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At least 811 records · Page 45Linked to original sources
PubMed2001

Behavioral effects of flunitrazepam: reinforcing and discriminative stimulus effects in rhesus monkeys and prevention of withdrawal signs in pentobarbital-dependent rats.

Flunitrazepam was evaluated in several procedures that have been used extensively to study the behavioral effects and abuse potential of positive GABA(A) modulators. One group of monkeys (n=3) responded to receive injections of methohexital or saline (i.v.) while other groups (n=2-4/group) discriminated vehicle from either pentobarbital or triazolam. Other monkeys (n=2) received diazepam daily and discriminated flumazenil from vehicle. Finally, the ability of flunitrazepam to prevent the emergence of withdrawal signs in pentobarbital-treated rats was evaluated. Flunitrazepam maintained i.v. self-administration that was, on average, less than that maintained by methohexital and greater than that maintained by saline. In drug discrimination studies, flunitrazepam substituted for pentobarbital and for triazolam and failed to substitute for flumazenil. In rats (n=3-6/group), signs of withdrawal were not evident when flunitrazepam treatment replaced pentobarbital treatment; withdrawal signs emerged when either pentobarbital or flunitrazepam treatment was terminated. Taken together with data from previous studies, these data suggest that the abuse liability of flunitrazepam is comparable to that of other benzodiazepines.

Animals↗
PubMed2003

GABA(A) receptor activation modulates corneal unit activity in rostral and caudal portions of trigeminal subnucleus caudalis.

Corneal nociceptors terminate at the trigeminal subnucleus interpolaris/caudalis (Vi/Vc) transition and subnucleus caudalis/upper cervical spinal cord (Vc/C1) junction regions of the lower brain stem. The aims of this study were to determine if local GABAA receptor activation modifies corneal input to second-order neurons at these regions and if GABAA receptor activation in one region affects corneal input to the other region. In barbiturate-anesthetized male rats, corneal nociceptors were excited by pulses of CO2 gas, and GABAA receptors were activated by microinjections of the selective agonist muscimol. Local muscimol injection at the site of recording inhibited all Vi/Vc and Vc/C1 units tested and was reversed partially by bicuculline. To test for ascending intersubnuclear communication, muscimol injection into the caudal Vc/C1 junction, remote from the recording site at the Vi/Vc transition, inhibited the evoked response of most corneal units, although some neurons were enhanced. Injection of the nonselective synaptic blocking agent, CoCl2, remotely into the Vc/C1 region inhibited the evoked response of all Vi/Vc units tested. To test for descending intersubnuclear communication, muscimol was injected remotely into the rostral Vi/Vc transition and enhanced the evoked activity of all corneal units tested at the caudal Vc/C1 junction. These results suggest that GABAA receptor mechanisms play a significant role in corneal nociceptive processing by second-order trigeminal brain stem neurons. GABAA receptor mechanisms act locally at both the Vi/Vc transition and Vc/C1 junction regions to inhibit corneal input and act through polysynaptic pathways to modify corneal input at multiple levels of the trigeminal brain stem complex.

Action Potentials↗
PubMed2005

GABA induces activity dependent delayed-onset uncoupling of GABA/benzodiazepine site interactions in neocortical neurons.

Changes in the function of type A gamma-aminobutyric acid receptors (GABA(A)Rs) are associated with neuronal development and tolerance to the sedative-hypnotic effects of GABA(A)R positive modulators. Persistent activation of GABA(A)Rs by millimolar concentrations of GABA occurs under physiological conditions as GABAergic fast-spiking neurons in neocortex and cerebellum exhibit basal firing rates of 5 to 50 Hz and intermittent rates up to 250 Hz, leaving a substantial fraction of synaptic receptors occupied persistently by GABA. Persistent exposure of neurons to GABA has been shown to cause a down-regulation of receptor number and an uncoupling of GABA/benzodiazepine (BZD) site interactions with a half-life of approximately 24 h. Here, we report that a single brief exposure of neocortical neurons in primary culture to GABA for 5-10 min (t(1/2) = 3.2 +/- 0.2 min) initiates a process that results in uncoupling hours later (t(1/2) = 12.1 +/- 2.2 h). Initiation of delayed-onset uncoupling is blocked by co-incubation with picrotoxin or alpha-amanitin but is insensitive to nifedipine, indicating that uncoupling is contingent upon receptor activation and transcription but is not dependent on voltage-gated Ca2+ influx. Delayed-onset uncoupling occurs without a change in receptor number or a change in the proportion of alpha1 subunit pharmacology, as zolpidem binding affinity is unaltered. Such activity dependent latent modulation of GABA(A)R function that manifests as delayed-onset uncoupling may be relevant to physiological, pathophysiological, and pharmacological conditions where synaptic receptors are transiently exposed to GABA agonists for several minutes.

Amanitins↗
PubMed2005

Pharmacological properties of GABAA receptors containing gamma1 subunits.

GABA(A) receptors composed of alpha(1), beta(2), gamma(1) subunits are expressed in only a few areas of the brain and thus represent interesting drug targets. The pharmacological properties of this receptor subtype, however, are largely unknown. In the present study, we expressed alpha(1)beta(2)gamma(1)-GABA(A) receptors in Xenopus laevis oocytes and analyzed their modulation by 21 ligands from 12 structural classes making use of the two-microelectrode voltage-clamp method and a fast perfusion system. Modulation of GABA-induced chloride currents (I(GABA)) was studied at GABA concentrations eliciting 5 to 10% of the maximal response. Triazolam, clotiazepam, midazolam, 2-(4-methoxyphenyl)-2,3,5,6,7,8,9,10-octahydro-cyclohepta-(b)pyrazolo[4,3-d]pyridin-3-one (CGS 20625), 2-(4-chlorophenyl)-pyrazolo[4,3-c]quinolin-3-one (CGS 9896), diazepam, zolpidem, and bretazenil at 1 microM concentrations were able to significantly (>20%) enhance I(GABA) in alpha(1)beta(2)gamma(1) receptors. Methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, 3-methyl-6-[3-trifluoromethyl-phenyl]-1,2,4-triazolo[4,3-b]pyridazine (Cl 218,872), clobazam, flumazenil, 5-(6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-3-methyl-[1,2,4]-oxadiazole (Ru 33203), 2-phenyl-4-(3-ethyl-piperidinyl)-quinoline (PK 9084), flurazepam, ethyl-7-methoxy-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c] [1,4]benzodiazepine-1-carboxylate (l-655,708), 2-(6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-methyl-thiazole (Ru 33356), and 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)phenylmethanone (Ru 32698) (1 microM each) had no significant effect, and flunitrazepam and 2-phenyl-4-(4-ethyl-piperidinyl)-quinoline (PK 8165) inhibited I(GABA). The most potent compounds triazolam, clotiazepam, midazolam, and CGS 20625 were investigated in more detail on alpha(1)beta(2)gamma(1) and alpha(1)beta(2)gamma(2S) receptors. The potency and efficiency of these compounds for modulating I(GABA) was smaller for alpha(1)beta(2)gamma(1) than for alpha(1)beta(2)gamma(2S) receptors, and their effects on alpha(1)beta(2)gamma(1) could not be blocked by flumazenil. CGS 20625 displayed the highest efficiency by enhancing at 100 microM I(GABA) (alpha(1)beta(2)gamma(2)) by 775 +/- 17% versus 526 +/- 14% I(GABA) (alpha(1)beta(2)gamma(1)) and 157 +/- 17% I(GABA) (alpha(1)beta(2)) (p < 0.05). These data provide new insight into the pharmacological properties of GABA(A) receptors containing gamma(1) subunits and may aid in the design of specific ligands for this receptor subtype.

Animals↗
PubMed1986

Modulation of the GABA-benzodiazepine receptor complex by taurine in rat brain membranes.

The interactions of taurine and its precursor hypotaurine with the GABA-benzodiazepine receptor complex were studied by investigating their effects on GABA and flunitrazepam binding in rat brain membranes. Taurine, and to a lesser degree also hypotaurine, displaced the high- and low-affinity GABA binding. The maximal binding capacities of both sites were decreased in the presence of taurine, while the binding constants remained the same, suggesting noncompetitive interactions. Taurine and hypotaurine affected flunitrazepam binding only at a very high concentration (50 mmol/l), whereas GABA (within the concentration range of 0.1-100 mumol/l) significantly enhanced the binding. Taurine inhibited the GABA-stimulated binding dose-dependently. These modulatory effects of taurine on the GABA-benzodiazepine receptor complex could result from interactions with the GABA recognition site but not from direct actions on the benzodiazepine site.

Animals↗
PubMed1996

Evidence for an in vivo and in vitro modulation of endogenous cortical GABA release by alpha-glycerylphosphorylcholine.

The effects of alpha-glycerylphosphorylcholine (alpha-GPC) on endogenous cortical GABA release were studied both in vivo and in vitro. In freely moving rats, equipped with epidural cups, alpha-GPC (30-300 mg/kg i.p.) increased GABA release. This effect was potentiated by atropine, both systematically administered (5 mg/kg i.p.) and locally applied (1.4 microM), but not by mecamylamine (4 mg/kg i.p.). The alpha-GPC-induced increase in GABA release was abolished in rats pretreated with the alpha 1 receptor antagonist prazosin (14 micrograms/kg i.p.). In cortical slices alpha-GPC (0.4 mM) increased the spontaneous GABA efflux. This effect was abolished by tetrodotoxin (0.5 microM) and prazosin (1 microM), but not by atropine (0.15 microM) or mecamylamine (2.5 microM). These results indicate that the facilitatory response by alpha-GPC on GABA release does not depend on a direct activation of either muscarinic or nicotinic receptors, but suggest the involvement of the noradrenergic system.

Animals↗
PubMed2001

Triazolam discrimination in squirrel monkeys distinguishes high-efficacy agonists from other benzodiazepines and non-benzodiazepine drugs.

RATIONALE: Triazolam is a high-efficacy benzodiazepine (BZ) agonist, which might be hypothesized to engender highly pharmacologically specific discriminative stimulus (DS) effects and distinguish among BZ agonists with different intrinsic efficacy. OBJECTIVES: The pharmacological specificity of the triazolam stimulus was determined by examining the effects of conventional and atypical BZ agonists, and other ligands active at the gamma-aminobutyric acidA (GABAA) receptor complex. Receptor mechanisms underlying the DS effects of triazolam were examined further using the BZ receptor antagonist flumazenil. METHODS AND RESULTS: Squirrel monkeys were trained to discriminate triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 (FR 10) schedule of food reinforcement. While the BZ agonists midazolam, diazepam, and lorazepam substituted fully for triazolam, chlordiazepoxide, oxazepam and nordiazepam produced only partial substitution, suggesting these latter compounds may have reduced intrinsic efficacy. The BZ/alpha1-preferring agonist zolpidem substituted fully for triazolam, and potencies for triazolam-like effects of BZ agonists were significantly correlated with potencies for their zolpidem-like effects (Rowlett et al. 1999). Flumazenil antagonized the DS effects of triazolam, but the slope of the Schild plot was significantly different from unity, suggesting multiple receptors may be involved in the DS effects of triazolam. CONCLUSIONS: BZ agonists can be distinguished on the basis of substitution for triazolam and, thus, the triazolam discrimination may be a useful tool for identifying compounds of different efficacy at BZ receptors. BZ/alpha1 receptors appear to play a prominent role in the DS effects of triazolam, but the contribution of other subtypes of BZ receptors cannot be ruled out.

Animals↗
PubMed2001

Forskolin modulation of desensitization at GABA(A) and glycine receptors is not mediated by cAMP-dependent protein kinase in isolated carp amacrine-like cells.

The effects of forskolin on gamma-aminobutyric acid type-A (GABA(A)) and glycine receptors in amacrine-like cells of carp (Carassius auratus) retina were studied using patch-clamp techniques. Application of 50 microM forskolin markedly accelerated the desensitization of whole-cell responses induced by 100 microM GABA or glycine without changing the peak amplitude of the response. Both 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) and 3-isobutyl-1 -methylxanthine (IBMX) (500 microM) failed to accelerate the desensitization of these two receptors. Protein kinase A (PKA) inhibitors, N- [2-[(p-bromocinnamyl)amino]ethyl)-5-isoquinolinesulfonamide dihydrochloride (H-89) and N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-8), could not block these effects of forskolin. An inactive analogue of forskolin, 1,9-dideoxyforskolin (DFSK), accelerated the desensitization effectively. These results suggest that forskolin's effects are not mediated by activation of the PKA pathway. Moreover, similar results were obtained using excised outside-out patches of these cells, suggesting that forskolin may act on an extracellular site(s). The neurosteroids 5alpha-pregnane-3alpha,21 -diol-20-one (THDOC) and 5-pregnen-31 -ol-20-one sulfate sodium (PS), structural analogues of forskolin, accelerated the desensitization of these receptors without changing the peak amplitudes, thus mimicking forskolin's effects. Furthermore, PS interacted with forskolin on these receptors so as to slow down the responses. These results raise the possibility that forskolin acts directly on an extracellular site(s) of the GABA(A) and glycine receptors, shared with neurosteroids, in carp amacrine-like cells.

Animals↗
PubMed1989

Central-type benzodiazepines and the octadecaneuropeptide modulate the effects of GABA on the release of alpha-melanocyte-stimulating hormone from frog neurointermediate lobe in vitro.

The involvement of the GABA-benzodiazepine receptor complex in the regulation of melanotropin secretion has been investigated using perfused frog neurointermediate lobes. The GABAA agonist 3-amino-1 propane sulfonic acid mimicked the biphasic effect of GABA on alpha-melanocyte-stimulating hormone secretion: a brief stimulation followed by an inhibition of melanotropin secretion. The GABAA antagonist SR 95531 (10(-4) M) inhibited both stimulation and inhibition of alpha-melanocyte-stimulating hormone release induced by GABA (10(-4) M). Since the inhibitory effect of baclofen (10(-4) M) was partially antagonized by SR 95531 (10(-4) M), it appears that the GABAergic control of alpha-melanocyte-stimulating hormone release is mainly achieved through activation of GABAA receptors. GABA-induced stimulation of alpha-melanocyte-stimulating hormone release was inhibited by tetrodotoxin (10(-5) M), an Na+ -channel blocker, or nifedipine (10(-5) M), a voltage-dependent Ca2+ -channel blocker, suggesting that Na+ and Ca2+ ions are involved in the stimulatory phase of GABA action. Only central-type benzodiazepine binding site agonists such as clonazepam (10(-4) M) modified alpha-melanocyte-stimulating hormone release. In fact, clonazepam (10(-7) to 10(-5) M) led to a dose-dependent potentiation of both GABA-induced stimulation and inhibition of alpha-melanocyte-stimulating hormone release. This potentiating effect was antagonized by the GABAA antagonist SR 95531 (10(-4) M) or by the central-type benzodiazepine binding site antagonist flumazenil (10(-4) M), whereas picrotoxin (10(-4) M) abolished only the stimulatory phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Neuronal localization of the GABA transporter GAT-3 in human cerebral cortex: a procedural artifact?

Gamma-amino butyric acid (GABA) plasma membrane transporters (GATs) contribute to the modulation of GABA's actions and are implicated in neuropsychiatric diseases. In this study, the localization of GAT-3, the major glial GAT, was investigated in human cortex using immunocytochemical techniques. In prefrontal and temporal cortices, GAT-3 immunoreactivity (ir) was present throughout the depth of the cortex, both in puncta and in neurons. GAT-3-positive puncta were dispersed in the neuropil or closely related to cell bodies; neuronal staining was in perikarya, especially of pyramidal cells, and proximal dendrites. Electron microscopic studies showed that GAT-3 ir was in astrocytic processes as well as in neuronal elements. All GAT-3-positive neurons co-expressed heat shock protein 70. To test the possibility that the collection procedure of human samples induced the expression of GAT-3 in neurons which normally do not express it, we analyzed rat cortical tissue resected using the same procedure and found that numerous neurons are GAT-3-positive and that they co-express heat shock protein 70. Results show that in human cortex GAT-3 is expressed in astrocytic processes and in neurons and suggest that neuronal expression is related to the procedure used for collecting human samples.

Animals↗
PubMed2005

Ethanol modulates the expression of GABA(B) receptor mRNAs in the prenatal rat brain in an age and area dependent manner.

Prenatal ethanol exposure has various deleterious effects on neuronal development. As GABA(B) receptor is known to play an important role during the development of the CNS, we now focused on its mRNA expression pattern in the rat brain during the late gestational days (GD) from 15.5 to GD 21.5. Ethanol's effect was also observed from GD 11.5 to GD 21.5. GABA(B1) receptor mRNA showed a high expression level in GD 15.5 and 19.5, while GABA(B2) receptor mRNA did in GD 15.5 and 21.5. The mRNAs levels depended on age and area during development. Ethanol exposure decreased GABA(B1) receptor from GD 11.5 to GD 19.5 with slight increases in GD 21.5. The decreasing effects were area dependent, with the highest effects in the forebrain including cortex, whereas slight effects were observed in the midbrain and hindbrain. The present results suggest an important role of GABA(B) receptor in the effects of ethanol on prenatal brain developmental processes.

Age Factors↗
PubMed1998

Neurotensin modulation of acetylcholine and GABA release from the rat hippocampus: an in vivo microdialysis study.

The effects of neurotensin (NT) on the release of acetylcholine (ACh), aspartate (Asp), glutamate (Glu) and gamma-aminobutyric acid (GABA) from the hippocampus of freely moving rats were studied by transversal microdialysis. ACh was detected by High Performance Liquid Chromatography (HPLC) with electrochemical detection while GABA, glutamate and aspartate were measured using HPLC with fluorometric detection. Neurotensin (0.2 and 0.5 microM) administered locally through the microdialysis probe to the hippocampus produced a long-lasting and concentration-dependent increase in the basal extracellular levels of GABA and ACh but not of glutamate and aspartate. The increase in the extracellular levels of GABA and ACh produced by 0.5 microM neurotensin in the hippocampus reached a maximum of about 310% for GABA and 250% for ACh. This stimulant effect of NT was antagonized by the NT receptor antagonist SR 48692 (100 microg/kg, i.p.). Local infusion of tetrodotoxin (1 microM) decreased the basal release of ACh, GABA, Asp, Glu and prevented the 0.2 microM NT-induced increase in GABA and ACh release. The effect of NT on the release of ACh was blocked by the GABA(A) receptor antagonist bicuculline (2-10 microM). Our findings indicate for the first time that neurotensin plays a neuromodulatory role in the regulation of GABAergic and cholinergic neuronal activity in the hippocampus of awake and freely moving rats. The potentiating effects of neurotensin on GABA and ACh release in the hippocampus are probably mediated by (i) NT receptors located on GABAergic cell bodies and (ii) through GABA(A) receptors located on cholinergic nerve terminals.

Acetylcholine↗
PubMed2000

Reciprocal modulation of glutamate and GABA release may underlie the anticonvulsant effect of phenytoin.

Although conventional wisdom suggests that the effectiveness of phenytoin as an anticonvulsant is due to blockade of Na+-channels this is unlikely to be it's sole mechanism of action. In the present paper we examined the effects of phenytoin on evoked and spontaneous transmission at excitatory (glutamate) and inhibitory (GABA) synapses, in the rat entorhinal cortex in vitro. Evoked excitatory postsynaptic potentials at glutamate synapses exhibited frequency-dependent enhancement, and phenytoin reduced this enhancement without altering responses evoked at low frequency. In whole-cell patch-clamp recordings the frequency of excitatory postsynaptic currents resulting from the spontaneous release of glutamate was reduced by phenytoin, with no change in amplitude, rise time or decay time. Similar effects were seen on miniature excitatory postsynaptic currents, recorded in the presence of tetrodotoxin. Evoked inhibitory postsynaptic potentials at GABA synapses displayed a frequency-dependent decrease in amplitude. Phenytoin caused a reduction in this decrement without affecting the responses evoked at low frequency. The frequency of spontaneous GABA-mediated inhibitory postsynaptic currents, recorded in whole-cell patch mode, was increased by phenytoin, and this was accompanied by the appearance of much larger amplitude events. The effect of phenytoin on the frequency of inhibitory postsynaptic currents persisted in the presence of tetrodotoxin, but the change in amplitude distribution largely disappeared. These results demonstrate for the first time that phenytoin can cause a simultaneous reduction in synaptic excitation and an increase in inhibition in cortical networks. The shift in balance in favour of inhibition could be a major factor in the anticonvulsant action of phenytoin.

2-Amino-5-phosphonovalerate↗
PubMed2000

Protein kinase and phosphatase modulation of quail brain GABA(A) and non-NMDA receptors co-expressed in Xenopus oocytes.

The GABA(A) receptor and the non-NMDA subtype of the ionotropic glutamate receptor were co-expressed in Xenopus oocytes by injection of quail brain mRNA. The oocytes were treated with various protein kinase (PK) and protein phosphatase (PP) activators and inhibitors and the effects on receptor functioning were monitored. Two phorbol esters, 4-beta-phorbol 12-myristate-13-acetate (PMA) and 4-beta-phorbol 12,13-dibutyrate (PDBu); the cGMP-dependent PK activators sodium nitroprusside (SNP) and S-nitrosoglutathione (SNOG); and the PP inhibitor okadaic acid (OA) reduced the amplitude of the GABA-induced currents, whilst the PK inhibitor staurosporine potentiated it. In addition, PMA, PDBu, SNP, and OA reduced the desensitization of the GABA-induced response. Identical treatments generally had similar but less pronounced effects on responses generated by kainate (KA) but the desensitization characteristic of the non-NMDA receptor was not affected. None of the treatments had any effect on the reversal potentials of the induced currents. Immunoblots revealed that the oocytes express endogenous PKG and guanylate cyclase. The results are discussed in terms of the molecular structures of GABA(A) and non-NMDA receptors and the potential functional consequences of phosphorylation/dephosphorylation.

Animals↗