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PubMed2001

Pathway-specific targeting of GABA(A) receptor subtypes to somatic and dendritic synapses in the central amygdala.

Neurons in the central amygdala express two distinct types of ionotropic GABA receptor. One is the classical GABA(A) receptor that is blocked by low concentrations of bicuculline and positively modulated by benzodiazepines. The other is a novel type of ionotropic GABA receptor that is less sensitive to bicuculline but blocked by the GABA(C) receptor antagonist (1,2,5,6-tetrohydropyridine-4-yl) methylphosphinic acid (TPMPA) and by benzodiazepines. In this study, we examine the distribution of these two receptor types. Recordings of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) showed a wide variation in amplitude. Most events had amplitudes of < 50 pA, but a small minority had amplitudes >100 pA. Large-amplitude events also had rise times faster than small-amplitude events. Large-amplitude events were fully blocked by 10 microM bicuculline but unaffected by TPMPA. Small amplitude events were partially blocked by both bicuculline and TPMPA. Focal application of hypertonic sucrose to the soma evoked large-amplitude mIPSCs, whereas focal dendritic application of sucrose evoked small-amplitude mIPSCs. Thus inhibitory synapses on the dendrites of neurons in the central amygdala express both types of GABA receptor, but somatic synapses expressed purely GABA(A) receptors. Minimal stimulation revealed that inhibitory inputs arising from the laterally located intercalated cells innervate dendritic synapses, whereas inhibitory inputs of medial origin innervated somatic inhibitory synapses. These results show that different types of ionotropic GABA receptors are targeted to spatially and functionally distinct synapses. Thus benzodiazepines will have different modulatory effects on different inhibitory pathways in the central amygdala.

Amygdala↗
PubMed2006

gamma-Hydroxybutyrate induces cyclic AMP-responsive element-binding protein phosphorylation in mouse hippocampus: an involvement of GABA(B) receptors and cAMP-dependent protein kinase activation.

gamma-Hydroxybutyrate is a widely used recreational drug. Its abuse has been associated with cognitive impairments and development of tolerance and dependence. However, the neural mechanisms underlying these effects remain unclear. In the present study we investigated the possible cellular signaling mechanisms that might mediate gamma-hydroxybutyrate's action. Acute administration of gamma-hydroxybutyrate (500 mg/kg, i.p.) was found to cause a rapid and long-lasting increase in the phosphorylation level of the cAMP-responsive element-binding protein in mouse (C57/BL6) hippocampus. Pretreatment with the specific GABA(B) receptor antagonist [3-[1-(R)-[(3-cyclohexylmethyl)hydroxyphosphinyl]-2-(S)-hydroxy-propyl]amino]ethyl]-benzoic acid (20 mg/kg, i.p.) prevented the action of gamma-hydroxybutyrate, confirming a GABA(B) receptor-mediated mechanism. In addition, acute gamma-hydroxybutyrate administration induced a significant increase in cytosolic cAMP-dependent protein kinase activity in the hippocampus, and pretreatment with the cAMP-dependent protein kinase inhibitor H-89 could prevent the effect of gamma-hydroxybutyrate on cAMP-responsive element-binding protein phosphorylation, indicating a direct involvement of cAMP-dependent protein kinase in gamma-hydroxybutyrate-induced cAMP-responsive element-binding protein phosphorylation. On the other hand, the increased expression of phosphorylated cAMP-responsive element-binding protein was not observed in the hippocampus of mice subjected to repeated gamma-hydroxybutyrate exposure, suggesting the development of a gamma-hydroxybutyrate-induced desensitization of the signaling pathway leading to cAMP-responsive element-binding protein activation. Since cAMP-responsive element-binding protein activation has been implicated in a variety of neural plasticities, our findings may have revealed a new mechanism underlying gamma-hydroxybutyrate-induced neuroadaptations.

Adjuvants, Anesthesia↗
PubMed1999

Purkinje cell inhibitory responses to 3-APPA (3-aminopropylphosphinic acid) in RAT cerebellar slices.

3-APPA is considered to be a GABA(B) agonist more potent than baclofen. We report here the results obtained by applying this agonist to Purkinje cells (PCs) recorded in current clamp mode on cerebellar slices. The responses were compared to those obtained with other GABA agonists and antagonists. The drugs were delivered either in the perfusion solution or by pressure to the molecular layer near the recorded cell. When applied to the PCs either in the bathing medium or by pressure, 3-APPA evoked a potent inhibitory response which was however different from that obtained with baclofen. The response was complex and similar to that evoked by application of GABA, the endogenous neurotransmitter. In fact it showed: (1) very sensitive dose-response not affected by TTX in the bath; (2) an equilibrium potential compatible with Cl-channel conductance; (3) a massive reduction with the competitive GABA(A) antagonist bicuculline; (4) a small reduction, if any, with the potent competitive GABA(B) antagonist CGP55845A; (5) persistence of the responses under 4-AP (4-aminopyridine), the potassium channel blocker, and inhibition of the 4-AP-induced calcium bursts of spikes. The conclusion was reached that the inhibitory response of PCs to 3-APPA is induced, like GABA inhibition, by binding to both GABA(A) and GABA(B) postsynaptic receptors.

4-Aminopyridine↗
PubMed1998

Effect of infusing gamma-aminobutyric acid receptor agonists and antagonists into the medial preoptic area and ventromedial hypothalamus on prolactin secretion in male sheep.

We investigated the effects of gamma-aminobutyric acid (GABA) agonists muscimol and baclofen (GABA(A) and GABA(B) agonists, respectively) and antagonists bicuculline methiodide (BMI, GABA(A) antagonist) or 2-hydroxysaclofen (SAC) and CGP 55845A (GABA(B) antagonists) on prolactin (PRL) secretion in castrated rams. The drugs were applied by microdialysis into either the medial preoptic area (mPOA) or ventromedial hypothalamus (VMH). Dialysis of baclofen into the mPOA significantly increased mean PRL (p < 0.05), whereas SAC caused a small, but significant decrease (p < 0.01). Dialysis of either muscimol or BMI into the mPOA had no effect on prolactin. In the VMH, baclofen significantly increased (p < 0.01) mean PRL but SAC and CGP 55845A were ineffective, whereas dialysis of either muscimol or BMI increased mean prolactin (p < 0.01). These results show that infusion into the mPOA of drugs that affect GABA(B) receptor alter PRL release, whereas infusion of a GABA(A) agonists and antagonist was without effect on PRL release. In contrast, infusion of both GABA(A) and GABA(B) agonists and a GABA(A) antagonist into the VMH altered PRL secretion. This suggest that GABAergic neurons in both regions participate in regulating PRL secretion, but by different receptor systems.

Animals↗
PubMed2003

Synaptic and non-synaptic mechanisms of amygdala recruitment into temporolimbic epileptiform activities.

Lateral amygdala (LA) activity during synchronized-epileptiform discharges in temporolimbic circuits was investigated in rat horizontal slices containing the amygdala, hippocampus (Hip), perirhinal (Prh) and lateral entorhinal (LEnt) cortex, through multiple-site extra- and intracellular recording techniques and measurement of the extracellular K+ concentration. Application of 4-aminopyridine (50 microm) induced epileptiform discharges in all regions under study. Slow interictal-like burst discharges persisted in the Prh/LEnt/LA after disconnection of the Hip, seemed to originate in the Prh as shown from time delay analyses, and often preceded the onset of ictal-like activity. Disconnection of the amygdala resulted in de-synchronization of epileptiform discharges in the LA from those in the Prh/LEnt. Interictal-like activity was intracellularly reflected in LA projection neurons as gamma-aminobutyric acid (GABA)A/B receptor-mediated synaptic responses, and depolarizing electrogenic events (spikelets) residing on the initial phase of the GABA response. Spikelets were considered antidromically conducted ectopic action potentials generated at axon terminals, as they were graded in amplitude, were not abolished through hyperpolarizing membrane responses (which effectively blocked evoked orthodromic action potentials), lacked a clear prepotential or synaptic potential, were not affected through blockers of gap junctions, and were blocked through remote application of tetrodotoxin at putative target areas of LA projection neurons. Remote application of a GABAB receptor antagonist facilitated spikelet generation. A transient elevation in the extracellular K+ level averaging 3 mm above baseline occurred in conjunction with interictal-like activity in all areas under study. We conclude that interictal-like discharges in the LA/LEnt/Prh spread in a predictable manner through the synaptic network with the Prh playing a leading role. The rise in extracellular K+ may provide a depolarizing mechanism for recruitment of interneurons and generation of ectopic action potentials at axon terminals of LA projection neurons. Antidromically conducted ectopic action potentials may provide a spreading mechanism of seizure activity mediated by diffuse axonal projections of LA neurons.

4-Aminopyridine↗
PubMed2002

Differential ontogeny of GABA(B)-receptor-mediated pre- and postsynaptic modulation of GABA and glycine transmission in respiratory rhythm-generating network in mouse.

Rhythm generation in mature respiratory networks is influenced strongly by synaptic inhibition. In early neonates, GABA(A)-receptor- and glycine-receptor-mediated inhibition is not present, thus the question arises as to whether GABA(B)-receptor-mediated inhibition plays an important role. Using brainstem slices of neonatal mice (postnatal day, P0-P15), we analysed the role of GABA(B)-mediated modulation of GABA and glycine synaptic transmission in the respiratory network. Blockade of GABA uptake by nipecotic acid (0.25-2 mM) reduced the respiratory frequency. This reduction was prevented by the selective GABA(B) receptor antagonist CGP55845A (CGP) alone at P0-P3, but by bicuculline as well as CGP at P7-P15. Blockade of GABA(B) receptors by CGP increased the respiratory frequency at P0-P3, whereas it caused a reduction of frequency in older animals. The effect of CGP on respiratory frequency was diminished in the presence of bicuculline and strychnine in older but not in younger animals. The relative contribution of GABA(B)-receptor-mediated pre- and postsynaptic modulation was examined by analysing the effect of GABA(B) receptors on spontaneous and miniature IPSCs. In younger animals (P0-P3), the GABA(B) receptor agonist baclofen had no detectable effect on IPSC frequency, but caused a significant decrease in the amplitude. In older animals (P7-P15), baclofen decreased both the frequency and amplitude of spontaneous and miniature IPSCs. These results demonstrate that GABA(B)-receptor-mediated postsynaptic modulation plays an important role in the respiratory network from P0 on. GABA(B)-receptor-mediated presynaptic modulation develops with a longer postnatal latency, and becomes predominant within the first postnatal week.

Aging↗
PubMed2005

Repeated administration of the GABAB receptor agonist CGP44532 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine-seeking in rats.

Acute administration of gamma-aminobutyric acid B (GABAB) receptor agonists decreased nicotine, cocaine, ethanol, and heroin self-administration. GABAB receptor agonists also decreased cue-induced cocaine craving or seeking in humans and animals, respectively. The present study investigated the effects of repeated subcutaneous administration of the GABAB receptor agonist CGP44532 on nicotine- and food-maintained responding under a fixed ratio 5 schedule of reinforcement. The second part of the study determined whether contingent presentation of previously nicotine-associated cues reinstated extinguished nicotine-seeking behavior, and whether acute subcutaneous CGP44532 administration affected cue-induced reinstatement of extinguished nicotine-seeking behavior. The results indicated that repeated administration of 0.25 mg/kg CGP44532 selectively decreased nicotine self-administration compared to food-maintained responding during the first 7 days of treatment. Repeated administration of 0.5 mg/kg/day CGP44532 nonselectively decreased both nicotine- and food-maintained responding. Contingent presentation of previously nicotine-associated cues reinstated extinguished nicotine-seeking behavior. Further, acute CGP44532 administration (0.125 and 0.25 mg/kg) decreased cue-induced reinstatement of nicotine-seeking behavior. In summary, the present results indicated that 0.25 mg/kg/day CGP44532 selectively decreased nicotine self-administration compared to food-maintained responding, and acute administration of CGP44532 (0.125 and 0.25 mg/kg) dose-dependently decreased cue-induced reinstatement of nicotine-seeking behavior.

Animals↗
PubMed2006

Phosphinic derivative of DTPA conjugated to a G5 PAMAM dendrimer: an 17O and 1H relaxation study of its Gd(III) complex.

A DTPA-based chelate containing one phosphinate group was conjugated to a generation 5 polyamidoamine (PAMAM) dendrimer via a benzylthiourea linkage. The Gd(III) complex of this novel conjugate has potential as a contrast agent for magnetic resonance imaging (MRI). The chelates bind Gd3+via three nitrogen atoms, four carboxylates and one phosphinate oxygen, and one water molecule completes the inner coordination sphere. The monomer Gd(III) chelates bearing nitrobenzyl and aminobenzyl groups ([Gd(DTTAP-bz-NO2)(H2O)]2- and [Gd(DTTAP-bz-NH2)(H2O)]2-) as well as the dendrimeric Gd(III) complex G5-(Gd(DTTAP))63) were studied by multiple-field, variable temperature 17O and 1H NMR. The rate of water exchange is faster than that of [Gd(DTPA)(H2O)]2- and very similar on the two monomeric complexes (8.9 and 8.3 x 10(6) s-1 for [Gd(DTTAP-bz-NO2)(H2O)]2- and [Gd(DTTAP-bz-NH2)(H2O)]2-, respectively), while it is decreased on the dendrimeric conjugate (5.0 x 10(6) s-1). The Gd(III) complex of the dendrimer conjugate has a relaxivity of 26.8 mM-1 s-1 at 37 degrees C and 0.47 T (corresponding to 1H Larmor frequency of 20 MHz). Given the contribution of the second sphere water molecules to the overall relaxivity, this value is slightly higher than those reported for similar size dendrimers. The experimental 17O and 1H NMR data were fitted to the Solomon-Bloembergen-Morgan equations extended with a contribution from second coordination sphere water molecules. The rotational dynamics of the dendrimeric conjugate was described in terms of global and local motions with the Lipari-Szabo approach.

Chelating Agents↗
PubMed1994

Pharmacological discrimination between gamma-aminobutyric acid type B receptors regulating cholecystokinin and somatostatin release from rat neocortex synaptosomes.

The gamma-aminobutyric acid (GABA)B receptors modulating the depolarization-evoked release of somatostatin (SRIF) or cholecystokinin (CCK) from superfused rat cerebrocortical synaptosomes have been characterized pharmacologically. GABA inhibited the 15 mM KCl-evoked overflow of both SRIF and CCK; the EC50 values were 1.3 microM and 1.4 microM, respectively. The GABAB receptor agonist (-)-baclofen also diminished the release of SRIF (EC50 = 1.9 microM) and CCK (EC50 = 2.6 microM). The novel compound CGP 47656, a highly selective GABAB receptor ligand, inhibited the release of SRIF, with its affinity and efficacy being similar to those of GABA or (-)-baclofen; however, the compound was unable to affect CCK release even when tested at 300 microM. The GABAB receptor antagonist phaclofen prevented, with identical affinities, the effects of (-)-baclofen on SRIF (pKb = 4.9) and CCK (pKb = 4.8) release. The same was true for CGP 35348, another GABAB receptor antagonist, which blocked (-)-baclofen with a pKb value of 6.1 at both the GABAB receptors regulating SRIF and CCK release. The effects of (-)-baclofen were also counteracted by the novel GABAB receptor antagonist CGP 52432. However, the affinity of the drug at the GABAB receptors modulating SRIF release (pKb = 6.2) was about 30-fold lower than that at the receptors regulating CCK release (pKb = 7.6). The data suggest that the GABAB receptors situated on nerve terminals releasing SRIF and CCK display pharmacological heterogeneity and may represent different subtypes of GABAB receptors.

Animals↗
PubMed2001

Reorganisation of respiratory network activity after loss of glycinergic inhibition.

gamma-Aminobutyric acid (GABA)-ergic and glycinergic inhibition is believed to play a major role in the respiratory network. In the present study we tested whether specific blockade of glycinergic inhibition resulted in changes in respiratory network interaction and function. Using the working heart-brainstem preparation from adult mice, we recorded phrenic nerve activity and the activity of different types of respiratory neurones located in the ventrolateral medulla. Strychnine (0.03-0.3 microM) was given systemically to block glycine receptors (Gly-R). During exposure to strychnine, post-inspiratory (PI) neurones shifted their onset of discharge into the inspiratory phase. As a consequence, the post-inspiratory phase failed and the rhythm changed from a three-phase cycle (inspiration, post-inspiration, expiration, with a frequency of about. 0.24 Hz) to a faster, two-phased cycle (inspiration expiration, frequency about 0.41 Hz). Inspiratory and expiratory neurones altered their augmenting membrane potential pattern to a rapidly peaking pattern. Smaller voltage oscillations at approximately 10 Hz and consisting of excitatory and inhibitory postsynaptic potential sequences occurred during the expiratory interval. Due to their high frequency and low amplitude, such oscillations would be inadequate for lung ventilation. We conclude that, under physiological conditions, glycinergic inhibition does indeed play a major role in the generation of a normal respiratory rhythm in adult mice. After failure of glycinergic inhibition a faster respiratory rhythm seems to operate through reciprocal GABAergic inhibition between inspiratory and expiratory neurones, while phase switching is organised by activation of intrinsic membrane properties.

Animals↗
PubMed1996

Activation of GABAB receptors increases a potassium conductance in rat bulbospinal neurons of the C1 area.

In anesthetized rats, iontophoresis of the gamma-aminobutyric acid (GABAB)-receptor agonist and antispastic drug baclofen inhibits the bulbospinal vasomotor neurons of the rostral ventrolateral medulla (RVLM). The present study was carried out to determine whether C1 adrenergic and other bulbospinal neurons of the RVLM have postsynaptic GABAB receptors. Retrogradely labeled RVLM bulbospinal neurons (n = 52) were recorded in 120-micron-thick slices from neonatal rat brain (3-10 days old). Most neurons (48/52) were tonically active (3 +/- 0.6 spikes/s). Twenty-six neurons were recovered histologically, and 18 of them were immunoreactive for tyrosine hydroxylase (TH). In current clamp, baclofen (0.3-10 microM) hyperpolarized RVLM bulbospinal cells in a dose-dependent manner (16 +/- 0.5 mV hyperpolarization by 3 microM baclofen; n = 19) and decreased input resistance by 40% (n = 10). In voltage clamp (1 microM tetrodotoxin present; holding potential: -40 to -60 mV), 3 microM baclofen induced an outward current of 21 +/- 2 pA (n = 29). This current exhibited inward rectification and reversed polarity close to the K+ equilibrium potential (external K+ from 2.5 to 10 mM). The current induced by baclofen was reduced 90% by 0.1-0.2 mM BaCl2 (n = 6) and was blocked reversibly by the selective GABAB-receptor antagonist CGP-55845A (0.5-1 microM; n = 6). All histologically verified TH-immunoreactive cells (n = 18) were sensitive to baclofen. In summary, RVLM bulbospinal neurons including C1 adrenergic cells possess GABAB receptors. Activation of these receptors increases an inwardly rectifying K+ conductance. This effect reduces the intrinsic firing frequency of RVLM vasomotor neurons "in vitro" and may contribute to the sympatholytic action of baclofen "in vivo."

Action Potentials↗
PubMed2001

Effects of high-affinity GABAB receptor antagonists on active and passive avoidance responding in rodents with gamma-hydroxybutyrolactone-induced absence syndrome.

RATIONALE: Absence seizures in man are behaviourally manifested as arrest and mild jerks mainly of facial muscles, associated in the electroencephalogram with synchronous spike and wave discharges. Gamma-hydroxybutyrolactone (GHBL) administration is currently used as an experimental model of absence seizures in rats and mice. OBJECTIVE: The aim of the present study was to examine the effects of three potent gamma-aminobutyric acid (GABA)B receptor antagonists CGP55845A, CGP62349 and CGP71982 (0.01 mg/kg) on the development of GHBL-induced absence epilepsy and in learning paradigms of active and passive avoidance tests in GHBL-treated mice and rats. METHODS: After 4 weeks of development of the absence syndrome, active and passive avoidance tests with negative reinforcement were performed. In both animal species, the absence syndrome was observed after 3 weeks of treatment in the saline group. RESULTS: The GABAB receptor antagonists CGP55845A and CGP62349 appeared to suppress the development of the absence syndrome to a greater degree in mice than in rats. CGP71982 suppressed it later than the other two antagonists (fifth week). In an active avoidance test in GHBL-treated mice, the GABAB antagonists had different effects - CGP62349 improved learning and memory retention to a greater extent than CGP55845A, whilst CGP71982 had no influence on it. In a passive avoidance test in GHBL-treated mice, the GABAB antagonists also had different effects - CGP71982 improved both learning and memory retrieval, whereas CGP55845A and CGP62349 had no effect. In the active avoidance test in GHBL-treated rats, the GABAB antagonist CGP55845A improved learning, whereas the other two, CGP62349 and CGP71982, had no effect. In the passive avoidance test the GHBL-treated rats showed an improvement in short memory retrieval. CGP55845A and CGP71982 improved this further, whilst CGP62349 had no effect. CONCLUSIONS: GHBL appeared to influence mice and rats in a different manner - rats learned the active avoidance task better than the GHBL-treated mice. The present study confirms previous data that GABAB antagonists suppress absence behaviour.

Animals↗
PubMed1997

Comparative in vivo and in vitro studies with the potent GABAB receptor antagonist, CGP 56999A.

CGP 56999A ([3-[1-(R)-[(3-cyclohexylmethyl)hydroxyphosphinyl]-2-(S)- hydroxy-propyl] amino]ethyl]-benzoic acid) is a potent GABAB receptor antagonist showing much more pronounced convulsant features in mice than do other previously studied GABAB receptor antagonists. The goal of this study was to elucidate the physiological mechanisms underlying this effect. In mice a dose of 0.6 mg/kg intraperitoneal (i.p.) CGP 56999A elicited behavioral activation and stereotypy with periods of intensive scratching and grooming. At 1 mg/kg i.p. most mice displayed myoclonic seizure-like episodes lasting several min. Pretreatment with the lower dose of 0.6 mg/kg i.p. also induced seizures after treatment with a subthreshold dose of pentylenetetrazole (40 mg/kg i.p.). In rats a dose of 3 mg/kg CGP 56999A (i.p.) induced convulsions of tonic-clonic nature. Intracellular sharp microelectrode recordings from rat cortical neurons in slices revealed no paroxysmal actions of CGP 56999A (10 microM). Similar to other GABAB receptor antagonists, CGP 56999A suppressed the late inhibitory postsynaptic potential (i.p.s.p.), but had no effect on the excitatory postsynaptic potential (e.p.s.p.) in the cortex. In cortical slices exposed to picrotoxin (10 microM), the compound evoked pronounced, spontaneous and intense epileptiform discharges. In conclusion, these findings demonstrated that the convulsive feature of the potent GABAB receptor antagonist, CGP 56999A, may be due to suppression of the late i.p.s.p., which becomes apparent in the intact brain only, whereas this action remains undetected in untreated brain slices. This remarkable discrepancy between in vitro and in vivo may be a consequence either of disruption of neuronal circuits during slice preparation or of the pronounced hyperpolarization of pyramidal neurons, at least in the case of cortical slice preparations.

Animals↗
PubMed2003

The GABAB receptor agonists baclofen and CGP44532 decreased nicotine self-administration in the rat.

RATIONALE: Previous work has indicated a potential role for gamma-aminobutyric acid-B (GABA(B)) receptor agonists in treating drug addiction in humans. Specifically, GABA(B) receptor agonists decreased cocaine, heroin and nicotine self-administration in rats. OBJECTIVES: The purpose of the present studies was to extend previous findings by assessing the effects of additional GABA(B) receptor agonists on nicotine self-administration and food-maintained responding, under both fixed and progressive ratio schedules in rats. METHODS: Male Wistar rats were exposed to a progressive ratio schedule where various nicotine doses were made available according to a within-subjects Latin Square design. Additional groups of rats were used to test the effects of the GABA(B) receptor agonists baclofen and CGP44532 on nicotine self-administration (0.01 and 0.03 mg/kg per infusion) and food-reinforced responding on fixed and progressive ratio (CGP44532 only) schedules. RESULTS: Nicotine maintained stable self-administration under a progressive ratio schedule with a linear dose-response function ( r=0.61). Both CGP44532 and (-)baclofen dose-dependently reduced nicotine self-administration on the fixed ratio schedule, and also decreased food-maintained responding at higher doses. Further, CGP44532 decreased breakpoints for nicotine and food at identical doses under the progressive ratio schedule. CONCLUSION: The present data demonstrate that administration of GABA(B) receptor agonists decreased intravenous nicotine self-administration under both fixed and progressive ratio schedules of reinforcement, possibly reflecting reduced rewarding effects of nicotine. Both baclofen and CGP44532 exhibited specificity for nicotine- versus food-maintained responding on the fixed ratio schedules but not on the progressive ratio schedule (CGP44532 tested only), indicating the potential usefulness of GABA(B) receptor agonists as therapeutics for smoking cessation.

Animals↗
PubMed1994

Contribution of presynaptic GABA-B receptors to paired-pulse depression of GABA-responses in the hippocampus.

The synaptic release of gamma-aminobutyric acid (GABA) is thought to be regulated by presynaptic GABA receptors of the B-type. It was the goal of this study to validate this concept electrophysiologically using four selective antagonists of GABA-B receptors. Experiments were performed in hippocampal slices exposed to 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX 30 microM) and D-2-amino-5-phosphonopentanoate (AP5 40 microM) in order to block excitatory transmission. Consequently, electrical stimulation of the Schaffer collateral/commissural fibers evoked monosynaptic inhibitory potentials (IPSP) recorded intracellularly from CA 1 pyramidal neurons. In a test called paired-pulse paradigm two identical stimuli were applied at intervals ranging from 350 to 4000 ms. The IPSP evoked by the second stimulation was smaller in its amplitude over the entire interval range. This reduction of the second GABA-response is thought to result from the activation of presynaptic GABA receptors. The GABA-uptake inhibitor SKF 89976 (100 microM) increased the amplitude of the IPSP's and increased the ratio of the first to the second IPSP amplitude. These findings indicate that the drug increases the GABA content in the synaptic cleft leading to a facilitation of paired-pulse depression. The actions of four bath-applied GABA-B receptor antagonists were examined in the paired-pulse paradigm. None of these compounds abolished paired-pulse inhibition completely even at concentrations higher than those required to block postsynaptic GABA-B responses. The potent GABA-B antagonists CGP 55845 and CGP 52432 reduced paired-pulse depression by 80% at 10 microM (maximal effect).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Beta gamma-mediated enhancement of corticotropin-releasing hormone-stimulated adenylyl cyclase activity by activation of gamma-aminobutyric acid(B) receptors in membranes of rat frontal cortex.

A number of studies have shown that activation of gamma-aminobutyric acid(B) (GABA(B)) receptors potentiates neurotransmitter-induced accumulation of cyclic AMP in brain slices, but the mechanisms involved in the facilitatory effect have not been fully elucidated. In the present study, we showed that in membranes of rat frontal cortex the GABA(B) receptor agonist (-)baclofen increased basal adenylyl cyclase activity and potentiated the maximal enzyme stimulation elicited by corticotropin-releasing hormone (CRH). The less active enantiomer (+)baclofen had no effect on cyclic AMP formation, whereas the natural agonist GABA mimicked the stimulatory action of (-)baclofen. In radioligand-binding experiments, the affinity and maximal binding capacity of (125)I-Tyr-CRH was not affected by (-)baclofen. The GABA(B) receptor antagonist CGP 55845A competitively counteracted the (-)baclofen potentiation of CRH-stimulated adenylyl cyclase activity with a pA(2) value of 6.70. Moreover, both (-)baclofen and GABA, but not (+)baclofen, caused a concentration-dependent stimulation of [(35)S]GTP gamma S binding to membrane G-proteins. The intracerebral injection of pertussis toxin significantly reduced the facilitatory effects of (-)baclofen on both basal and CRH-stimulated adenylyl cyclase activities. Moreover, membrane incubation with the GDP-bound form of the alpha subunit of transducin, a scavenger of G protein beta gamma subunits, blocked the stimulatory effects of (-)baclofen. The data indicate that in rat frontal cortex activation of GABA(B) receptors potentiates the CRH stimulation of adenylyl cyclase activity through a mechanism involving the beta gamma subunits of the pertussis toxin-sensitive G protein G(i)/G(o).

Adenylate Cyclase Toxin↗
PubMed2004

Genetic and pharmacological evidence of a role for GABA(B) receptors in the modulation of anxiety- and antidepressant-like behavior.

Although there is much evidence for a role of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the pathophysiology of anxiety and depression, the role of GABA(B) receptors in behavioral processes related to these disorders has not yet been fully established. GABA(B) receptors are G-protein-coupled receptors, which act as functional heterodimers made up of GABA(B(1)) and GABA(B(2)) subunits. Using recently generated GABA(B(1)) -/- mice, which lack functional GABA(B) receptors, and pharmacological tools we assessed the role of GABA(B) receptors in anxiety- and antidepressant-related behaviors. In the light-dark box, GABA(B(1)) -/- mice were more anxious than their wild-type littermates (less time spent in the light; reduced number of transitions). GABA(B(1)) -/- mice were also more anxious in the staircase test. Conversely, acute and chronic treatment with GS39783, a novel GABA(B) receptor positive modulator, decreased anxiety in the light-dark box and elevated zero maze tests for anxiety. On the other hand, GABA(B(1)) -/- mice had decreased immobility (antidepressant-like behavior) in the forced swim test (FST). These behavioral effects are unrelated to alterations in locomotor activity. In confirmation of the genetic data, acute and chronic treatment with CGP56433A, a selective GABA(B) receptor antagonist, also decreased immobility in the FST, whereas GS39783 did not alter this behavior. Taken together, these data suggest that positive modulation of the GABA(B) receptor may serve as a novel therapeutic strategy for the development of anxiolytics, whereas GABA(B) receptor antagonism may serve as a basis for the generation of novel antidepressants.

Analysis of Variance↗
PubMed2006

Enaminones and norepinephrine employ convergent mechanisms to depress excitatory synaptic transmission in the rat nucleus accumbens in vitro.

We recently reported that anticonvulsant anilino enaminones depress excitatory postsynaptic currents (EPSCs) in the nucleus accumbens (NAc) indirectly via gamma-aminobutyric acid (GABA) acting on GABA(B) receptors [S.B. Kombian et al. (2005)Br. J. Pharmacol., 145, 945-953]. Norepinephrine (NE) and dopamine (DA), both known to be involved in seizure disorders, also depress EPSCs in this nucleus. The current study explored a possible interaction between enaminones and adrenergic and/or dopaminergic mechanisms that may contribute to their synaptic depression and anticonvulsant effect. Using whole-cell recording in rat forebrain slices containing the NAc, we show that NE-induced, but not DA-induced, EPSC depression occludes E139-induced EPSC depressant effect. UK14,304, a selective alpha(2) receptor agonist, mimicked the synaptic effect of NE and also occluded E139 effects. Phentolamine, a non-selective alpha-adrenergic antagonist that blocked NE-induced EPSC depression, also blocked the E139-induced EPSC depression. Furthermore, yohimbine, an alpha(2)-adrenoceptor antagonist, also blocked the E139-induced EPSC depression, while prazosin, a selective alpha(1)-adrenergic antagonist, and propranolol, a non-selective beta-adrenoceptor antagonist, did not block the E139 effect. Similar to the E139-induced EPSC depression, the NE-induced EPSC depression was also blocked by the GABA(B) receptor antagonist, CGP55845. By contrast, however, neither SCH23390 nor sulpiride, D1-like and D2-like DA receptor antagonists, respectively, blocked the E139-induced synaptic depression. These results suggest that NE and E139, but not DA, employ a similar mechanism to depress EPSCs in the NAc, and support the hypothesis that E139, like NE, may act on alpha(2)-adrenoceptors to cause the release of GABA, which then mediates synaptic depression via GABA(B) receptors.

Adrenergic alpha-Agonists↗