inpatients who developed symptoms of AWS received symptom‐triggered benzodiazepine treatment using lorazepam by standard protocol, and were randomized to receive baclofen 10 mg or placebo, 3 times per day, orally.MEASUREMENTS:AWS severity was assessed using the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA‐Ar); lorazepam dose was monitored.RESULTS:Seventy‐nine subjects were enrolled. The 44 subjects who developed symptoms of AWS were randomized to baclofen or placebo. Thirty‐one subjects (18 baclofen, 13 placebo) completed 72 hours of assessments, either entirely as inpatients or with outpatient follow‐up. The need for high doses of benzodiazepines (20 mg or more of lorazepam over 72 hours) to control AWS was less likely in the baclofen treatment group (1 of 18) than in the placebo‐treated group (7 of 13) (P = 0.004).CONCLUSIONS:We found that the use of baclofen was associated with a significant reduction in the use of high doses of benzodiazepine (lorazepam) in the management of symptomatic AWS. The use of low‐dose baclofen in the management of AWS deserves further study, as reduced dependence on high‐dose benzodiazepines in AWS management could improve patient safety. Journal of Hospital Medicine 2011;6:474–479. © 2011 Society of Hospital Medicine

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confidence: 99%

Treating alcohol withdrawal with oral baclofen: A randomized, double‐blind, placebo‐controlled trial

Lyon

Khan

Gessert

et al. 2011

Journal of Hospital Medicine

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“…GABA is the principal inhibitory neurotransmitter in cerebral cortex (21,22); GABA is found in all layers (23) and powerfully inhibits all, or nearly all, neurons (24). Although the inhibitory action of GABA is generally associated with a direct postsynaptic effect (25), GABA has also been shown to have a presynaptic effect-namely, that of reducing neurotransmitter release from presynaptic nerve terminals (26)(27)(28). In all cases, however, this activity has been shown to be mediated through the GABA-B receptor, at which muscimol and other GABA agonists, such as 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol and 3-aminopropane sulfonic acid, are not, or are only minimally, active (26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

“…In all cases, however, this activity has been shown to be mediated through the GABA-B receptor, at which muscimol and other GABA agonists, such as 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol and 3-aminopropane sulfonic acid, are not, or are only minimally, active (26)(27)(28). In addition, muscimol binding can always be antagonized by bicuculline, a GABA antagonist active at the GABA-A binding site, whereas the effects associated with binding to the GABA-B receptor are completely or largely bicuculline-insensitive (25)(26)(27)(28). In the kitten visual cortex, GABAergic inhibition is already present (29)(30)(31), and muscimol appears to bind only to GABA-A receptors (32,33).…”

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confidence: 99%

“…Although the inhibitory action of GABA is generally associated with a direct postsynaptic effect (25), GABA has also been shown to have a presynaptic effect-namely, that of reducing neurotransmitter release from presynaptic nerve terminals (26)(27)(28). In all cases, however, this activity has been shown to be mediated through the GABA-B receptor, at which muscimol and other GABA agonists, such as 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol and 3-aminopropane sulfonic acid, are not, or are only minimally, active (26)(27)(28). In addition, muscimol binding can always be antagonized by bicuculline, a GABA antagonist active at the GABA-A binding site, whereas the effects associated with binding to the GABA-B receptor are completely or largely bicuculline-insensitive (25)(26)(27)(28).…”

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Neural plasticity without postsynaptic action potentials: less-active inputs become dominant when kitten visual cortical cells are pharmacologically inhibited.

Reiter

Stryker

1988

Proc. Natl. Acad. Sci. U.S.A.

244

140

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Models of synaptic plasticity in the nervous system have conventionally assumed a mechanism in which spike activity of a postsynaptic cell enhances the efficacy of recently active presynaptic inputs. Making use of the prompt and dramatic response of the visual cortex to occlusion of vision in one eye during the critical period, we tested the role of postsynaptic activity in ocular dominance plasticity. To do so, we selectively blocked cortical cell discharges with a continuous intracortical infusion of the inhibitory neurotransmitter agonist muscimol during a period of monocular deprivation. This drug inhibits cortical cell discharges with no apparent effect on the activity of their presynaptic geniculocortical inputs. Recording from single cortical cells after they had recovered from the muscimol-induced blockade, we found a consistent shift in the responsiveness of the visual cortex in favor of the less-active, closed eye, while the normal shift in favor of the more-active, open eye was evident in regions not affected by the treatment. Such an inhibition-coupled expression of plasticity in favor of the less-active, closed eye cannot be explained by a nonspecific disruption of cortical function. We interpret these results to indicate (i) that the postsynaptic cell is crucially involved in plasticity of the visual cortex, (ii) that the direction of cortical plasticity depends on postsynaptic membrane conductance or polarization, and (iii) that plasticity can occur in the absence of postsynaptic spike activity.Synaptic plasticity is known to be widespread in both the developing and the mature central nervous system. A hypothesis about the mechanism of plasticity in development, put forward by Hebb, is that spike activity in the postsynaptic cell enhances the efficacy of recently active inputs (1-6). Hebb's hypothesis has been used to explain many instances of neural plasticity (7). This hypothesis stands in contrast to one favoring a purely presynaptic mechanism, as was reported for classical conditioning in Aplysia, in which responses of cells were facilitated even while their somata were hyperpolarized by an intracellular microelectrode (8).In the visual (9-14) and motor cortices (15), however, several types of evidence favor an excitation-coupled postsynaptic mechanism of plasticity.Synaptic connections serving the two eyes to the visual cortex are reorganized during normal development (16-18).This reorganization is most dramatic when vision in one eye is occluded during a critical period in early life (17)(18)(19)(20): the occluded eye loses its ability to drive most cortical cells, which come to respond exclusively to the nonoccluded eye. This phenomenon is called ocular dominance plasticity.Previous experiments in which a region of visual cortex was infused with tetrodotoxin during a period of monocular deprivation demonstrated that activity at the level of the visual cortex is crucial for ocular dominance plasticity (10). Because tetrodotoxin blocks pre-as well as postsynaptic activities in the vis...

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“…On day 7, the binding of (-)-[3H]baclofen by larvae was measured as described in the legend to Fig. 2. central nervous system, including the GABAA receptor [where muscimol is the most potent (27,28)] and the GABAB receptor [where (-)-baclofen and GABA are approximately equipotent (29)(30)(31)]. In experiments similar to those shown, we have found that the receptors characterized in these studies are stereochemically specific; (+)-baclofen is several orders of magnitude less effective than the (-)-enantiomer, in competition for the labeled receptors and in the induction of metamorphosis.…”

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Availability of chemosensory receptors is down-regulated by habituation of larvae to a morphogenetic signal.

Trapido-Rosenthal¹,

Morse²

1986

Proc. Natl. Acad. Sci. U.S.A.

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Larvae of the gastropod mollusc Haliotis rufescens are induced to settle from the plankton and metamorphose in response to exogenous y-aminobutyric acid (GABA) and a number of GABA-mimetic compounds, including a GABA-mimetic inducer uniquely associated with the surfaces of the naturally recruiting algae. Previous evidence has shown that recognition of these inducers is mediated by specialized chemosensory receptors on the larval epithelium and that transduction of the morphogenetic signal then is mediated by cAMP and excitatory depolarization. We demonstrate here the specific and saturable labeling of a population of larval receptors with the GABA analog f-(p-chlorophenyl)-[3H]GABA ([3H]baclofen); identification of these labeled receptors with those controlling metamorphosis is suggested by four independent criteria: (i) the effectiveness of GABA and its close structural analogs to induce metamorphosis is closely correlated with the effectiveness ofthese compounds to compete for binding to this receptor; (ii) the natural inducer purified from the recruiting algae competes for binding to this receptor; (iii) (-)-[3H]baclofen specifically bound to the receptors is shed from the larvae after %20 hr, at the time corresponding to the metamorphic abscission and shedding of sensory cilia and other structures from the larvae; and (iv) the availability of the receptors for labeling and the ability of the larvae to respond to GABA and GABA analogs can be down-regulated in parallel by habituation of the larvae early in their development. These down-regulated larvae are fully capable of settlement and metamorphosis in response to agents that elevate intracellular cAMP or depolarize the chemosensory membrane, confirming that down-regulation is confined to the receptors, with no effect on the postreceptor pathway. The results reported here thus suggest that the sensitivity of marine invertebrate larvae to morphogenetic stimuli from the environment can be downregulated by reduction in the number of chemosensory receptors available for interaction with the molecules that induce settlement and metamorphosis. In this respect, chemosensory receptors for environmental and morphogenetic signals are demonstrated biochemically to respond to habituation in a similar manner to neuronal and hormonal receptors.Larvae of many benthic marine invertebrate animals, after dispersal in the plankton, are induced to settle and metamorphose only upon recognition of specific substrata (1-8). Larvae (0.2 mm) of the Pacific red abalone, Haliotis rufescens, a gastropod mollusc, are induced to settle, attach to substrata, and metamorphose by chemosensory recognition of y-aminobutyric acid (GABA)-mimetic molecules that are uniquely associated with the surfaces of crustose red algae (9, 10). These purified natural inducers alone, GABA, and a number of GABA analogs are sufficient to induce this genetically programed behavioral and morphogenetic sequence (11-14); in the absence of such inducers, the larvae do not settle or metamorphose (11)(12)(13)...

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3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABAB sites in rat brain

Cited by 1,038 publications

References 12 publications

Treating alcohol withdrawal with oral baclofen: A randomized, double‐blind, placebo‐controlled trial

Treating alcohol withdrawal with oral baclofen: A randomized, double‐blind, placebo‐controlled trial

Neural plasticity without postsynaptic action potentials: less-active inputs become dominant when kitten visual cortical cells are pharmacologically inhibited.

Availability of chemosensory receptors is down-regulated by habituation of larvae to a morphogenetic signal.

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