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PubMed1998

Biosynthesis of progesterone derived neurosteroids by developing avian CNS: in vitro effects on the GABAA receptor complex.

It has been demonstrated in different vertebrate species that the GABAA receptor complex is modulated by certain steroids. Theses results prompted work on the synthesis of these neurosteroids in the Central Nervous System. However, there are scarcely any studies analyzing their production or their modulatory effects on this receptor during development. In this work, the biosynthesis of [14C]progesterone metabolites as well as the characterization of their in vitro effects on the GABAA receptor complex in developing chick optic lobe were investigated. Studies on progesterone metabolism indicated that this steroid was converted to 5 beta-pregnanedione, 5 beta-pregan-3 beta-ol-20-one, and a 20-hydroxy derivative. Radioactive progesterone was completely metabolized at early embryonic stages, and a great proportion of 5 beta-pregnanedione was converted to 5 beta-pregnan-3 beta-ol-20-one. Thus, it seems that some of the steroidogenic activities present in chick optic lobe are age-dependent, though greater at embryonic stages. Results from in vitro modulation of [3H]flunitrazepam binding by 5 beta-pregnan-3 beta-ol-20-one indicated that this steroid produces a one-component-concentration dependent enhancement above control binding. 5 beta-pregnan-3 beta-ol-20-one EC50 values were 0.195 +/- 0.049, 0.101 +/- 0.017, 0.147 +/- 0.009, and 0.569 +/- 0.114 microM, and Emax were 22.37 +/- 1.57, 23.67 +/- 4.02, 29.01 +/- 1.08, and 15.11 +/- 2.67% at embryonic days 11, 14, hatching, and postnatal day 21, respectively. In conclusion, the biosynthesis of 5 beta-pregnan-3 beta-ol-20-one from progesterone in developing chick optic lobe, together with its ability to modulate the GABAA receptor present in such tissues, suggests a physiological role of this neurosteroid in developing avian Central Nervous System.

Animals↗
PubMed2001

GABA(A) receptor gene expression in rat cortex: differential effects of two chronic diazepam treatment regimes.

Diazepam is widely prescribed as an anxiolytic but its therapeutic application is limited because with daily use tolerance develops to certain aspects of its pharmacological profile. We compared the effects of two dosing paradigms on GABA(A) receptor gene expression and benzodiazepine binding characteristics. Equivalent daily doses of 15 mg/kg/day diazepam were delivered either via constant infusion or daily subcutaneous injection for 14 days. The two distinct treatment regimes produced significantly different changes in GABA(A) receptor alpha4-, beta2-, beta3- and gamma1-subunit mRNA steady-state levels. Similar changes in the GABA enhancement of flunitrazepam binding and the BZ3/BZ2 subtype ratio determined ex vivo were produced, however, significant differences were found in [(3)H]-Ro 15-4513 binding between cortical tissue from diazepam injected animals compared with diazepam infused animals. Our data suggest that it is the diurnal fluctuations in receptor occupancy that are responsible for the different effects produced by these two dosing regimes.

Affinity Labels↗
PubMed1992

Local application of bicuculline potentiates NMDA-receptor-mediated sensory responses of brain noradrenergic neurons.

Direct application of bicuculline methiodide (BIC) to noradrenergic locus coeruleus (LC) neurons potently enhanced their sensory responsiveness. This increased responsiveness was due to the long-lasting expression of a new, N-methyl-D-aspartate (NMDA) receptor-mediated component of the synaptic response. This enhancement only occurred when a high stimulus intensity was used to induce the sensory response. A similar increase in responsiveness was observed with stimulation of the nucleus paragigantocellularis (PGi), one of the major direct afferents to LC. This action of BIC was neither mimicked by picrotoxin, penicillin, or the GABA-B antagonist, 2-hydroxy-baclofen, nor by agents that directly depolarize LC neurons. In addition, the inverse agonist of the benzodiazepine receptor, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), did not mimic this effect of BIC. The BIC-potentiated response component was eliminated by direct application of the neurotransmitter gamma-aminobutyric acid (GABA). These results indicate that BIC, acting at a possibly novel site, unmasks NMDA receptors that can be activated by sensory stimuli. This may reflect a mechanism whereby interactions between two major neurotransmitter systems, excitatory amino acids (EAAs) and GABA, potently modulate signal transmission in the brain.

2-Amino-5-phosphonovalerate↗
PubMed1996

Effect of the neuroactive steroid alpha-THDOC on staircase test behavior in mice.

This study examined the effect of the neuroactive steroid 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone (alpha-THDOC) as compared to the benzodiazepines diazepam and midazolam and the barbiturate phenobarbital on the number of rearing events and the number of steps ascended in the mouse staircase test. The benzodiazepines, phenobarbital and alpha-THDOC all reduced rearing activity at doses that did not affect climbing. The rearing-suppression effect of the benzodiazepines and alpha-THDOC, but not of phenobarbital, was blocked by the benzodiazepine antagonist flumazenil. It appears that, although such neuroactive steroids, like barbiturates, bind to distinct sites within the chloride ion channel of the gamma-aminobutyric acid type A (GABAA) receptor complex, alpha-THDOC behavioral activity is modulated by the benzodiazepine recognition site.

Animals↗
PubMed2005

Benzodiazepine involvement in LTP of the GABA-ergic IPSC in rat hippocampal CA1 neurons.

Benzodiazepine binding sites are present on gamma-aminobutyric acid (GABA) receptors in hippocampal neurons. Diazepam is known to potentiate the amplitude and prolong the decay of GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs). In this study, benzodiazepine involvement in long-term potentiation (LTP) of the IPSC was examined. Whole-cell recordings of IPSCs were made from rat hippocampal CA1 neurons in a slice preparation. LTP was induced by a tetanic stimulation in the stratum radiatum (2 trains of 100 Hz for 1 s, 20 s inter-train interval) while pharmacologically blocking ionotropic glutamate receptors. During LTP, the amplitude of the IPSCs was potentiated in the majority of neurons with the IPSC decay and shape unaffected. Diazepam (5 microM) potentiated the IPSC amplitude and prolonged the decay when applied before, but not during, LTP. In neurons in which LTP could not be induced by a tetanic stimulation, diazepam did not increase the amplitude of the pre-tetanic IPSC. Flumazenil, at a concentration (10 microM) that blocked the enhancement of the IPSC by applied diazepam, had no effect on the IPSC amplitude when applied before LTP induction but significantly decreased the IPSC when applied during LTP maintenance. The antagonist, when applied during the tetanic stimulation, did not block LTP, suggesting that benzodiazepine receptors do not participate in LTP induction. These results indicate that the maintenance of LTP of the IPSC involves (a) the release of endogenous benzodiazepine agonist(s) and/or (b) the participation of benzodiazepine binding sites on subsynaptic GABA(A) receptors.

Action Potentials↗
PubMed1997

Diazepam protects against rat hippocampal neuronal cell death induced by antisense oligodeoxynucleotide to GABA(A) receptor gamma2 subunit.

Antisense oligodeoxynucleotides (ODNs) are used for the selective inhibition of gene expression. Antisense ODNs are promising tools for the investigation of physiological implications of proteins in the central nervous system of rodents in vivo. We have previously demonstrated that a phosphorothioate antisense ODN to the GABA(A) receptor gamma2 subunit, but not sense or mismatch control ODNs, induces a decrease in ex vivo benzodiazepine receptor radioligand binding in rat hippocampus when infused into the hippocampus in vivo [Karle et al., Neurosci. Lett., 202 (1995) 97-100]. This effect is parallelled by a decrease in the number of GABA(A) receptors and an extensive loss of hippocampal neurones. There is increasing awareness of risks of toxic 'non-antisense' effects induced by ODNs, and in particular phosphorothioate ODNs. The present experiments were designed to investigate the specificity of effects induced by the gamma2 subunit antisense ODN. The temporal development of changes in [3H]flunitrazepam and [3H]quinuclidinyl benzilate binding as well as in tissue protein levels supports the notion that the antisense ODN primarily acts by blocking the expression of the targeted receptor subunit protein. Furthermore, it is shown that a threshold for the elicitation of neurodegenerative changes exists. Finally, it is demonstrated that diazepam treatment of rats protects against the development of neuronal cell death induced by the antisense ODN. Collectively, the results support the hypothesis that the neurodegeneration induced by the antisense ODN is a consequence of diminished GABAergic inhibitory tonus following a selective down-regulation of gamma2 subunit-containing GABA(A) receptor complexes.

Animals↗
PubMed1996

Reversible modification of GABAA receptor subunit mRNA expression during tolerance to diazepam-induced cognition dysfunction.

Benzodiazepines (BZs) that are endowed with full positive allosteric modulatory (FAM) activity on GABAA receptors cause anterograde amnesia in both animals and humans. In rats subjected to a delayed object recognition test, diazepam, endowed with FAM activity, exerted an amnesic action, whereas BZs endowed with partial allosteric modulatory (PAM) activity on GABAA receptors, such as imidazenil, failed to induce amnesia, even if administered at doses five times higher than those equipotent to a standard anticonvulsant dose of diazepam (17.6 mumol/kg/os). After discontinuation of 14 days' treatment with vehicle, diazepam, or imidazenil (three times daily with increasing doses starting from 17.6 mumol/kg/os for diazepam and 2.5 mumol/kg/os for imidazenil), we compared the persistence of tolerance to the amnesic effect of diazepam with the persistence of the changes in the context of four (alpha 1, alpha 5, gamma 2L, gamma 2S) GABAA receptor subunit mRNAs in the fronto-parietal motor (FrPaM) cortex and the hippocampus. Rats receiving the long-term treatment with diazepam developed a tolerance to the amnesic effect of this drug and showed a decrease (30-50%) in the expression of mRNAs encoding for alpha 1 gamma 2L, gamma 2S GABAA receptor subunits, an increase, by approximately 30%, of the expression of mRNA of the alpha 5 subunit in the FrPaM cortex and a decrease, by approximately 25%, in the expression of mRNA, of the alpha 1 subunit in the hippocampus. These changes of subunit mRNA expression and the tolerance to the amnesic effect of diazepam returned to control values 72 hr after termination of the long-term treatment with diazepam. No tolerance to the amnesic effect of diazepam and no changes in GABAA receptor subunit mRNA expression were found in rats undergoing long-term treatment with imidazenil.

Animals↗
PubMed2001

Dehydroepiandrosterone sulphate prevents oxygen-glucose deprivation-induced injury in cerebellar granule cell culture.

Decreased levels of dehydroepiandrosterone sulphate have been hypothesized to contribute to increased vulnerability of the ageing or stressed human brain to ischemia. To help to address the question of whether of dehydroepiandrosterone sulphate has a possible neuroprotective effect against ischemic neuronal injury, we tested its effect on the neurodegeneration induced by oxygen-glucose deprivation in rat cultured cerebellar granule cells. Dehydroepiandrosterone sulphate added to the medium after injury demonstrated a neuroprotective effect with a median inhibitory concentration of 0.5 microM. At 10 microM concentration almost full neuroprotection was observed. Even more pronounced neuroprotective effect was found when dehydroepiandrosterone sulphate was added for 48h before injury. Furthermore, partial neuroprotection of dehydroepiandrosterone sulphate was also found against 1-methyl-4-phenylpyridinium, colchicine, glutamate and N-methyl-D-aspartate-induced toxicity. Further analysis demonstrated that dehydroepiandrosterone sulphate eliminated the apoptotic features of the oxygen-glucose deprivation-induced neuronal death: DNA fragmentation and nuclear condensation/fragmentation.Thus, our data suggest that dehydroepiandrosterone sulphate may have therapeutic potential in the prevention and treatment of ischemic/hypoxic neuronal damage. The neuroprotective action of dehydroepiandrosterone sulphate was inhibited by both a GABA(A) receptor-linked chloride channel agonist and an antagonist, pentobarbital and picrotoxin, respectively. It seems that GABA(A) receptor-mediated neuronal inhibition as well as neuronal excitation can reduce the neuroprotective action of dehydroepiandrosterone sulphate.

1-Methyl-4-phenylpyridinium↗
PubMed1997

Plasticity in fast synaptic inhibition of adult oxytocin neurons caused by switch in GABA(A) receptor subunit expression.

We found that magnocellular oxytocin neurons in adult female rats exhibit an endogenous GABA(A) receptor subunit switch around parturition: a decrease in alpha1:alpha2 subunit mRNA ratio correlated with a decrease in allopregnanolone potentiation and increase in decay time constant of the GABA(A) receptor-mediated IPSCs in these cells. The causal relationship between changes in alpha1:alpha2 mRNA ratio and the ion channel kinetics was confirmed using in vitro antisense deletion. Further, GABA(A) receptors exhibited a tonic inhibitory influence upon oxytocin release in vivo, and allopregnanolone helped to restrain oxytocin neuron in vitro firing only before parturition, when the alpha1:alpha2 subunit mRNA ratio was still high. Such observations provide evidence for the physiological significance of GABA(A) receptor subunit heterogeneity and plasticity in the adult brain.

Animals↗
PubMed2002

Structure-activity relationships of flavonoids, isolated from Scutellaria baicalensis, binding to benzodiazepine site of GABA(A) receptor complex.

Twenty-six flavonoids were isolated from Scutellaria baicalensis. Their affinities for the benzodiazepine (BDZ) binding site of GABA A receptor have been studied using [ 3H]flunitrazepam binding to rat cortical membranes in vitro. The structure-activity relationships suggested that 2'-OH flavones exhibited the most potent binding affinity, which could lead to the design and discovery of new BDZ receptor ligands.

Animals↗
PubMed1999

Postoperative obstructive apnea.

UNLABELLED: We studied electromyography (EMG) of the geniohyoid muscle (Gh) and diaphragm (Di) in 12 postoperative, premedicated (flunitrazepam 2 mg PO), asymptomatic patients who snored after recovering from general anesthesia, the induction of which was partly achieved by i.v. midazolam. After extubation of the trachea, integrated EMG activity of Gh (E-Gh(MTA)) and Di (E-Di(MTA)) were measured. For Gh, tonic and phasic activity were distinguished. Patients were studied during obstructive apnea, at the end of apnea, while breathing through an artificial Guedel airway, and during quiet breathing 5 min after flumazemil. All patients experienced episodes of postoperative upper airway obstruction and nine became apneic. Flumazenil restored consciousness and predominant tonic E-GhMTA associated with upper airway patency in all patients. Reduced tonic E-GhMTA characterized postoperative obstructive apnea. Resolution of apnea required a burst of both tonic and phasic E-GhMTA associated with intense E-Di(MTA). Breathing through the Guedal airway resulted in patent airway in 8 of 10 patients and was associated with low tonic and phasic E-GhMTA and reduced E-Di(MTA). In this study, we demonstrated that the tonic pharyngeal muscular support modulates airway patency in the postoperative period. Because it is reversed by flumazemil, benzodiazepines are certainly the main cause of airway obstruction in these patients. IMPLICATIONS: Upper airway obstruction during recovery from general anesthesia induced by i.v. midazolam is associated with low tonic pharyngeal muscular support, which modulates upper airway patency in the postoperative period.

Adult↗
PubMed1999

Acetazolamide and amiloride inhibit pentobarbital-induced facilitation of nocifensive reflexes.

BACKGROUND: Neuronal excitation may result from stimulation of gamma-aminobutyric acid A (GABA(A)) receptors that prolong the channel opening, depolarizing the postsynaptic membrane. Drugs such as acetazolamide or amiloride can block GABA depolarization. Barbiturates facilitate nociceptive reflexes and also prolong the GABA(A) channel open-time. To evaluate the possible mechanism, the authors studied the impact of acetazolamide and amiloride on pentobarbital-induced nocifensive reflex facilitation. Because nitric oxide (NO) is a mediator of reflex facilitation, the authors evaluated the effects of NO synthase inhibition. METHODS: Nocifensive reflex thresholds were quantified with the hind paw withdrawal latency from radiant heat (HPW latency) in the rat. Nocifensive reflexes were facilitated with intraperitoneal injection of pentobarbital (30 mg/kg). The authors tested the roles of GABA-mediated depolarization and NO in reflex facilitation by pretreatment with acetazolamide and amiloride and inhibition of NO synthase with L-NAME and 7-NI, respectively. Sedative effects of pentobarbital were evaluated with the righting reflex, the response to vibrissal stimulation, and plasma drug concentrations. RESULTS: Pentobarbital decreased the hind paw withdrawal latency from 11.2+/-1 to 8.3+/-1 s (P < 0.001). Pretreatment with each of the four test drugs limited the reduction in reflex facilitation after pentobarbital to 1.3 s or less, similar to the reduction seen after saline injection, without altering sedation. L-NAME increased plasma pentobarbital concentrations by 10% without changing the concentration associated with return of responsiveness. CONCLUSIONS: Pentobarbital-induced nocifensive reflex facilitation was inhibited by all four tested drugs without evidence of increased sedation. The results are consistent with a role for GABA(A) receptor-mediated depolarization in barbiturate-induced hyper-reflexia.

Acetazolamide↗
PubMed1999

Analgesic interaction between intrathecal midazolam and glutamate receptor antagonists on thermal-induced pain in rats.

BACKGROUND: Two major neurotransmitters, gamma-aminobutyric acid (GABA) and the excitatory amino acid, glutamate, may be involved in nociception in the spinal cord. GABA and glutamate receptors may operate in concert to modify signals in the central nervous system. The purpose of this study was to investigate the spinal analgesic interaction between midazolam, a benzodiazepine-GABA(A) receptor agonist, and two glutamate receptor antagonists on acute thermal nociception. METHODS: Sprague-Dawley rats were implanted with chronic lumbar intrathecal catheters and were tested for their tail withdrawal response by the tail flick test after intrathecal administration of saline, midazolam (1-100 microg), AP-5 (1-30 microg), or YM872 (0.3-30 microg). AP-5 is an N-methyl-D-aspartate (NMDA) receptor antagonist and YM872 is an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist. The combination of midazolam and the other two agents were also tested by isobolographic analyses. Motor disturbance and behavioral changes were observed. RESULTS: Dose-dependent increases in the tail flick latency were observed with midazolam, AP-5, and YM872 with 50% effective dose values of 1.57+/-0.34 (SEM) microg, 5.54+/-0.19 microg, and 1.0+/-0.22 microg, respectively. A potent synergy in analgesia with decreased behavioral changes and motor disturbance was obtained when combining midazolam with AP-5 or YM872. CONCLUSIONS: Spinally administered midazolam and an NMDA- or an AMPA-receptor antagonist exhibited potent synergistic analgesia on acute thermal nociception in rats. Side effects, shown by behavioral changes and motor disturbance, decreased with the combination of the agents. These results point out an important direction for the study of acute nociception.

2-Amino-5-phosphonovalerate↗
PubMed2001

Confluence of antianalgesic action of diverse agents through brain interleukin(1beta) in mice.

Spinal dynorphin A(1-17) (Dyn) has been shown previously to produce an antianalgesic action against intrathecal morphine in the tail-flick test in CD-1 mice. This action is known to be mediated indirectly from the spinal cord through an afferent pathway that activates flumazenil-sensitive benzodiazepine receptors in the brain and a descending circuit back down to the spinal cord sequentially involving cholecystokinin, leu-enkephalin, and N-methyl-D-aspartate receptors to produce antianalgesia. Interleukin (IL)-1beta is also known to act on peripheral afferent nerves to the brain to activate a descending circuit to release spinal cholecystokinin. The present investigation determined whether IL1beta is a supraspinal mediator for intrathecal Dyn-induced antianalgesia in CD-1 mice. Intracerebroventricular Lys193-D-Pro-Thr195, an IL1beta antagonist, or pretreatment with IL1beta antiserum eliminated intrathecal dynorphin antianalgesia, implicating brain IL1beta; 10 ng of IL(1beta) given intracerebroventricularly produced antianalgesia. Fittingly, Dyn was not antianalgesic in C3H/HeJ mice, which are genetically deficient in release of IL1beta. Activation of central benzodiazepine receptors preceded the IL1beta step because flumazenil inhibited Dyn but not IL1beta antianalgesia. On the other hand, [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide], an antagonist for peripheral benzodiazepine receptors that have also recently been detected in brain tissue, inhibited IL1beta antianalgesia; these latter benzodiazepine receptors formed a separate step after the flumazenil-sensitive benzodiazepine receptor step. IL1beta action in the brain was linked to the linear steps in the spinal cord (cholecystokinin/N-methyl-D-aspartate receptors) as shown by inhibition with appropriate antagonists. Thus, IL1beta is a central physiological mediator in the antianalgesic action evoked by spinal dynorphin.

Analgesics, Opioid↗
PubMed2003

Rapid critical period induction by tonic inhibition in visual cortex.

Mice lacking a synaptic isoform of glutamic acid decarboxylase (GAD65) do not exhibit ocular dominance plasticity unless an appropriate level of GABAergic transmission is restored by direct infusion of benzodiazepines into the brain. To better understand how intracortical inhibition triggers experience-dependent changes, we dissected the precise timing requirement for GABA function in the monocular deprivation (MD) paradigm. Diazepam (DZ) or vehicle solution was infused daily before and/or during 4 d of MD in GAD65 knock-out mice. Extracellular single-unit recordings from the binocular zone of visual cortex were performed at the end of deprivation. We found that a minimum treatment of 2 d near the beginning of MD was sufficient to fully activate plasticity but did not need to overlap the deprivation per se. Extended delay after DZ infusion eventually led to loss of plasticity accompanied by improved intrinsic inhibitory circuit function. Two day DZ treatment just after eye opening similarly closed the critical period prematurely in wild-type mice. Raising wild-type mice in complete darkness from birth delayed the peak sensitivity to MD as in other mammals. Interestingly, 2 d DZ infusion in the dark also closed the critical period, whereas equally brief light exposure during dark-rearing had no such effect. Thus, enhanced tonic signaling through GABA(A) receptors rapidly creates a milieu for plasticity within neocortex capable of triggering a critical period for ocular dominance independent of visual experience itself.

Animals↗
PubMed1996

Inhibition of rho1 receptor GABAergic currents by alcohols and volatile anesthetics.

We studied the effects of alcohols and anesthetics on homomeric gamma-aminobutyric acid (GABA) receptors formed of rho1 subunits expressed in Xenopus laevis oocytes. This subunit shares considerable amino acid sequence homology with the GABA(A) receptor subunits. In contrast to our previous findings with a variety of GABA(A) receptors, ethanol (10-100 mM) significantly inhibited the current induced by a low concentration (400 nM) of GABA, in an apparently competitive manner. Butanol (2-40 mM), hexanol (0.5-4 mM), heptanol (0.3-1 mM), octanol (0.055-1 mM) and nonanol (45 and 113 microM) also inhibited these GABAergic currents. Although efficacious positive modulators of GABA(A) receptor function, the volatile anesthetics enflurane, halothane and isoflurane inhibited the function of rho1 receptors. All of these drug effects were fully reversed by a 6-min washout period. When higher concentrations of GABA were used (5 microM) producing approximately 80-90% of a maximal response) neither the alcohols nor enflurane had any effect. In agreement with previous reports, pentobarbital (50 and 200 microM) was ineffective at any GABA concentration tested. Alphaxalone and propofol were also without effect. Furthermore, none of these compounds produced any significant effects when applied to oocytes in the absence of exogenously added GABA. The opposite effects of alcohols and anesthetics on rho1 and GABA(A) receptors, despite their significant amino acid sequence homology, may help in the identification of the particular amino acids responsible for the actions of these compounds on these receptors.

Alcohols↗
PubMed2001

Honokiol and magnolol selectively interact with GABAA receptor subtypes in vitro.

Honokiol and magnolol have been identified as modulators of the GABAA receptors in vitro. Our previous study suggested a possible selectivity of honokiol and magnolol on GABAA receptor subtypes. This possibility was examined in the current study by 3H-muscimol and 3H-flunitrazepam binding assays on various rat brain membrane preparations and human recombinant GABA(A) receptor subunit combinations expressed by the Sf-9/baculovirus system. Generally, honokiol and magnolol have a similar enhancing effect on (3)H-muscimol binding to various membrane preparations in nonsaturation binding assays. Honokiol and magnolol preferentially increased (3)H-muscimol binding to hippocampus compared to cortex and cerebellum (with a maximum enhancement of 400% of control). As for subunit combinations, honokiol and magnolol have a more potent enhancing effect on alpha2 subunit containing combinations (with a maximum enhancement of 400-450% of control). This action was independent of the gamma subunit. In saturation binding assays, magnolol affected either the number of binding sites (ca. 4-fold on alpha2 containing combinations) or the binding affinity (on alpha1 containing combinations) of (3)H-muscimol binding to various GABAA receptor subunit combinations. In contrast, honokiol increased only binding sites on alpha2beta3gamma2s and alpha2beta3 combinations, but both the number of binding sites and the binding affinity on alpha1beta2gamma2S and alpha(1)beta2 combinations. These results indicate that honokiol and magnolol have some selectivity on different GABAA receptor subtypes. The property of interacting with GABAA receptors and their selectivity could be responsible for the reported in vivo effects of these two compounds.

Animals↗
PubMed1999

Postnatal development of hippocampal dentate granule cell gamma-aminobutyric acidA receptor pharmacological properties.

Postnatal development of hippocampal dentate granule cell gamma-aminobutyric acidA (GABAA) receptor pharmacological properties was studied. Granule cells were acutely isolated from hippocampi of 7- to 14- and 45- to 52-day-old rats, and whole cell patch-clamp recordings were obtained. The sensitivity of GABAA receptors to GABA and modulation of GABAA receptor currents by benzodiazepines (BZ), zinc, furosemide, and loreclezole was studied. Multiple changes in the pharmacological properties of dentate granule-cell GABAA receptors occurred during the first 52 days of postnatal development: GABA-evoked maximal current increased with postnatal age; GABAA receptors changed from BZ type 3 in young rats to BZ type 1 in adult rats; furosemide and zinc inhibited GABAA receptor currents in young rats but not in adult rats; the fraction of cells that expressed loreclezole-sensitive GABAA receptors increased with postnatal age. These findings suggest that dentate granule cells in young and adult animals express pharmacologically distinct GABAA receptors and that the postnatal development of these receptors is prolonged, lasting at least 45 days. Comparison with the previously reported pharmacological properties of GABAA receptors on dentate granule cells acutely isolated from hippocampi of 28- to 35-day-old rats suggests that receptors expressed at that age have properties intermediate between young and adult rats.

Animals↗