Neurochemistry of brain chloride channels: genetic variation in modulation by GABA agonists, alcohol and benzodiazepines.
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Animals↗
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Bidirectional modulation of GABA function by beta-carbolines.
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Acoustic Stimulation↗
Rotational behaviour and striatal dopamine metabolism following unilateral activation of nigral GABA mechanisms: GABA-like modulation of dopaminergic and non-dopaminergic neurons in rat substantia nigra [proceedings].
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Aminobutyrates↗
Human brain cholecystokinin: release of cholecystokinin-like immunoreactivity (CCK-LI) from isolated cortical nerve endings and its modulation through GABA(B) receptors.
The release of cholecystokinin-like immunoreactivity (CCK-LI) in human brain was investigated using synaptosomes prepared from neocortical specimens removed during neurosurgery. CCK-LI basal release from superfused synaptosomes was increased 3 to 4-fold during depolarization with 15 mM KCI. The K(+)-evoked overflow of CCK-LI was strictly Ca(++)-dependent. The gamma-aminobutyric acidB (GABA(B)) receptor agonist (-)baclofen (0.3-100 microM) inhibited CCK-LI overflow in a concentration-dependent manner (EC50 = 2.20 microM; maximal effect: 45%). The novel GABA(B) receptor ligand CGP 47656 mimicked (-)baclofen (EC50 = 2.45 microM; maximal effect: 50%), whereas the GABA(A) agonist muscimol was ineffective up to 100 microM. The inhibitory effect of 10 microM (-)baclofen on the CCK-LI overflow was concentration-dependently prevented by two selective GABA(B) receptor antagonists, CGP 35348 (IC50 = 13.91 microM) and CGP 52432 (IC50 = 0.08 microM). The effect of 10 microM CGP 47656 was abolished by 1 microM CGP 52432. In experiments on [3H]GABA release, CGP 47656 behaved as an antagonist at the GABA(B) autoreceptors: added at 10 microM, it prevented the inhibitory effect of 10 microM (-)baclofen on the K+ (15 mM)-evoked release of [3H]GABA from human synaptosomes. We conclude that 1) the release of CCK-LI evoked from human brain tissue appears of neuronal origin; 2) the CCK-releasing terminal possess inhibitory presynaptic GABA(B) receptors; 3) these receptors differ pharmacologically from human neocortex GABA(B) autoreceptors, which are CGP 35348-insensitive (Fassio et al., 1994) but can be blocked by CGP 47656; 4) because cholecystokinin has been implicated in anxiety, the GABA(B) receptors here characterized may represent targets for novel anxiolytic agents.
Benzylamines↗
Dieldrin and picrotoxinin modulation of GABA(A) receptor single channels.
The insecticide dieldrin is known to suppress the GABA(A) receptor-channel complex in a manner similar to that of picrotoxin. To elucidate the more detailed mechanisms of dieldrin and picrotoxin interactions with the GABA system, single-channel patch clamp experiments were performed using rat dorsal root ganglion neurons in primary culture. Dieldrin did not alter the open time distribution and mean current amplitude or the distribution of burst duration and the mean burst duration. However, the mean closed time was prolonged indicating that dieldrin decreased the channel open probability. Previous studies have demonstrated that dieldrin and picrotoxin share the common binding site on the GABA receptor. Thus, the effects of picrotoxinin on the GABA(A) receptor single channels were also examined. Dieldrin and picrotoxinin had similar effects at the single-channel level. These changes of single-channel parameters explain the suppressive effects of these chemicals on GABA-induced whole-cell currents.
Animals↗
GABAergic modulation of the discriminative stimulus effects of methamphetamine.
To assess whether gamma-aminobutyric acid (GABA) modulation of dopamine is important in mediation of the discriminative stimulus effects of methamphetamine, the GABA compounds chlordiazepoxide (benzodiazepine site agonist), pentobarbital (barbiturate site agonist), bicuculline and pentylenetetrazol (GABA(A) receptor antagonists) were tested in Sprague-Dawley rats trained to discriminate methamphetamine (1 mg/kg, i.p.) from saline. Each of the compounds produced modest amounts of methamphetamine-appropriate responding (20-35%) when tested alone. When tested in combination with methamphetamine, the antagonists (bicuculline and pentylenetetrazol) failed to shift the methamphetamine dose-effect curve. In contrast, chlordiazepoxide (25 mg/kg, i.p.) reduced methamphetamine-appropriate responding at each dose of methamphetamine tested, and pentobarbital (10 mg/kg, i.p.) dose-dependently decreased the discriminative stimulus effects of 1 mg/kg methamphetamine. In conclusion, GABA(A) antagonists and positive modulators likely do not produce methamphetamine-like stimulus effects. However, activation of GABA(A) receptors can interfere with the discriminative stimulus effects of methamphetamine.
Animals↗
Changes in gamma-aminobutyrate type A receptor subunit mRNAs, translation product expression, and receptor function during neuronal maturation in vitro.
The amounts of mRNAs encoding alpha 1, alpha 6, beta 2, beta 3, gamma 2, and delta subunits of gamma-aminobutyrate type A (GABAA) receptors and the gold immunolabeling density of their translation products were monitored during the growth of neonatal rat granule cells in primary culture. We investigated possible correlations (i) between temporal changes in mRNA content and expression density of their respective translation products and (ii) between the quantitative changes of receptor subunit expression, the GABA EC50 for Cl- channel activation, and diazepam efficacy in modulating GABA action on the Cl- channels. At 3 days in vitro, the amount of GABAA receptor subunit mRNAs and the expression of their respective translation products were very low. During the next 2 weeks both parameters for every subunit studied increased asynchronously; moreover, at 14 days in vitro the sum of gamma 2 and delta subunit expression was smaller than the expression of the alpha 1 or alpha 6 or beta 2/beta 3 subunits. This suggests that during in vitro maturation each subunit may be regulated independently and invites speculation as to possible changes in specific GABAA receptor subtype abundance during development in vitro. The maximal current intensity elicited by GABA failed to increase from 5 to 14 days in vitro, though the amount of mRNA encoding various subunits and the expression density of their respective translation products increased. Thus, qualitative changes in the GABAA receptor subtypes expressed and/or abnormalities in the subunit assembly very likely account for the uniformity of the maximal current intensity elicited by GABA during in vitro development. Also, during maturation of neuronal cultures from 5 to 20 days in vitro the extent of the positive modulation of GABA action by diazepam decreased dramatically. This finding might be related to an increase in the abundance of GABAA receptors including the alpha 6 subunit and/or to the expression, during granule cell maturation in vitro, of GABAA receptors devoid of gamma 2 subunits.
Animals↗
Effects of chronic ethanol exposure on GABA receptors and GABAB receptor modulation of 3H-GABA release in the hippocampus.
Chronic ethanol treatment (CET), sufficient for decreasing long-term potentiation (LTP) in rats, also enhances 3H-GABA release from hippocampal slices in these same animals. The mechanism for an increase in GABA release may involve changes in presynaptic receptors. Therefore, we characterized presynaptic autoreceptor modulation of 3H-GABA release in hippocampal slices from control and CET rats. The effects of a GABAB receptor agonist (baclofen) and antagonist [2-hydroxy (OH)-saclofen] were tested for their ability to modulate electrically stimulated 3H-GABA release from superfused hippocampal slices. Baclofen decreased stimulated release in a dose-dependent manner and 2-OH-saclofen increased release consistent with the existence of presynaptic GABAB autoreceptors in hippocampus. The GABAA antagonist bicuculline did not significantly modulate basal or stimulated release. When the effects of baclofen and 2-OH-saclofen were measured in animals 48 hr after withdrawal from CET, presynaptic modulation of release by baclofen and 2-OH-saclofen was decreased. In addition, we examined the density of 3H-baclofen and 3H-bicuculline binding in the hippocampal formation using quantitative autoradiographic techniques. We found that the density of 3H-baclofen binding sites was not affected by CET, whereas the density of 3H-bicuculline binding sites was increased by 28% in ethanol-treated rats. These data may explain how CET increases presynaptic regulation of GABA release from hippocampus that may contribute to the decrease in LTP seen in rats after CET.
Alcoholism↗
Protein kinase C regulation of GABAA receptors.
Pharmacological studies with drugs that activate or inhibit several protein kinase C (PKC) isozymes have identified the PKC family of serine-threonine kinases as important in the regulation of gamma-aminobutyric acid type A (GABA(A)) receptor function. PKC modulates GABA(A) receptor surface density, chloride conductance and receptor sensitivity to positive allosteric modulators such as neurosteroids, ethanol, benzodiazepines and barbiturates. Recent studies using PKC isozyme-selective reagents and gene-targeted mice have begun to identify critical roles for three isozymes, PKCbetaII, PKCvarepsilon and PKCgamma, in various aspects of GABA(A) receptor regulation. Progress in this field touches upon therapeutic areas that are of great clinical importance such as anxiety and addiction. Increased understanding of how PKC regulates GABA(A) receptors and which PKC isozymes are involved holds promise for development of new treatments for diverse neuropsychiatric disorders.
Allosteric Regulation↗
Involvement of peripheral type of benzodiazepine receptor in social isolation stress-induced decrease in pentobarbital sleep in mice.
Our previous studies have shown that central-type benzodiazepine (BZD) receptors (CBR) and neurosteroids capable of modulating GABA(A) receptor function are involved in the decrease of pentobarbital (PB)-induced sleep caused by social isolation stress in mice. In this study, to further clarify the mechanism underlying this decrease, we investigated the possible involvement of peripheral-type BZD receptors (PBR) which play an important role in neurosteroidogenesis in PB sleep in socially isolated mice. Socially isolated mice showed significantly shorter duration of PB-induced sleep than group-housed animals. When injected intracerebroventricularly (i.c.v.), FGIN-1-27 (FGIN, 25-100 nmol), a selective PBR agonist, and PK11195 (PK, 14-28 nmol), a PBR antagonist, and pregnenolone (PREG, 15-30 nmol), a neurosteroid precursor, dose-dependently normalized the PB sleep in isolated mice without having an effect on the group-housed animals. In contrast, pregnenolone sulfate (PS, 24 nmol), an endogenous neurosteroidal negative allosteric modulator of the GABA(A) receptor, reduced PB sleep in group-housed but not isolated mice. PS, at the same dose, significantly attenuated the effects of FGIN (100 nmol), PK (28 nmol) and PREG (30 nmol) in isolated mice, while FGIN (100 nmol), PK (28 nmol) and pregnenolone (30 nmol) significantly blocked the effect of PS (24 nmol) in group-housed mice. These results suggest that the PBR-mediated decrease in the genesis of neurosteroid(s) possessing a GABA(A) receptor agonistic profile is also partly involved in the down regulation of the GABA(A) receptor following long-term social isolation and contributes to the decrease of PB-induced sleep in isolation stressed mice.
Animals↗
Heterogeneity of GABA(A) receptor-mediated responses in the human IMR-32 neuroblastoma cell line.
The gamma-aminobutyric acid (GABA) response profiles of IMR-32 human neuroblastoma cells were examined using whole-cell patch clamp and RT-PCR techniques. GABA activated a concentration-dependent and bicuculline-sensitive current, and RT-PCR revealed the expression of multiple GABA(A) receptor subunit mRNAs (alpha(1), alpha(3), alpha(4), beta(1), beta(3), gamma(2), and delta). A pharmacological profile of the GABA-induced current was derived using several subunit-selective agents. Diazepam, which requires the presence of a gamma subunit in order to modulate GABA(A) receptor-mediated responses, potentiated GABA-induced currents in a subset of IMR-32 cells. Two populations of GABA-activated currents were also evident based on sensitivity to modulation by zinc. Comparison of zinc- and diazepam-induced modulation of GABA-induced current responses in the same cells revealed an inverse correlation between these two modulators. No differences, however, were observed with the GABA(A) receptor modulators loreclezole, allopregnanolone, and pentobarbital. Thus, IMR-32 cells maintained in culture are heterogeneous in terms of expression of GABA(A) receptor isoforms.
Anticonvulsants↗
Alcohol modulation of single GABA(A) receptor-channel kinetics.
Alcohol modulation of single-channel kinetics of GABA(A) receptor currents was studied with rat dorsal root ganglion neurons using the excised outside-out patch clamp technique. GABA (1 microM) alone or GABA (1 microM) plus ethanol (30-300 mM) or n-Octanol (30-300 microM) were applied by pressure ejection to evoke single-channel currents. The main single-channel conductance was not changed by either ethanol or n-Octanol at 25 pS. Both alcohols exerted the same effects on the single-channel kinetics, although n-Octanol was more potent than ethanol. The frequency of openings, the mean open time, the percentage of open time, the frequency of bursts, and the mean burst duration were all increased, but the mean closed time was decreased. These changes in channel kinetics account for the increase in whole-cell current amplitude caused by ethanol and n-Octanol.
1-Octanol↗
GABA stimulation of gonadotropin-II release in goldfish: involvement of GABAA receptors, dopamine, and sex steroids.
The involvement of gamma-aminobutyric acid (GABA) in regulation of pituitary gonadotropin-II (GTH-II) release was studied in the goldfish. Intraperitoneal injection of GABA (300 micrograms/g) stimulated an increase in serum GTH-II levels at 30 min postinjection. The GABAA receptor agonist muscimol (0.1-10 micrograms/g) stimulated GTH-II in a dose-dependent manner. Baclofen, a GABAB receptor agonist, had a small but significant stimulatory effect at 1 and 10 micrograms/g; the amount of GTH-II released in response to baclofen was significantly less (P < 0.05) than that released by muscimol. Pretreatment of goldfish with bicuculline, a GABAA receptor antagonist, but not saclofen, a GABAB receptor antagonist, blocked the stimulatory effect of GABA on serum GTH-II. Elevation of brain and pituitary GABA levels with the GABA transaminase inhibitor, gamma-vinyl-GABA (GVG), decreased hypothalamic and pituitary dopamine (DA) turnover rates, indicating that GABA may stimulate GTH-II release in the goldfish by decreasing dopaminergic inhibition of GTH-II release. The release of GTH-II stimulated by muscimol and GVG was potentiated by pharmacological agents that decrease inhibitory dopaminergic tone, indicating that DA may also inhibit GABA-stimulated GTH-II release. Based on the linear 24-h accumulation of GABA in brain and pituitary after GVG injection, implantation of testosterone, estradiol, or progesterone, previously shown to regulate the serum GTH-II release response to gonadotropin-releasing hormone and GABA, was also found to modulate GABA synthesis in the brain and pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)
Aminocaproates↗
Positive allosteric modulators of the GABA(A) receptor: differential interaction of benzodiazepines and neuroactive steroids with ethanol.
Endogenous pregnane steroids, such as allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one; 3alpha, 5alpha-P) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one; 3alpha,5beta-P), allosterically modulate GABA(A) receptor function and exhibit behavioral effects similar to benzodiazepines, though acting at a distinct recognition site. Inasmuch as some positive allosteric modulators of GABA(A) receptor function exhibit profound interactions with ethanol, the effects of 3alpha,5alpha-P and 3alpha,5beta-P were compared to those of two benzodiazepines, triazolam and diazepam, on the motor function of mice and rats when administered either alone or in combination with ethanol. All four test compounds exhibited dose-related impairment of motor function in the horizontal wire task in mice and the rotorod task in rats. Ethanol caused a marked enhancement of triazolamand diazepam-induced motor impairment. In contrast, ethanol enhanced to a lesser extent the motor impairment induced by both neurosteroids in mice and not at all in rats. All four compounds increased ethanol-induced behavioral sleep time in mice, although the benzodiazepines did so at a much smaller fraction of their ataxic doses as compared to the neurosteroids. As one of the undesired side-effects of therapeutic use of benzodiazepines is their interaction with ethanol, development of neuroactive steroids as drugs may offer therapeutic advantages.
Allosteric Regulation↗
Chronic cocaine administration decreases the functional coupling of GABA(B) receptors in the rat ventral tegmental area as measured by baclofen-stimulated 35S-GTPgammaS binding.
Results of numerous studies indicate that the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) modulates central dopamine systems, and that GABA(B) receptors may play a primary role in decreasing dopamine release. To determine if chronic cocaine administration alters the functional coupling of GABA(B) receptors to G-proteins in central dopamine systems, male F-344 rats received cocaine (15 mg/kg/injection) or saline three times a day at hourly intervals for fourteen consecutive days. Rats were decapitated one hour after the last injection and crude membrane preparations were made from the substantia nigra, caudate-putamen, ventral tegmental area, nucleus accumbens, and frontal cortex of individual rats. The ability of the specific GABA(B) receptor agonist baclofen to stimulate 35S-GTPgammaS binding in each of these regions was determined for individual animals. Additionally, baclofen-stimulated 35S-GTPgammaS binding in each of these regions in rats that received cocaine was compared to baclofen-stimulated 35S-GTPgammaS binding in rats that received control injections of saline. The EC50 of baclofen and maximal baclofen-stimulated 35S-GTPgammaS binding over basal levels were determined in each brain region in the saline group and in the cocaine group. Two-way ANOVA revealed a significant decrease in GABA(B) receptor-stimulated 35S-GTPgammaS binding in the ventral tegmental area of the cocaine group compared to the saline group. These data suggest that chronic exposure to cocaine decreases the functional coupling of GABA(B) receptors to G-proteins selectively in the ventral tegmental area. This finding may have implications in the augmented extracellular dopamine levels seen in the nucleus accumbens of rats that have been sensitized to cocaine.
Animals↗
A noncanonical release of GABA and glutamate modulates neuronal migration.
Immature neurons express GABA and glutamate receptors before synapse formation, and both transmitters are released at an early developmental stage. We have now tested the hypothesis that the ongoing release of GABA and glutamate modulates neuronal migration. Using 5-bromo-2'-deoxyuridine labeling and cocultures of hippocampal slices obtained from naive and green fluorescent protein-transgenic mice, we report that migration is severely affected by GABA(A) or NMDA receptor antagonist treatments. These effects were also present in munc18-1 knock-out slices in which soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent vesicular secretion of transmitters has been deleted. GABA(A) antagonists were more efficient than NMDA antagonists to reduce cell migration, in keeping with the earlier maturation of GABAergic mechanisms. We conclude that GABA and, to a lesser degree, glutamate released in a SNARE-independent mechanism exert a paracrine action on neuronal migration.
2-Amino-5-phosphonovalerate↗
Zinc and flunitrazepam modulation of GABA-mediated currents in rat suprachiasmatic neurons.
The suprachiasmatic nucleus (SCN) of the hypothalamus is responsible for generating circadian rhythms in mammals, and GABA is the predominant neurotransmitter in the SCN. Properties of gamma-aminobutyric acid-A (GABAA) responses in SCN neurons were examined in acutely prepared hypothalamic slices from 3- to 8-wk-old rats with the use of whole cell voltage-clamp techniques. Zn2+ reduced the amplitude of GABAA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in a concentration-dependent manner ranging from a reduction of control amplitude to 88% at 10 microM to 27% at 1,000 microM. Zn2+ reduced IPSC amplitude to a similar degree in the presence of tetrodotoxin and also significantly reduced the amplitude of currents evoked by application of exogenous GABA (100 microM, pressure applied). Zn2+ increased the frequency of IPSCs at lower concentrations and decreased it at higher ones. Flunitrazepam (100 nM) usually failed to potentiate the amplitude of sIPSCs, but prolonged sIPSC kinetics. Two exponential components were normally resolved in the sIPSC decay constants, and flunitrazepam significantly increased those two components. Thus flunitrazepam increased the duration of sIPSCs and potentiated the amplitude of currents evoked by pressure application of GABA. Zn2+ and benzodiazepine each modulated the effect of GABA in nearly all cells, suggesting that most SCN neurons have a similar GABAA receptor subunit composition in this respect. Zn2+ also affected sIPSC frequency, which suggests that Zn2+ increased neuronal firing rate at lower concentrations. These results begin to define the cellular roles that these GABAA receptor modulators might play in circadian regulation.
Animals↗
Effects of treatment with GABA(A) receptor subunit antisense oligodeoxynucleotides on GABA-stimulated 36Cl- influx in the rat cerebral cortex.
GABA(A) receptor function was studied in cerebral cortical vesicles prepared from rats after intracerebroventricular microinjections of antisense oligodeoxynucleotides (aODNs) for alpha1, gamma2, beta1, beta2 subunits. GABA(A) receptor alpha1 subunit aODNs decreased alpha1 subunit mRNA by 59+/-10%. Specific [3H]GABA binding was decreased by alpha1 or beta2 subunit aODNs (to 63+/-3% and 64+/-9%, respectively) but not changed by gamma2 subunit aODNs (94+/-5%). Specific [3H]flunitrazepam binding was increased by alpha1 or beta2 subunit aODNs (122+/-8% and 126+/-11%, respectively) and decreased by gamma2 subunit aODNs (50+/-13%). The "knockdown" of specific subunits of the GABA(A )receptor significantly influenced GABA-stimulated 36Cl- influx. Injection of alpha1 subunit aODNs decreased basal 36Cl- influx and the GABA Emax; enhanced GABA modulation by diazepam; and decreased antagonism of GABA activity by bicuculline. Injection of gamma2 subunit aODNs increased the GABA Emax; reversed the modulatory efficacy of diazepam from enhancement to inhibition of GABA-stimulation; and reduced the antagonist effect of bicuculline. Injection of beta2 subunit aODNs reduced the effect of diazepam whereas treatment with beta1 subunit aODNs had no effect on the drugs studied. Conclusions from our studies are: (1) alpha1 subunits promote, beta2 subunits maintain, and gamma2 subunits suppress GABA stimulation of 36Cl- influx; (2) alpha1 subunits suppress, whereas beta2, and gamma2 subunits promote allosteric modulation by benzodiazepines; (3) diazepam can act as an agonist or inverse agonist depending on the relative composition of the receptor subunits: and (4) the mixed competitive/non-competitive effects of bicuculline result from activity at alpha1 and gamma2 subunits and the lack of activity at beta1 and beta2 subunits.
Animals↗