Interactions of pentobarbital and phenobarbital with GABAergic drugs against chemoconvulsants in rats

Pentobarbital and phenobarbital exhibited anticonvulsant effects against picrotoxin (10 mg/kg, IP) as well as against strychnine (4 mg/kg, IP). Pentobarbital was also effective against bicuculline whereas only hypnotic doses of phenobarbital provided some protection against bicuculline- (8 mg/kg, IP) induced convulsions. Diazepam as well as THIP, but not baclofen, were also effective against all the three chemoconvulsants. Baclofen or subeffective doses of diazepam or THIP, but not baclofen, were also effective against all of pentobarbital exhibited anticonvulsant activity against all the chemoconvulsants studied. On the other hand, a combination of subeffective doses of these agents with subeffective doses of phenobarbital provided protection only against picrotoxin and strychnine. These observations indicate that pentobarbital is quite effective against convulsions caused by agents acting at picrotoxin site, GABA_A receptor or glycine receptor whereas phenobarbital is effective only against agents acting at picrotoxin site and glycine receptor, and is very weak anticonvulsant against agents causing blockade of GABA_A receptors. Furthermore, activation of GABA_A receptors or benzodiazepine receptors also provide protection against agents acting at GABAergic system or glycine receptors. On the contrary, activation of only GABA_B receptors is inadequate to provide the protective effect. However, the activation of GABA_A as well as GABA_B receptors facilitate the anticonvulsant effect of both the barbiturates. Furthermore, pentobarbital, but not phenobarbital, facilitates the anticonvulsant effect of benzodiazepines against chemoconvulsants acting at GABAergic site or glycine receptors.     

On the mechanism of anticonvulsant effect of tramadol in mice

The present study was conducted to examine the effects of tramadol, an atypical opioid on convulsive behaviour in maximal electroshock (MES) seizure test on mice. Moreover, an attempt was also made to investigate the role of possible receptor mechanisms involved. MES seizures were induced via transauricular electrodes (60 mA, 0.2 sec). Seizure severity was determined by (1) the duration of tonic hindlimb extensor (THE) phase and by (2) mortality due to electroconvulsions. Intraperitoneal (i.p.) administration of tramadol dose-dependently (10-50 mg/kg) decreased the duration of THE phase of MES. The anticonvulsant effect of tramadol was antagonized by the opioid antagonists, naloxone in high dose, and MR2266, a selective kappa antagonist but not by naltrindole, a delta opioid antagonist. Coadministration of either gamma-aminobutyric acid (GABA)-ergic drugs (diazepam, GABA, muscimol and baclofen) or N-methyl-D-aspartate (NMDA) receptor antagonist, MK801 with tramadol augmented the anticonvulsant effect of the latter drug. By contrast, flumazenil, a central benzodiazepine (BZD) receptor antagonist, counteracted the diazepam-induced facilitation of anti-MES effect of tramadol. Similarly, delta-aminovaleric acid (DAVA), a GABAB receptor antagonist, abolished the facilitatory effect of baclofen, a GABAB agonist on anti-MES action of tramadol. These BZD-GABAergic antagonists, flumazenil or DAVA, on their own also antagonized the anti-MES effect of tramadol administered alone. No significant effect on mortality was observed in any of the studied groups. Taken together, the current results have demonstrated a possible role for multitude of important neurotransmitter systems, i.e., opioid (kappa), GABAA-BZD receptors system, GABAB receptors and NMDA channel involvement in the antielectroshock effect of tramadol in mice.     

Anticonvulsant profile of drugs which facilitate GABAergic transmission on convulsions mediated by a GABAergic mechanism

The effects of selected modulators of GABAergic transmission, either alone or in combination, were tested for their potency on the seizure pattern and mortality induced by convulsant drugs in rat. Pentobarbital and diazepam were effective against both tonic and clonic seizure components induced by bicuculline and picrotoxin. The anticonvulsant profile of ethanol closely resembled that of pentobarbital. Pentobarbital, diazepam and ethanol did not modify seizures induced by strychnine. In contrast, progabide, a central gamma-aminobutyric acid (GABA) receptor agonist, caused significant protection only against convulsions induced by strychnine and its lethality, but did not protect against seizures induced by bicuculline or picrotoxin. Data on interaction of drugs with subprotective doses of these agents clearly demonstrated potentiation of the anticonvulsant actions of these modulators. Thus, seizures induced by bicuculline were more sensitive to the inhibition by pentobarbital in combination with diazepam or ethanol, while pentobarbital with progabide was equally effective against convulsions induced by GABA antagonists. Diazepam, in combination with progabide, blocked only convulsions induced by picrotoxin. Ethanol, in combination with either pentobarbital or with diazepam, was effective against all the three convulsant drugs. These results are consistent with the concept that drugs which facilitate GABAergic transmission are effective against seizures related to an impairment of GABA transmission. Further, the present data indicate that tonic seizures are more susceptible to the actions of drugs than the clonic component. Smaller doses of these drugs, alone or in combination, modified the seizure patterns and mortality, whereas at larger doses, the possible involvement of a nonspecific depressant action cannot be ruled out.     

四氢孕酮对小鼠不同惊厥模型的保护作用

目的观察四氢孕酮对不同动物惊厥模型的保护作用。方法C57小鼠腹腔注射四氢孕酮15min后观察其对最大电休克实验(maximalelectricalseizure,MES)或印防己所致惊厥的保护作用。结果在MES试验 ,四氢孕酮或苯巴比妥产生剂量依赖性的保护作用。苯巴比妥的ED50 为2.40mg·kg-1,95 %可信限为1.22至4.72mg·kg-1。四氢孕酮的ED50为0.086mg·kg-1,95 %可信限为0.037至0.201mg·kg-1,显著较苯巴比妥强 (P<0.01)。四氢孕酮对印防己所致惊厥保护作用的ED50为0.12mg·kg-1。两药各1/2ED50量的联合用药在MES试验产生80 %的保护作用 ,高于50 %。提示四氢孕酮和苯巴比妥具协同抗惊厥作用。在印防己致惊厥试验 ,四氢孕酮亦产生剂量依赖性保护作用 ,ED50 为0.123mg·kg-1,95 %可信限为0.085至0.263mg·kg-1。结论腹腔注射四氢孕酮对MES或印防己所致惊厥具有剂量依赖性的保护作用 ;对MES ,四氢孕酮的保护作用显著大于苯巴比妥 ,并与后者有协同作用。     

Stimulation of GABAB receptors increases the expression of the proenkephalin gene in slice cultures of rat neocortex

In rat neocortex the proenkephalin gene is expressed in GABAergic interneurons. Immunocytochemistry and in situ hybridisation show only a small number of cells in layers II to VI which express the gene. In organotypic slices of rat neocortex, the GABAA receptor inhibitor bicuculline methiodide enhances the expression of the gene in numerous cells. In the present study, we have investigated how GABA regulates the expression of the proenkephalin gene. The GABAA receptor antagonist bicuculline methiodide and the inhibitor of ligand-gated Cl- channels picrotoxin strongly enhanced the expression of the gene in numerous cells which were arranged in neocortical layers II/III and V/VI. Since bicuculline methiodide can also block Ca(++)-activated K+ channels, the possible involvement of such channels was tested. However, apamin which blocks only Ca(++)-activated K+ channels had no effect on the expression of the proenkephalin gene indicating that the effect of bicuculline methiodide was due to inhibition of GABAA receptors. In addition, the GABAB receptor agonist baclofen increased the neocortical expression of the proenkephalin gene mainly in cells located in layers V/VI of the neocortex. The effect of baclofen was inhibited by the GABAB receptor antagonists CGP35348 and CGP52432. Also muscimol, an agonist at GABAA receptors, enhanced the expression of the proenkephalin gene. This effect was blocked by CGP52432 confirming previous observations that muscimol can also stimulate GABAB receptors. Our results indicate that GABA can regulate the expression of the opioid peptide in neocortical neurons in a bidirectional manner. The expression is suppressed via GABAA and enhanced via GABAB receptors.     

Effects of GABAA and GABAB receptor agonists on reticular-elicited hippocampal rhythmical slow activity.

Hippocampal rhythmical slow activity (RSA) can be elicited by stimulation of the midbrain reticular formation. All classes of anxiolytic drug so far tested reduce the frequency of this RSA. Anxiolytic barbiturates and benzodiazepines, as opposed to compounds such as buspirone, are thought to act as receptor agonists of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). In the present study muscimol (a GABAA receptor agonist) and baclofen (a GABAB receptor agonist) were injected into freely moving rats. Baclofen produced a dose-related decrease in frequency of RSA in the range 1 to 9 mg/kg i.p. and abolished RSA at 27 mg/kg. Muscimol produced an increase in RSA frequency with an inverted U-shaped dose response curve in the range 0.0001 to 1.0 mg/kg with maximal effect at 0.001 mg/kg. The effects of classical anxiolytic drugs in the present test resemble those of the GABAB receptor agonist baclofen more than they resemble those of the GABAA receptor agonist muscimol but it is possible that they are acting via GABA systems which employ low rather than high affinity GABAA receptors or through some transmitter system other than GABA.     

Characterization of GABAergic seizure regulation in the midline thalamus

This study characterized the role of GABA in the central medial intralaminar nucleus on seizures induced by pentylenetetrazol given systemically. Injections of the direct selective GABAA agonist, piperidine-4-sulfonic acid or the indirect GABAA agonists, flurazepam and pentobarbital, in this region depressed arousal and facilitated myoclonic and clonic seizures induced by pentylenetetrazol but only caused slight inhibition of tonic seizures. In contrast the GABAB agonist (-)baclofen facilitated all three types of seizures. Recording after injection of piperidine-4-sulfonic acid and (-)baclofen revealed marked suppression and slowing of thalamic and cortical electrical activity. Thalamic injections of the GABAA antagonist, bicuculline methiodide, had opposite behavioral effects, causing hyperactivity and episodes of violent running, not accompanied by EEG discharges. When pentylenetetrazol was infused concommitantly there was marked facilitation of the tonic seizures, which occurred without preceding myoclonic of clonic seizures, or EEG spikes. These results demonstrate that GABA-mediated neurotransmission in the central medial intralaminar nucleus can control the threshold of seizures and that GABA agonists and antagonists have opposite effects. It is suggested that the central medial intralaminar nucleus is not a site of origination or spread of seizures, but controls seizures indirectly by regulating the excitability of other structures and that different synaptic mechanisms and anatomical connections mediate effects on different types of seizures.     

Effects of the putative antagonists phaclofen and delta-aminovaleric acid on GABAB receptor biochemistry.

1. Phaclofen and delta-aminovaleric acid (delta-AVA) have been reported to be antagonists at gamma-aminobutyric acidB (GABAB) receptors. Phaclofen, delta-AVA and related compounds were examined for potency and specificity at GABAB and GABAA receptors in rat cortical membranes labelled with [3H]-(-)-baclofen and [3H]-muscimol, respectively. Additionally phaclofen and delta-AVA were examined in two functional tests of central GABAB activity in rat cortical slices, namely the inhibition of forskolin-stimulated cyclic AMP accumulation, and the potentiation of isoprenaline-stimulated cyclic AMP accumulation. 2. delta-AVA (IC50 = 11.7 microM) was 20 fold more potent than phaclofen (IC50 = 229 microM) on GABAB receptor binding. All compounds possessing a phosphonic acid group, including phaclofen, which were active at GABAB receptors were inactive at GABAA receptors, while delta-AVA was equally potent at both receptors. Several compounds exhibited Hill coefficients of less than unity in displacing [3H]-(-)-baclofen binding. 3. (-)-Baclofen inhibited forskolin-stimulated cyclic AMP accumulation (IC50 = 7.9 microM) but this effect was not stereospecific. Phaclofen (1 mM) was inactive against this inhibition but produced a potentiation of the forskolin effect. delta-AVA (1 mM) failed to antagonize the effect of baclofen; rather it mimicked baclofen. 4. (-)-Baclofen (10 microM) potentiated isoprenaline-stimulated cyclic AMP accumulation, an effect antagonized by phaclofen (1 mM). delta-AVA (1 mM) may be a weak antagonist but also potentiated basal cyclic AMP accumulation. 5. We conclude that neither delta-AVA nor phaclofen are potent specific GABAB receptor antagonists.     

Tonic activation of presynaptic GABA(B) receptors on rat pallidosubthalamic terminals

Aim: The subthalamic nucleus plays a critical role in the regulation of movement, and abnormal activity of its neurons is associated with some basal ganglia motor symptoms. We examined the presence of functional presynaptic GABAB receptors on pallidosubthalamic terminals and tested whether they were tonically active in the in vitro subthalamic slices. Methods: Whole-cell patch-clamp recordings were applied to acutely prepared rat subthalamic nucleus slices. The effects of specific GABAB agonist and antagonist on action potential-independent inhibitory postsynaptic currents (IPSCs), as well as holding current, were examined. Results: Superfusion of baclofen, a GABAa receptor agonist, significantly reduced the frequency of GABAA receptor-mediated miniature IPSCs (mIPSCs), ina Cd^2 -sensitive manner, with no effect on the amplitude, indicating presynaptic inhibition on GABA release. In addition, baclofen induced a weak outward current only in a minority of subthalamic neurons. Both the pre-and post-synaptic effects of baclofen were prevented by the specific GABAB receptor antagonist, CGP55845. Furthermore, CGP55845 alone increased the frequency of mIPSCs, but had no effect on the holding current. Conclusion: These findings suggest the functional dominance of presynaptic GABAB receptors on the pallidosubthalamic terminals over the postsynaptic GABAB receptors on subthalamic neurons. Furthermore, the presynaptic, but not the postsynaptic, GABAB receptors are tonically active, suggesting that the presynaptic GABAB receptors in the subthalamic nucleus are potential therapeutic target for the treatment of Parkinson disease.     

The action of GABAB antagonists in the trigeminal nucleus of the rat.

The iontophoretic administration of the GABAB antagonists (P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid (CGP 35348) and 2-hydroxy-saclofen blocked the action of iontophoretically applied L-baclofen on neurons in the trigeminal nucleus of rats, anesthetized with halothane. The substance CGP 35348 appeared to be more potent than 2-hydroxy-saclofen. The iontophoretic administration of GABA resembled L-baclofen in depressing excitatory transmission and facilitating segmental inhibition in the trigeminal nucleus. The depression of excitatory transmission was also blocked by CGP 35348 and the facilitation of segmental inhibition produced by GABA was partially blocked. These observations indicate that CGP 35348 is not only a baclofen antagonist but actually a GABAB receptor antagonist and the baclofen was acting at GABAB receptors in the trigeminal nucleus. The portion of the effect of GABA, not blocked by CGP 35348, was probably mediated by GABAA receptors, since it was previously found that segmental inhibition in the trigeminal nucleus could be modulated by GABAA agonists and antagonists as well.     

Involvement of GABAergic neurotransmission in the neurobiology of the apomorphine-induced aggressive behavior paradigm, a model of psychotic behavior in rats

The effect of treatment with the acute GABAA receptor agonist THIP and the GABAB receptor agonist baclofen on apomorphine-induced aggressive behavior was studied in adult male Wistar rats. Both THIP (10 mg/kg i.p.) and baclofen (8 mg/kg i.p.) attenuated the aggressiveness, thereby indicating the involvement of GABAergic neurotransmission in the mediation of apomorphine-induced aggressiveness. On the basis of our data it can be proposed that both GABAA and GABAB receptor subtypes are involved in the neurobiology of apomorphine-induced aggressive behavior, as this phenomenon is evidently subject to the general inhibitory effect of GABAergic neurotransmission.     

Involvement of a GABAergic mechanism in the anticonvulsant effect of pentobarbital against maximal electroshock-induced seizures in rats

The interaction between pentobarbital and other modulators of GABAergic transmission (diazepam, ethanol and progabide) was investigated on maximal electroshock seizures and on the loss of righting reflexes in rats. Pentobarbital, diazepam and ethanol produced a dose-dependent protection against electroshock seizures, with pentobarbital being more potent (3- and 50-times) than diazepam and ethanol. Progabide neither provided protection nor caused loss of righting reflex. Subprotective doses of pentobarbital and diazepam, together or when combined with a single ineffective dose of ethanol or progabide, caused protection against seizures and loss of righting reflex for variable durations, while ethanol and progabide combination did not provide protection. The protective effect of diazepam was antagonized by RO15-1788, picrotoxin and bicuculline pretreatments. The antagonism of pentobarbital protection by a specific GABA receptor antagonist, bicuculline suggests involvement of the GABAergic system in the anticonvulsant effect of pentobarbital. These results indicate that, like diazepam, the anticonvulsant effect of pentobarbital appears to be mediated through a GABAergic mechanism.     

GABAB receptor modulation of the release of substance P from capsaicin-sensitive neurones in the rat trachea in vitro.

1. The role of gamma-aminobutyric acid (GABA) as an inhibitory transmitter in the central nervous system is well documented. Recently, GABAA and GABAB receptors have been identified in the peripheral nervous system, notably on primary afferent neurones (PAN). We have utilised a multi-superfusion system to investigate the effect of selective GABA receptor agonists and antagonists on the release of substance P (SP) from the rat trachea in vitro. 2. GABA (1-100 microM) did not affect spontaneous release of SP-like immunoreactivity (LI) but caused dose-related inhibition of calcium-dependent potassium (60 mM)-stimulated SP-LI release. The greatest inhibition of 77.7 +/- 18.8% was observed at 100 microM. 3. The inhibitory effect of GABA was mimicked by the GABAB receptor agonist, (+/-)-baclofen (1-100 microM), but not the GABAA receptor agonist, 3-amino-1-propane-sulphonic acid (3-APS, 1-100 microM). Baclofen (100 microM) had no effect on SP-LI release stimulated by capsaicin (1 microM). 4. The inhibitory effect of baclofen (30 microM) was significantly reduced by prior and concomitant exposure to the GABAB receptor antagonist, phacolofen (100 microM) but not the GABAA receptor antagonist, bicuculline (10 microM). Neither antagonist, alone, affected spontaneous or potassium-stimulated SP-LI release. 5. We conclude that activation of pre-synaptic GABAB receptors on the peripheral termini of PANs in the rat trachea inhibits SP-LI release and suggest that GABAB receptor agonists may be of value in the therapeutic treatment of asthma.     

The role of GABA receptors in the control of nigrostriatal dopaminergic neurons: dual-probe microdialysis study in awake rats.

A microdialysis probe implanted into the substantia nigra was used to infuse gamma-aminobutyric acid-ergic (GABAergic) compounds onto cell bodies/dendrites of dopaminergic neurons, while a second microdialysis probe was used to record the extracellular concentrations of dopamine and 3,4-dihydroxy-phenylacetic acid (DOPAC) in the ipsilateral striatum. The GABAA receptor agonist muscimol (10 mumol/l) increased the release of dopamine in the ipsilateral striatum to 120% of the control values. The GABAB receptor agonist, (Z)-3[(aminoiminomethyl)-thiol]-prop-2- enoic acid (500 mumol/l), was without effect. Infusion of the GABAA receptor antagonists, bicuculline (50 mumol/l) and picrotoxin (50 mumol/l), stimulated the release of dopamine in the ipsilateral striatum to 160 and 130% of the controls, respectively. The GABAB receptor agonist, baclofen (10 and 50 mumol/l), strongly inhibited the release of striatal dopamine, whereas infusion of the GABAB receptor antagonist, 2-hydroxy-saclofen (100 mumol/l), was without effect. The results indicate that, in the substantia nigra, GABAA as well as GABAB receptors participate in controlling the activity of dopaminergic neurons.     

Differential regulation of 5-hydroxytryptamine release by GABAA and GABAB receptors in midbrain raphe nuclei and forebrain of rats.

1. Extracellular 5-hydroxytryptamine (5-HT) was determined in dorsal raphe nucleus (DRN), median raphe nucleus (MRN) and nucleus accumbens by use of microdialysis in unanaesthetized rats. 2. Infusion of the gamma-aminobutyric acid (GABA)A receptor agonist muscimol into DRN and MRN resulted in decreased 5-HT in DRN and MRN, respectively. Muscimol infusion into nucleus accumbens had no effect on 5-HT. 3. Infusion of the GABAA receptor antagonist bicuculline into DRN resulted in increased DRN and nucleus accumbens 5-HT. Bicuculline infusion into MRN had no effect on 5-HT. This suggests that endogenous GABA had a tonic, GABAA receptor-mediated inhibitory effect on 5-HT in DRN, but not in MRN. 4. Infusion of the GABAB receptor agonist baclofen into DRN produced a decrease in DRN 5-HT. Baclofen infusion into nucleus accumbens resulted in decreased nucleus accumbens 5-HT. This suggests that GABAB receptors are present in the area of cell bodies and terminals of 5-hydroxytryptaminergic neurones. 5. Infusion of the GABAB receptor antagonists phaclofen and 2-hydroxysaclofen had no effect on midbrain raphe and forebrain 5-HT. This suggests that GABAB receptors did not contribute to tonic inhibition of 5-HT release. 6. In conclusion, 5-HT release is physiologically regulated by distinct subtypes of GABA receptors in presynaptic and postsynaptic sites.     

Opioid and prostaglandin mechanisms involved in the effects of GABAergic drugs on body temperature.

1. Intraperitoneal (i.p.) injection to restrained rats of GABA (250-1000 mg/kg) or the GABAA-receptor agonist muscimol (0.05-1 mg/kg) induced a dose-dependent decrease in body temperature (BT). 2. Intraperitoneal injection of low doses of the GABAB-receptor agonist (+/-)-baclofen (1-10 mg/kg) did not significantly affect BT. However, baclofen, at high doses (30 mg/kg), produced an increase in BT. 3. Pretreatment with either bicuculline (3 mg/kg) or naloxone (1 mg/kg) did not significantly modify the hypothermic response observed with GABA or muscimol, except for the high dose of GABA (1000 mg/kg) which was potentiated by bicuculline pretreatment. 4. Indomethacin pretreatment (5 mg/kg) significantly antagonized the hypothermia induced by GABA and muscimol. 5. Injection of baclofen alone (1 mg/kg) did not significantly affect BT, but in presence of the GABAA antagonist bicuculline, baclofen significantly decreased BT. 6. Baclofen-induced hyperthermia appear to be via prostaglandin and opioid mechanisms since both indomethacin and naloxone abolish this effect. 7. The hypothermia induced by GABA-agonists appears to be due to simultaneous activation of GABAA and GABAB receptors, while the hyperthermic effect of baclofen appears to be due to stimulation of GABAB receptors. 8. The present results suggest that involvement of prostaglandins in the effects of GABA, muscimol and baclofen, while endogenous opiates seem to be implicated only in baclofen induced hyperthermia. 9. It can be concluded that GABA may be involved in the control of BT through GABAA and GABAB receptors.     

Effects of baclofen on the olfactory cortex slice preparation

Baclofen has been shown to be ineffective against first order excitatory synaptic transmission in the olfactory cortex slice, whereas it is known that GABA-mediated inhibition depresses this transmission in a bicuculline-sensitive manner. In contrast, second and third order synaptic transmission, excitatory and inhibitory respectively, were depressed by baclofen. This suggests that the distribution of baclofen (GABAB) receptors differs from that of bicuculline-sensitive GABAA receptors in the olfactory cortex.     

Studies on the anticonvulsant effect of U50488H on maximal electroshock seizure in mice

The present study was designed to investigate the effect of U50488H, a prototype non-peptide kappa opioid agonist on convulsive behaviour using a maximal electroshock (MES) seizure test in mice. An attempt was also made to explore the role of possible receptors involved. MES seizures were induced via transauricular electrodes (60 mA, 0.2 s). Seizure severity was evaluated by means of two parameters, i.e., (1). duration of tonic hindlimb extensor phase and (2). mortality due to convulsions. Intraperitoneal (i.p.) administration of U50488H dose dependently (5-20 mg/kg) decreased the hindlimb extensor phase of MES. The anticonvulsant effect of U50488H was attenuated by the general opioid antagonist, naloxone at a high dose, and by MR2266, a selective kappa antagonist, but not by naltrindole, a delta antagonist. Coadministration of gamma-aminobutyric acid (GABA)ergic drugs (diazepam, GABA, muscimol, and baclofen) and the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK801), with U50488H augmented the anticonvulsant effect of the latter drug in mice. On the other hand, flumazenil, a central benzodiazepine (BZD) receptor antagonist, reversed the protective effect of diazepam and similarly, delta-aminovaleric acid (DAVA), a GABA(B) receptor antagonist, blocked the protective effect of baclofen, a GABA(B) agonist on the anti-MES action of U50488H. These BZD-GABAergic antagonists, namely, flumazenil or DAVA, on their own also counteracted the anti-electroshock seizure effect of U50488H given alone. However, mortality was not significantly altered in any of the above animal groups. Taken together, the findings have shown a possible role for multitude of important neurotransmitter systems, i.e., opioid (kappa), NMDA channel, GABA(A)-BZD-chloride channel complex, and GABA(B) receptors in the anticonvulsant action of U50488H.     

GABAergic mechanisms of analgesia: an update

Both directly acting (GABAA and GABAB agonists) and indirectly acting GABAergic agents (GABA uptake inhibitors and GABA-transaminase inhibitors) produce analgesia in a variety of animal test systems. Analgesia produced by GABAA agonists is probably due to a supraspinal action, although spinal sites may also play a role. GABAA agonist analgesia is insensitive to naloxone, bicuculline, picrotoxin and haloperidol, but is blocked by atropine, scopolamine and yohimbine suggesting a critical role for central cholinergic and noradrenergic pathways in this action. The lack of blockade by the GABAA antagonist bicuculline is difficult to explain. Both bicuculline and picrotoxin have intrinsic analgesia actions which may not necessarily be mediated by GABA receptors. The GABAB agonist baclofen produces analgesia by actions at both spinal and supraspinal sites. Baclofen analgesia is insensitive to naloxone, bicuculline and picrotoxin, and blockade by cholinergic antagonists occurs only under limited conditions. Catecholamines are important mediators of baclofen analgesia because analgesia is potentiated by reserpine, alpha-methyl-p-tyrosine, phentolamine, ergotamine, haloperidol and chlorpromazine. A role for serotonergic mechanisms is less well defined. Methylxanthines, which produce a clonidine-sensitive increase in noradrenaline (NA) turnover, increase baclofen analgesia by a clonidine-sensitive mechanism. Both ascending and descending NA pathways are implicated in the action of baclofen because dorsal bundle lesions, intrathecal 6-hydroxydopamine and medullary A1 lesions markedly decrease baclofen analgesia. However, simultaneous depletion of NA in ascending and descending pathways by locus coeruleus lesions potentiates baclofen analgesia suggesting a functionally important interaction between the two aspects. Baclofen analgesia within the spinal cord may be mediated by a distinct baclofen receptor because GABA does not mimic the effect of baclofen and the rank order of potency both of close structural analogs of baclofen as well as antagonists differs for analgesia and GABAB systems. The spinal mechanism may involve an interaction with substance P (SP) because SP blocks baclofen analgesia, and desensitization to SP alters the spinal analgesic effect of baclofen. GABA uptake inhibitors produce analgesia which is similar to that produced by GABAA agonists because it is blocked by atropine, scopolamine and yohimbine. Analgesia produced by GABA-transaminase inhibitors is similar to that produced by GABAA agonists because it can be blocked by atropine, but it is potentiated by haloperidol while THIP analgesia is not.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of intrahippocampal injection of GABAergic drugs on memory retention of passive avoidance learning in rats

The effect of post-training intrahippocampal injection of gamma-aminobutyric acid (GABA) receptor agonists and antagonists, immediately after a training session on memory retention of passive avoidance learning in rats, was measured in the presence and absence of physostigmine. Post-training treatments were carried out in all the experiments. The different doses of the GABAA receptor agonist muscimol (2, 4 and 6 microg/rat) decreased memory retention in rats dose-dependently. The higher response was obtained with 6 microg/rat of the drug. When the GABAA receptor antagonist bicuculline (0.5, 1, 2 and 4 microg/rat) was administered, only one dose of the drug (1 microg/rat) increased memory retention; however, the antagonist reduced the effect of muscimol. The GABAB receptor agonist, baclofen (0.25, 0.5, 1 and 2 microg/rat) also reduced memory retention in the animals. Intrahippocampal injection of lower doses of the GABAB receptor antagonist CGP35348 (P-[3-aminopropyl]-p-diethoxymethyl-phosphinic acid) (2.5, 5, 10 microg/rat) did not effect memory retention, although the higher doses of the drug (25 and 50 microg/rat) decreased memory retention. The doses of antagonist (2.5, 5 and 10 microg/rat), which did not elicit any response alone, reduced the effect of baclofen. The inhibitory response of CGP35348 was also decreased by bicuculline. In another series of experiments, physostigmine improved memory retention. The GABA receptor agonists, muscimol and baclofen, as well as the GABA receptor antagonists bicuculline and CGP35348, decreased the effect of physostigmine. Atropine decreased memory retention by itself and potentiated the response of muscimol and baclofen. It is concluded that GABAA and GABAB receptor activation may be involved in the impairment of memory retention.