Combined effect of drug and drive on the consolidation process

Rats of the Maudsley strains were trained in the Hebb-William's maze under three levels of food deprivation, i.e. 22, 25, and 7 h (drives) for 10 consecutive days. Immediately after each daily trial the experimental animals of all three drives were injected with a 1.0 mg/kg dose of picrotoxin, and the animals of the control groups were administered distilled water. Picrotoxin increased the efficiency of learning at all levels of drive, and higher drive level resulted in greater performance. The Reactive strain performed better in the maze learning than the Non-Reactive.This work was carried out at the Institute of Psychiatry, London S.E. 5.     

A possible role of a GABAergic mechanism in the convulsant action of RO5-4864

The purpose of the present investigation was to determine the possible role of GABAergic mechanism in the convulsant action of RO5-4864. Benzodiazepines (BZ) and other agents which facilitate central GABAergic transmission delayed the onset of facial and forelimb clonus, whereas tonic hind limb extension was blocked in a dose-dependent manner. RO5-4864-induced convulsions were blocked by diazepam, clonazepam, pentobarbital, ethanol and amino-oxyacetic acid (AOAA). RO5-4864-induced convulsions were not blocked by the BZ antagonist RO15-1788. Specifically, RO15-1788 caused a decrease in the onset of severity component of tonic seizures, which tended to become generalized and precipitated in a tonic extension of the hindlimbs. Further, subconvulsive doses of a direct GABA receptor antagonist, bicuculline, enhanced the proconvulsant action of RO5-4864, indicating thereby a potential antagonism of the central GABAergic transmission. These observations strongly suggest that RO5-4864 probably elicits convulsions by selective impairment of the GABAergic transmission.     

The effect of in vitro and in vivo ethanol administration on [S]t-Butylbicyclophosphorothionate binding in C57 mice

Previous studies have shown that ethanol may produce some of its effects by facilitation of GABAergic transmission. One of the potential sites of drug action at the GABA receptor complex is the picrotoxin site, which can be studied with [35S]t-butylbicyclophosphorothionate (TBPS). Ethanol inhibited the binding of [35S]TBPS to C57 mice brain regions in vitro. This inhibition appears to be noncompetitive since ethanol decreased the Bmax and not the KD value of [35S]TBPS. C57 mice were chronically treated with ethanol in liquid diet to determine if the sensitivity of TBPS binding is altered following chronic treatment or during withdrawal. Chronic treatment with ethanol and during withdrawal did not alter the KD or Bmax values of [35S]TBPS binding in C57 mice brain regions. It is suggested that the sensitivity of picrotoxin site on the oligomeric GABA receptor complex is not altered during ethanol tolerance or withdrawal. The effects of ethanol on GABA system may be mediated by its interaction with the coupling mechanism(s) or a direct effect on the chloride channels.     

Picrotoxin-sensitive receptors mediate γ-aminobutyric acid-induced modulation of synaptic plasticity in rat superior cervical ganglion

Activity-dependent changes of synaptic efficacy in the superior cervical ganglion (SCG) can be prevented by γ-aminobutyric acid (GABA). We have studied the effects of picrotoxin (PTX) on GABA-mediated inhibition of long-term potentiation (LTP) of synaptic transmission in the rat SCG. Compound action potentials were recorded extracellularly in the postganglionic internal carotid nerve in response to preganglionic nerve stimulation. PTX (100 μM) antagonized the inhibition by exogenous GABA (250 μM) of LTP induced by strong tetanic stimulation (20 Hz, 20 s, supramaximal stimulation, partial blockade of transmission by hexamethonium). Additionally, PTX alone (50 μM) facilitated the induction of LTP by a weak tetanus (20 Hz, 5 s, submaximal stimulation). These results further support previous data indicating that activation of GABA_A-like receptors can prevent the occurrence of synaptic plasticity at this peripheral synapse. © 1997 Elsevier Science B.V. All rights reserved.     

Anticonvulsant effect of felbamate in the pentylenetetrazole kindling model of epilepsy in the rat

The present study was designed to examine the ability of felbamate, a novel antiepileptic agent, to antagonize the increase in seizure severity (i.e., chemical kindling) produced by chronic treatment with initially subconvulsant doses of pentylenetetrazol (PTZ). Rats were treated with PTZ (30 mg/kg, i.p., three times a week) for 8 consecutive weeks. Two other groups of rats received felbamate (300 or 400 mg/kg, i.p.), 90 min before each dose of PTZ. Pretreatment with felbamate at either dose prevented the progression of rank of seizures during chronic treatment with PTZ. Thus, the mean seizure score by the end of the chronic treatment (0–5 scale) was 0 in vehicle treated controls, 3.3 in rats treated with PTZ alone, 1.5 in rats treated with PTZ plus felbamate (300 mg/kg, i.p.) and 0.9 in the group treated with PTZ plus felbamate (400 mg/kg, i.p.). Felbamate also antagonized the long-term increase in the sensitivity to the convulsant effects of GABA function inhibitors observed in PTZ-kindled rats. Thus, the administration of a challenge dose of isoniazid (120 mg/kg, s.c.), picrotoxin (1.5 mg/kg, i.p.) or PTZ itself (15 mg/kg, i.p.), 15 to 45 days after the end of the chronic treatment regimen, induced convulsions in > 80% of PTZ-kindled rats and in < 20% of rats treated with PTZ + felbamate (400 mg/kg). The results are discussed in terms of the multiple mechanisms that can contribute to the anticonvulsant action of felbamate in the PTZ kindling model of epilepsy.     

The role of inhibitory processes in the formation of functional properties of neurons in vibrissal projection zone of the cat somatosensory cortex

Summary The role of intracortical inhibitory processes in the formation of neuronal receptive fields in the vibrissal projection zone of the somatosensory cortex was studied. Iontophoretic application of picrotoxin and bicuculline blocks the inhibition and causes the loss of directional sensitivity in neurons. Activation of inhibition by distant glutamate application gives opposite results — neurons become direction sensitive. A dependence was found between spatial location of activated cells and the pattern of changes of their detector properties. Inhibitory processes caused by natural afferent stimulation lead to similar changes in the functional properties of neurons.     

Susceptibility of Flinders sensitive and resistant rats to pharmacologically induced seizures

The Flinders sensitive (FSL) and Flinders resistant (FRL) line rats have been selectively bred for hyper- and hyposensitivity to the hypothermie effect of cholinergic agonists respectively. In this study, pilocarpine (250 mg/kg) and physostigmine (0.8 mg/kg) doses that are subconvulsant to outbread Sprague-Dawley rats were systemically injected to the FSL and FRL rats and a heterogenous F2 cross. All of the FRL rats developed severe motor limbic seizures in response to pilocarpine, while none of the FSL animals did. The F2 crosses showed intermediate reaction. The FRL rats were also more affected by physostigmine than the other two groups. However, the FSL rats were confirmed to be more sensitive to the hypothermic effects of pilocarpine (20 mg/kg) and physostigmine (0.6 mg/kg). Picrotoxin and kainic acid produced similiar responses in the both lines, i.e., induced clonk convulsions in some animals when applied in subtreshold doses (2 and 10 mg/kg, respectively). Thus, the normally cholinergicinsensitive rats are more sensitive to the convulsant effects of high doses of cholinergic agonists, but this increased sensitivity does not extend to noncholinergic convulsants.     

Layer-Specific Pathways for the Horizontal Propagation of Epileptiform Discharges in Neocortex

Summary: Purpose: Epileptiform discharges that resemble interictal spikes can be generated by slices of neocortex treated with antagonists of γ-aminobutyric acid A (GABA_A) receptors. These discharges can propagate horizontally for long distances. We tested the hypothesis that propagation occurs through preferred horizontal pathways that lie in a particular cortical layer. Methods: Slices were prepared from the primary somatosensory cortex of rats, maintained in vitro, and bathed with the GABA_A receptor antagonist picrotoxin. Electrical stimuli were used to evoke single all-or-none paroxysmal field potentials (PFP) that were recorded with pairs or arrays of field potential electrodes. Results: To test which laminae are necessary for propagation, vertical cuts were made to force the PFP to spread horizontally through particular layers. If slices were bathed in a high dose of picrotoxin (35 μM, a bridge of cortex 350 μm thick placed at any lamina was sufficient to support PFP propagation. However, in low picrotoxin doses (2.5 μM), similarly sized bridges had to include tissue from layers 415 or 516 to support propagation. When slices were cut horizontally (i.e., parallel to the pia) in strips, either upper-, middle-, or lower-layer strips were sufficient to support PFP propagation if the picrotoxin concentration was high; however, in low picrotoxin doses, only horizontal strips that included layer 5 could support propagation. Finally, in intact picrotoxin-treated slices, focal applications of GABA were systematically applied to different laminae as the PFP propagated past; GABA was most effective at blocking or delaying propagation when it was applied to layer 5b. Conclusions: We conclude that epileptiform propagation can occur through a variety of horizontal pathways when cortical inhibition is strongly impaired. However, when inhibition is reduced only moderately, axonal pathways in layer 5 are critical for seizure spread.     

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.