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PubMed1994

Effects of inhibition of the GABAergic systems by picrotoxin on retention of a nociceptive experience in the rat, with special reference to the influence of cerebellar cortex output.

Adult cerebellectomized and noncerebellectomized DA/HAN strain (pigmented) female rats were submitted to a one-trial passive avoidance conditioning procedure consisting in associating darkness with a nociceptive stimulus. Seven days later, they were tested again to assess the retention stage. The results demonstrate that in noncerebellectomized rats, picrotoxin, whatever the dose, administered prior to the retention test, does not significantly impair retrieval. On the contrary, when administered just prior to the initial conditioning, impairments of the initial single nociceptive experience were evident (the greater the picrotoxin dose, the greater the impairments). In animals that were cerebellectomized 1 week before the experiment, picrotoxin administered at a low dose before the initial experience elicited memory impairments that were similar to those induced in noncerebellectomized rats but that were greater than those elicited in cerebellectomized, nontreated animals. However, in cerebellectomized rats, picrotoxin administered at a low dose elicited memory impairments that were weaker than in noncerebellectomized animals injected with a high dose of the drug. Considering that a low dose of picrotoxin administered to cerebellectomized animals had effects that were similar to those of a high dose injected to noncerebellectomized rats, and given that it has previously been demonstrated that a cerebellectomy performed after a single nociceptive experience impairs its memory, it is tempting to suggest that the two different doses of the drug administered to cerebellectomized and noncerebellectomized rats have similar effects on memory. If such an interpretation is valid, the information would have to leave the cerebellar cortex to be stored for long.

Animals↗
PubMed1983

Variations in response of the GABA-picrotoxin-benzodiazepine receptor complex to flurazepam.

Two effects of flurazepam have been studied on electrophysiological responses to muscimol in a slice preparation of rat cuneate nucleus. Flurazepam potentiated the responses to muscimol and also reduced the antagonism of these responses by picrotoxin. Repeated series of experiments over a 3 year period showed significant variations in the potentiation of muscimol by flurazepam which were negatively correlated with the apparent reduction in picrotoxin potency. A more reproducible reduction in picrotoxin potency by flurazepam was obtained when the data were re-calculated to take account of the possibility that picrotoxin might antagonize the potentiating effect of flurazepam as well as the direct response to muscimol. The simplest explanation of this relationship is that flurazepam and picrotoxin mutually antagonize each others effects on the GABA system. The underlying cause of the variation in flurazepam effect remains unknown.

Animals↗
PubMedDate not supplied

GABA-specificity of behaviour responses to picrotoxin injected into the colliculus superior of cats.

The behavioural response to picrotoxin (25-500 ng) injected into the colliculus superior (CS) of freely moving cats was investigated. The maximal response to unilateral injections of picrotoxin (greater than or equal to 200 ng) was characterized by the following sequence of behavioural events. During the first 5 min after the injection the cat executed retroflexions of the contralateral ear. After 1-5 min these contralateral ear movements were followed by short, contralateral head movements. As time progressed the front part of the body, including the forelimbs, became involved in the movements resulting in contralateral torso movements. Finally, as the response was maximal, the whole body became involved in the movements resulting in contralateral body movements. Data are shown indicating that most of these behavioural phenomena were dose-dependent, locus-specific, and GABA-specific. Bilateral injections of picrotoxin resulted in similar characteristic movements, but now directed towards both sides and/or directed 'ventrocaudally'. Finally, it was found that blindfolding the animals did not change the response to unilaterally injected picrotoxin. As the behavioural phenomena described here are dissimilar to the effects observed after disturbing the GABAergic activity in the substantia nigra, pars reticulata (SNR), it is concluded that the CS, being an output station of the SNR, transforms its input signals into new output signals. Finally, it is suggested that picrotoxin resulted in a fixed code at the level of the CS, forcing the animal to execute characteristic motor patterns.

Animals↗
PubMed1987

Picrotoxin induced epileptiform activity in amygdaloid neurons.

The effects of the epileptogenic agent, picrotoxin, on inhibitory postsynaptic potentials (IPSPs) were studied in the amygdala in vitro slice preparation. Picrotoxin was superfused onto the tissue and intracellular recordings were obtained from basolateral amygdaloid neurons (BLANs). Stimulation of the stria terminalis pathway evoked an excitatory postsynaptic potential (EPSP)--IPSP sequence. Depolarization of the membrane potential increased the amplitude of the IPSP, whereas hyperpolarization of the membrane potential decreased the amplitude of the IPSP. The IPSP reversed polarity at -74 mV. Application of picrotoxin reduced the IPSP and resulted in the development of paroxysmal depolarizing shifts. Picrotoxin itself had no apparent effect on the resting membrane potential or input resistance. These results indicate that epileptiform activity induced by picrotoxin in the basolateral amygdaloid neuron is of synaptic origin.

Action Potentials↗
PubMed1990

Gender difference in susceptibility to picrotoxin-induced seizures is seizure- and stimulation-dependent.

In a dose-response study, the pattern of sex-associated susceptibility to picrotoxin-induced myoclonic, focal, akinetic, and generalized tonic-clonic (GTC) seizures was investigated in rats to determine whether the reported heightened susceptibility of females to seizures was a general phenomenon in rats or whether it was limited to specific types of seizures. The latency to and incidence of specifically categorized seizures were used as indices of susceptibility after male and female rats had been injected with picrotoxin (3-10 mg/kg). The results revealed that at low doses of picrotoxin (4 mg/kg), female rats had significantly shorter latencies to myoclonic seizures and significantly shorter latencies and higher incidences of GTC seizures. At higher doses of picrotoxin (8 and 10 mg/kg), the pattern of relative susceptibility of males and females to myoclonic seizures was reversed, with males having shorter latencies than females. There were no significant sex differences in the incidence of or latency to focal or akinetic seizures at any of the doses tested. These findings indicate 1) that there are significant sex differences in seizure susceptibility only for specific seizure categories in rats; and 2) that for seizure categories where significant sex differences were identified, the observed pattern of relative susceptibility of males and females depends on the dose of picrotoxin tested. Thus, patterns of sex-associated seizure susceptibility favoring either males or females are both seizure- and stimulation-limited and do not reflect general dispositions to seizures in either sex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Prenatal treatment with picrotoxin promotes heterotypical sexual behavioral and neurochemical changes in male rat offspring.

The effects of maternal prenatal exposure to picrotoxin (0.75 mg/kg S.C. days 16-19 of pregnancy) in male rat offspring were observed. Adult sexually experienced and inexperienced animals were evaluated for heterotypical sexual behavior, as well as the testosterone plasma levels and striatal neurotransmitters. In relation to sexual behavior and analysis of sexual organs, the results showed that animals treated with picrotoxin exhibited a more intense reproductive behavior, and this could be expressed by a significant decrease in the number of mounts and intromissions and increase in the numbers of ejaculation, showed that these males are most motivate for sexual behavior. Testosterone levels as well as weight for sexual organs did not differ from control group. The neurochemical analysis showed that picrotoxin did not alter DA, 5-HT, 5-HIAA and GABA in animals. The DOPAC/DA and HVA/DA relation showed that the treatment increased the DA system activity in animals sexually experienced, as well as promote a decrease in 5-HT/5-HIAA relation, that is known was an inhibitory neurotransmitter system, blockade a male sexual behavior. There are no alterations observed in GABA levels. It's could be explained by suggests that picrotoxin modification DA system activity through GABAergic system, permitting that DA system to be freely active and facilitate the heterotypical behavior of male rats. These results show that the maternal prenatal exposure to picrotoxin produced changes in the neurochemical and sexual behavior of the adult male rats. Also previous heterotypical experience leads to changes in biogenic amine concentrations in these animals.

Animals↗
PubMed2004

Laminar distribution of GABAA- and glycine-receptor mediated tonic inhibition in the dorsal horn of the rat lumbar spinal cord: effects of picrotoxin and strychnine on expression of Fos-like immunoreactivity.

Inhibitory mechanisms are essential in suppressing the development of allodynia and hyperalgesia in the normal animal and there is evidence that loss of inhibition can lead to the development of neuropathic pain. We used Fos expression to map the distribution of tonically inhibited cells in the healthy rat lumbar spinal cord. In a control group, Fos-like immunoreactive (Fos-LI) cells were rare, averaging 7.5+/-2.2 cells (mean+/-SEM; N=13 sections) per 20 microm thick section of dorsal horn. This rose to 103+/-11 (mean+/-SEM; N=20) in picrotoxin-treated rats and to 88+/-11 (mean+/-SEM; N=18) in strychnine-treated rats. These changes were significant (ANOVA; P<0.001). There were marked regional variations in the distribution of Fos-LI cells between picrotoxin- and strychnine-treated animals. Picrotoxin induced a significant increase in the number of Fos-LI cells throughout the dorsal horn (lamina I-VI) while strychnine significantly elevated Fos-like immunoreactivity only in deep laminae (III-VI). For both picrotoxin and strychnine, the increase in Fos-like immunoreactivity peaked in lamina V (at 3579+/-319 and 3649+/-375% of control, respectively; mean+/-SEM) but for picrotoxin an additional peak was observed in the outer part of lamina II (1959+/-196%). Intrathecal administration of both GABAA and glycine receptor antagonists has been shown elsewhere to induce tactile allodynia. The present data suggest that this allodynia could arise due to blockade of tonic GABAA and glycine-receptor mediated inhibition in the deep dorsal horn. GABAA antagonists also induce hypersensitivity to noxious inputs. The blockade of tonic inhibition in the superficial dorsal horn shown here may underlie this hyperalgesia.

Animals↗
PubMed2002

Relative picrotoxin insensitivity distinguishes ionotropic GABA receptor-mediated IPSCs in hippocampal interneurons.

Inhibitory GABAergic signalling in the hippocampus plays an important role in synchronizing principal cells and regulating the excitability of this seizure-prone structure. Distinct mechanisms modulate release from GABAergic terminals in the hippocampus, depending on whether the postsynaptic partner is an interneuron or a principal cell. Here, we report that postsynaptic ionotropic GABA receptors in principal cells and interneurons also show a striking pharmacological difference. The broad-spectrum antagonist picrotoxin (PTX) was less potent at blocking IPSCs evoked in stratum radiatum interneurons than in pyramidal neurons in the CA1 region. GABA-evoked currents in membrane patches from interneurons showed a smaller mean unitary conductance than in patches from pyramidal neurons. Because retinal GABA(C) receptors show decreased picrotoxin sensitivity and conductance, we examined the effect of the GABA(C) receptor agonist cis-aminocrotonic acid (CACA). Although this agent evoked picrotoxin-resistant currents in interneurons, these were enhanced by the GABA(A) allosteric modulator pentobarbital. Moreover, both picrotoxin-resistant IPSCs and CACA-evoked currents were blocked by the GABA(A) receptor-selective antagonist bicuculline. The presence of relatively picrotoxin-resistant GABA(A) receptors in interneurons provides a potential target for agents to modulate the activity of sub-populations of hippocampal neurons.

Animals↗
PubMed2003

Prevention of picrotoxin convulsions-induced learning and memory impairment by nitric oxide increasing dose of L-arginine in rats.

Learning and memory processes were tested in adult male rats using a traditional pole-climbing apparatus 30 min after the administration of L-arginine (500 and 1000 mg/kg), the precursor of nitric oxide (NO), and N-nitro-L-arginine methyl ester (L-NAME) (50 and 100 mg/kg), the inhibitor of NO synthesis. The effects of the convulsant (5.0 mg/kg) and a smaller nonconvulsant (2.5 mg/kg) dose of picrotoxin were tested on learning and memory 120 min and 24 h after their administration. The tests were carried out 30 min after L-arginine in animals treated 120 min previously with the convulsant dose of picrotoxin. A dose-dependent enhancement and an inhibition of learning and memory were observed in animals treated with L-arginine and L-NAME, respectively. The convulsant dose of picrotoxin impaired both learning and memory processes. The effect of picrotoxin was reverted following the administration of L-arginine (1000 mg/kg). An interpretation of these results indicates that convulsions induced by picrotoxin produces learning and memory impairment, and that this defect is reversible if NO synthesis is increased in the brain by the systemic administration of L-arginine.

Animals↗
PubMed1990

Picrotoxin enhances latent extinction of conditioned fear.

Male CD1 mice received 20 pairings of tone and footshock (FS) or tone alone in an arm of a Y-maze on Day 1. On Day 2 either extinction (tone alone) or no extinction was followed immediately by saline or picrotoxin (0.5 or 1.0 mg/kg ip). Nonextinguished groups received only saline or picrotoxin (1.0 mg/kg ip) on Day 2. Other groups received saline or picrotoxin (1.0 mg/kg) 2 hr after extinction. On Day 3 all mice were placed in the Y-maze (with doors to all 3 alleys open), and total alley entries during a 2-min test session were recorded. Day 1 FS training resulted in reduced alley entries during the test session. Day 2 extinction session significantly attenuated the effects of the FS training. Day 3 performance of mice given picrotoxin (1.0 but not 0.5 mg/kg) immediately postextinction was comparable to that of mice not given FS on Day 1. The findings suggest that picrotoxin enhanced extinction of conditioned fear.

Animals↗
PubMed1995

Mutations affecting the glycine receptor agonist transduction mechanism convert the competitive antagonist, picrotoxin, into an allosteric potentiator.

Contrary to its effects on the gamma-aminobutyric acid type A receptor, picrotoxin antagonism of the alpha 1 subunit of the human glycine receptor is shown to be competitive, not use-dependent, and nonselective between the picrotoxin components, picrotin, and picrotoxinin. Competitive antagonism and non-use dependence are consistent with picrotoxin binding to a site in the extracellular domain. The mutations Arg-->Leu or Arg-->Gln at residue 271 of the glycine receptor alpha 1 subunit, which are both associated with human startle disease, have previously been demonstrated to disrupt the transduction process between agonist binding and channel activation. We show here that these mutations also transform picrotoxin from an allosterically acting competitive antagonist to an allosteric potentiator at low (0.01-3 microM) concentrations and to a noncompetitive antagonist at higher (> or = 3 microM) concentrations. This demonstrates that arginine 271 is involved in the transduction process between picrotoxin binding and its mechanism of action. Thus, the allosteric transduction pathways of both agonists and antagonists converge at a common residue prior to the activation gate of the channel, suggesting that this residue may act as an integration point for information from various extracellular ligand binding sites.

Allosteric Regulation↗
PubMed2005

Intrathecal picrotoxin minimally alters electro-encephalographic responses to noxious stimulation during halothane and isoflurane anesthesia.

BACKGROUND: Isoflurane and halothane act in the spinal cord to blunt ascending transmission of impulses to the brain resulting from noxious stimulation. Because intrathecal picrotoxin (an antagonist at the gamma-aminobutyric acid-A receptor) partially reverses the immobilizing effect of isoflurane and halothane, we hypothesized that the electroencephalographic response to noxious stimulation would likewise be partially reversed by intrathecal picrotoxin. METHODS: Rats were anesthetized with isoflurane (n = 8) or halothane (n = 8) and a laminectomy performed. Following determination of minimum alveolar concentration (MAC), the electroencephalogram (EEG) was recorded during separate applications of a hindpaw clamp, tail clamp and electrical current to the tail at 0.8 and 1.2 MAC. Picrotoxin was then applied to the exposed spinal cord and the EEG response to noxious stimulation again determined. RESULTS: The EEG was more active during halothane anesthesia than isoflurane (spectral edge frequency for 95% power: 25.6 +/- 2.1 Hz vs. 23.1 +/- 1.6 Hz, P < 0.05). Noxious stimulation usually caused the EEG to shift to higher frequencies (e.g. for 0.8 MAC halothane, median edge frequency for 50% power: from 7.6 +/- 3.1 Hz to 10.7 +/- 2.6 Hz, P < 0.05). Picrotoxin minimally affected this response. CONCLUSIONS: Noxious stimulation evokes an EEG response that is minimally altered by intrathecal picrotoxin. This suggests that isoflurane and halothane do not have GABAergic actions in the spinal cord that indirectly suppress the EEG response.

Anesthetics, Inhalation↗
PubMed1983

Modulation of [3H]muscimol binding in rat cerebellar and cerebral cortical membranes by picrotoxin, pentobarbitone, and etomidate.

Modulation of [3H]muscimol binding by picrotoxin, pentobarbitone, and etomidate was investigated in rat cerebellar and cerebral cortical membranes. In cerebellum, at 37 degrees C in the presence of chloride ions (150 mM), picrotoxin and picrotoxinin decreased specific [3H]muscimol binding to 43 +/- 3% of control, with an EC50 of 1.2 +/- 0.1 microM. [3H]Muscimol saturation experiments in the presence and absence of picrotoxin indicated that the picrotoxin effect was primarily due to a loss of high-affinity muscimol sites with KD approximately equal to 10 nM. Pentobarbitone enhanced specific [3H]muscimol binding to 259 +/- 3% of control, with EC50 = 292 +/- 37 microM, and etomidate increased binding to 298 +/- 18%, with EC50 = 7.1 +/- 1.0 microM. The influence of temperature and chloride ion concentration on these effects was investigated by comparing experiments at 37 and 0 degrees C in the presence or absence of chloride at constant ionic strength. The results indicate that studies at 0 degrees C underestimate the coupling between GABA receptors and barbiturate sites and that they greatly overestimate the importance of chloride ions in this phenomenon. In cerebral cortical membranes (37 degrees C, 150 mM Cl-), the effect of picrotoxin was similar to that observed in cerebellum, whereas the effects of pentobarbitone and etomidate were greater, but occurred at higher concentrations.

Animals↗
PubMed1984

Modification of seizures elicited by the benzodiazepine Ro 5-3663--a comparison with picrotoxin.

Ro 5-3663 is a convulsant 1,4-benzodiazepine that does not act at the benzodiazepine, but at the picrotoxin, site. To characterize the behavioural actions of Ro 5-3663, a comparison was made between its effects and those of picrotoxin, when combined with several compounds that act at the GABA-benzodiazepine receptor complex. The quinolines, PK 8165, PK 9084 and CGS 8216 caused myoclonic jerks when combined with subconvulsant doses of Ro 5-3663 or picrotoxin; in combination with picrotoxin they also caused full tonic-clonic convulsions. Ro 15-1788 (1, 10 mg kg-1) caused myoclonic jerks when it was given 10 min before, or at the same time as, subconvulsant doses of either compound. Diazepam (2, 4 mg kg-1) was anticonvulsant against both compounds. However, Ro 15-1788 (10, 20 mg kg-1, 20 min before), PK 8165 (80 mg kg-1) and PK 9084 (60 mg kg-1) were effective only against the convulsions induced by Ro 5-3663. It is not possible to determine whether these differences between Ro 5-3663 and picrotoxin are quantitative or qualitative.

Animals↗
PubMed2006

Stoichiometry of a pore mutation that abolishes picrotoxin-mediated antagonism of the GABAA receptor.

Picrotoxin, a potent antagonist of the inhibitory central nervous system GABAA and glycine receptors, is believed to interact with residues that line the central ion pore. These pore-lining residues are in the second transmembrane domain (TM2) of each of the five constituent subunits. One of these amino acids, a threonine at the 6' location, when mutated to phenylalanine, abolishes picrotoxin sensitivity. It has been suggested that this threonine, via hydrogen bonding, directly interacts with the picrotoxin molecule. We previously demonstrated that this mutation, in the alpha, beta or gamma subunit, can impart picrotoxin resistance to the GABA receptor. Since the functional pentameric GABA receptor contains two alpha subunits, two beta subunits and one gamma subunit, it is not clear how many alpha and beta subunits must carry this mutation to impart the resistant phenotype. In this study, by coexpression of mutant alpha or beta subunits with their wild-type counterparts in various defined ratios, we demonstrate that any single subunit carrying the 6' mutation imparts picrotoxin resistance. Implications of this finding in terms of the mechanism of antagonism are considered.

Animals↗
PubMed1995

Effects of propofol and thiopentone on picrotoxin convulsive threshold in the rabbit.

The purpose of the present study was to examine the effect of intravenous administration of propofol and thiopentone on picrotoxin-induced seizures using the picrotoxin convulsive threshold test in the rabbit. Neither propofol nor thiopentone at a dose of 1.25 mg/kg had any significant effect on picrotoxin seizure threshold. However, at higher doses (2.5, 5, 10 mg/kg) both propofol and thiopentone produced a significant and dose-dependent increase in the picrotoxin convulsive threshold. These findings suggest that propofol is an effective anticonvulsant against picrotoxin-induced seizures in the rabbit.

Animals↗
PubMed2001

Evidence for an involvement of the ammonia-decreasing action of L-arginine in suppressing picrotoxin-induced convulsions in rats and its additive action with diazepam.

The effects of pre- (30 min before challenge) and post-treatment (5 min after challenge) of L-arginine (840 mg kg(-1)) were tested on picrotoxin-induced increase in ammonia concentrations in brain regions (cerebral cortex, brain stem and cerebellum) and the accompanying convulsive responses in adult male rats. The effect of pre- and post-treatment of L-arginine was tested on the action of diazepam against picrotoxin-induced convulsions. Picrotoxin-induced increase in ammonia concentrations in the brain regions was reverted partially by L-arginine pre-treatment. However, L-arginine pre-treatment failed to inhibit convulsions independently and concurrently with diazepam. On the other hand, L-arginine post-treatment reverted ammonia to control level in all brain regions. A partial but significant inhibition of convulsions was found in these animals. The effect produced concurrently by L-arginine and diazepam post-treatment was much greater than that produced by these agents independently. These results suggest that brain ammonia has a partial but significant participation in the convulsant action of picrotoxin. L-arginine has produced a partial protection of picrotoxin-induced convulsions by reverting brain ammonia to control level. The data further suggest that the duration of action of L-arginine is considerably short and that L-arginine has an additive anticonvulsant action with diazepam.

Ammonia↗
PubMed1999

Effects of L-arginine on picrotoxin-induced increase in brain ammonia concentrations and convulsions in rats.

The effect of L-arginine (840 mg/kg) pre- (30 min before challenge) and post-treatment (5 min after challenge) period was tested on picrotoxin-induced increase in ammonia concentrations in brain regions (cerebral cortex, brain stem and cerebellum) and the accompanying convulsive responses in adult male rats. The combined effect of L-arginine and diazepam was also tested against picrotoxin-induced convulsions. Picrotoxin-induced increase in ammonia was reverted partially by L-arginine pretreatment. However, L-arginine pretreatment did not show anticonvulsant effect independently or concurrently with diazepam. On the other hand, L-arginine post-treatment reverted ammonia to control level in all brain regions. A partial but significant inhibition of convulsion responses was found in these animals. The combined effect of diazepam and L-arginine post-treatment was much greater than that produced by these agents independently. These findings suggest that ammonia has a partial but significant participation in the convulsant action of picrotoxin. L-arginine has a potential to revert brain ammonia to control level in picrotoxin-treated animals and thereby it has produced a partial protection. The data further indicate that the duration of action of L-arginine is considerably short and has an additive anticonvulsant action with diazepam.

Ammonia↗