Purinergic modulation of the seizure threshold for pentylenetetrazol in the rat

The effects of various metabolically-stable analogs of adenosine on the threshold for seizures in rats was determined by measuring the dose of pentylenetetrazol (PTZ), infused through a tail vein, required to elicit a myoclonic jerk. The adenosine receptor agonists, 2-chloroadenosine (2-ClAdo), cyclohexyladenosine (CHA) and L- and D-phenylisopropyladenosine (L- and D-PIA), all produced dose-dependent elevations of the seizure threshold for pentylenetetrazol in rats. L-Phenylisopropyl-adenosine was the most potent analog of adenosine tested with a dose as small as 5 micrograms/kg (i.v.) producing a 23% increase in seizure threshold for pentylenetetrazol. The rank order of the potency of adenosine agonists in increasing the seizure threshold was L-PIA greater than 2-ClAdo greater than CHA greater than D-PIA, with L-PIA being 79 times more potent than D-PIA. In contrast to these effects, the adenosine receptor antagonist, theophylline, elicited a proconvulsant effect in doses from 15 to 60 mg/kg (i.p.). The effect of theophylline in reducing seizure threshold for pentylenetetrazol peaked at 30 mg/kg, a dose which reduced the seizure threshold by approx. 27%. Support for the involvement of recognition sites for adenosine in the observed modulation of seizure threshold was provided by the antagonism of the elevation of the seizure threshold for pentylenetetrazol induced by 2-ClAdo, by pretreatment with theophylline (5 mg/kg, i.v.). These findings provide support for the idea that endogenous adenosine may function as a regulator of seizure susceptibility.     

The partial benzodiazepine agonist properties of Ro 15-1788 in pentylenetetrazol-induced seizures in cats

The effects of Ro 15-1788, a specific benzodiazepine antagonist, were studied on pentylenetetrazol-induced seizures in cats. Ro 15-1788 decreased the number of myoclonic jerks induced by a subconvulsive dose of pentylenetetrazol (12.5 mg/kg, i.m.). Ro 15-1788 suppressed generalized convulsive seizures induced by a minimal convulsive dose of pentylenetetrazol (25-35 mg/kg), but did not block the effects of higher doses (35-45 mg/kg). These results indicate that Ro 15-1788 is not a pure benzodiazepine antagonist, but has partial agonistic properties.     

Effects of amphetamine isomers and CNS catecholaminergic blockers on seizures in mice.

The effects of (+)- and (?)-amphetamine on intravenous pentylenetetrazol(PTZ)-induced clonic seizure threshold were studied in CD-1 mice. The (+)-isomer elicited a biphasic effect, increasing seizure threshold 5–21% at low doses (1.25–2.5 mg/kg) and decreasing PTZ-induced clonic seizure threshold 15–28% at high doses (10–15 mg/kg). (?)-Amphetamine (1.25–10 mg/kg) increased PTZ-induced clonic seizure threshold 28–49%; doses of 15–45 mg/kg were without effect. Studies utilizing blockers of α- and β-noradrenergic (phentolamine, azapetine, (?)-sotalol, and (?)-INPEA), and dopa-minergic (pimozide and haloperidol) receptors suggest that the biphasic effects of (+)-amphetamine may be dependent upon α- and β-noradrenergic activation, while the decrease in PTZ-induced clonic seizure threshold possibly also involves the dopaminergic system. The increase in PTZ-induced clonic seizure threshold by (?)-amphetamine is primarily mediated by the β-noradrenergic system with α-noradrenergic and dopaminergic involvement also possible. These results show quantitative differences in the relative potency of the amphetamine isomers, [(?)- > (+)], and suggest that qualitative differences may exist as well.     

Effect of clonidine on motoneuron excitability in spinalized rats

In a dose of 0.1 mg/kg clonidine, an alpha-2 receptor agonist, depressed the spontaneous EMG activity of the biceps and quadriceps femoris in chronically-spinalized rats. It also antagonized in a dose-dependent manner the stimulating effect of 5-hydroxytryptophan (5-HTP, 100 mg/kg). Doses of more than 0.1 mg/kg were less potent in antagonizing the effect of 5-HTP. Clonidine reduced the tonic activity of the hindlimb muscles but allowed walking movements. The depressant effect of clonidine in animals pretreated with 5-HTP was prevented by yohimbine (1.25 mg/kg), while the depressant action of the serotonin antagonist, cyproheptadine was not. In chronically-spinalized rats, clonidine (0.1 mg/kg) increased the threshold of electrically-induced flexor and extensor reflexes and decreased their amplitude. No significant modification of reflexes was seen with this dose 24 hr after spinalization. Thus, clonidine in doses of 0.1 mg/kg or less reduced directly or indirectly the excitability of motoneurons. Clonidine may prove to be a useful therapeutic adjunct in the treatment of spasticity.     

Repeated administration of subconvulsant doses of GABA antagonist drugs

Repeated subconvulsant doses of the GABA antagonist drugs picrotoxin (5 mg/kg), pentylenetetrazol (PTZ) (30 mg/kg), and bicuculline (3.5 mg/kg), were given IP once daily to rats. Picrotoxin produced rapid kindling to full seizures in about 5 days, PTZ produced sporadic myoclonic seizures after 17 days, PTZ produced sporadic myoclonic seizures after 17 days whereas bicuculline only produced occasional mild jerking. Following these treatments, seizure thresholds to these drugs were measured by an IV infusion method to minimise problems of systemic uptake and metabolism of the drugs. Picrotoxin- and PTZ-treated animals showed no alteration in seizure threshold. However, following bicuculline pretreatment, seizure threshold was raised. Methodological problems in the interpretation of pharmacological kindling are discussed.     

The anticonvulsant effects of diazepam and phenobarbital in prekindled and kindled seizures in rats

The effects of various doses of diazepam (0.5–4 mg/kg) and phenobarbital (7.5–60 mg/kg) were determined on prekindled and kindled amygdaloid seizures in the same rats. Diazepam was ineffective against the prekindled focal seizures, but demonstrated profound and statistically significant control of the kindled seizures. In the kindled state, diazepam reduced the afterdischarge duration and seizure rank score to prekindled levels. Only the largest sedating dose of phenobarbital produced a reduction of both prekindled afterdischarge duration and seizure rank score. Against the kindled seizure, phenobarbital showed a marked and statistically significant increase in effectiveness in all but the smallest dose tested. The afterdischarge duration of kindled seizures was reduced to prekindled levels by 15–60 mg/kg of phenobarbital, while seizure rank score was reduced to prekindled levels by 30 and 60 mg/kg phenobarbital. The effects of two doses of diazepam (0.5 and 2.5 mg/kg) and phenobarbital (7.5 and 30 mg/kg) were tested against prekindled and kindled pentylenetetrazol (PTZ)-induced seizures. Preliminary work with 3 doses of pentylenetetrazol (30, 40 and 60 mg/kg) demonstrated that repeated doses of 30 mg/kg readily kindled seizures without the significant mortality seen with larger doses. Both diazepam and phenobarbital were less effective against seizures kindled with 30 mg/kg pentylenetetrazol compared to prekindled seizures. The comparative lack of effect that was seen with diazepam and phenobarbital against the pentylenetetrazol kindled seizure at doses associated with control of the kindled amygdaloid seizure may reflect an underlying difference in the pathogenesis of kindling between these seizure models. Further, the lack of suppression of the prekindled amygdaloid afterdischarge duration by large doses of diazepam, in contrast to large doses of phenobarbital, may also reflect differences between the mechanisms of action of these two drugs. This paradigm provides a model for testing the effectiveness of anticonvulsants during the progressive development of various epileptogenic seizures.     

Vasopressin and oxytocin content in cerebrospinal fluid and in various brain areas after administration of histamine and pentylenetetrazol

The content of vasopressin (AVP) and oxytocin (OXT) in the septum, hippocampus, hypothalamus and cortex was determined at 5 min and 24 hr after peripheral (intraperitoneal) administration of histamine (20.0 mg/kg) and pentylenetetrazol (45.0 mg/kg) and in the cerebrospinal fluid at 24 hr after pentylenetetrazol treatment. At 5 min after administration of histamine the AVP content in the septum was increased whereas the OXT level in the various areas was not changed. At 24 hr, neurohypophyseal peptide contents were unaffected in the brain regions analyzed. Pentylenetetrazol did not alter AVP content at 5 min after its administration, however, the OXT level in the septum and the cortex was diminished. At 24 hr after administration of pentylenetetrazol a decreased AVP content in the hippocampus and in the cortex was observed. In contrast, OXT content in the cortex was increased at this time. AVP and OXT levels in CSF were not changed at 24 hr following pentylenetetrazol treatment. The present results suggest that the levels of neurohypophyseal hormones can be differentially altered in particular brain regions at short- (5 min) and long- (24 hr) term intervals after treatment with histamine or pentylenetetrazol. Long-term changes in AVP and OXT levels after pentylenetetrazol may be implicated in the amnesic properties of this convulsive drug. Furthermore, the present findings point to a possible relationship with previously reported pentylenetetrazol-induced changes in peptide levels in the CSF.     

Nitric oxide signaling pathway in the anti-convulsant effect of adenosine against pentylenetetrazol-induced seizure threshold in mice

The present study was performed to examine the involvement of nitric oxide (NO) signaling pathway in the anti-convulsant effect of adenosine against pentylenetetrazol seizure threshold in mice. Minimal dose of pentylenetetrazol (i.v., mg/kg) needed to induce different phases (myoclonic jerks, generalized clonus and tonic extension) of convulsions was recorded as an index of seizure threshold. Adenosine (100 or 200 mg/kg i.p.) produced a significant increase in the seizure threshold for convulsions induced by pentylenetetrazol i.v. infusion. The anti-convulsant effect of adenosine (100 mg/kg i.p.) was prevented by either L-arginine (50 mg/kg i.p.) [substrate for nitric oxide synthase (NOS)] or sodium nitroprusside (3 mg/kg i.p.) [a NO donor]. On the other hand, N(G)-nitro-L-arginine methyl ester (L-NAME, 2.5 mg/kg i.p.) [a non-selective NOS inhibitor] or 7-nitroindazole (7-NI) (25 mg/kg i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] potentiated the anti-convulsant action of sub-effective dose of adenosine (50 mg/kg i.p.). Aminoguanidine (100 mg/kg i.p.) [a specific inducible NOS (iNOS) inhibitor] pre-treatment was not effective in inducing anti-convulsant effect with sub-effective dose of adenosine (50 mg/kg i.p.). Furthermore, the increase in seizure threshold elicited by adenosine (100 mg/kg i.p.) was also inhibited by concomitant administration with sildenafil (5 mg/kg i.p.) [phosphodiesterase 5 inhibitor]. In contrast, treatment of mice with methylene blue (1 mg/kg i.p.) [a direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] failed to induce anti-convulsant action with adenosine (50 mg/kg i.p.) against pentylenetetrazol i.v. infusion. The results demonstrated that the anti-convulsant action of adenosine in the pentylenetetrazol i.v. seizure threshold paradigm may possibly involve an interaction with the L-arginine-NO-cGMP pathway which may be secondary to the activation of adenosine receptors.     

Effects of ascorbate on a dopaminergic response: Apomorphine-induced modification of pentylenetetrazol-induced seizures in mice

The threshold for pentylenetetrazol (PTZ)-induced clonic seizures is below control levels 15 min after administration of apomorphine (APO) but above them 60 min after APO administration. Pretreatment with ascorbic acid (10 mg/kg) or the presence of ascorbic acid in the APO solution (1 mg/ml) inhibited the early (15 min) decrease in seizure threshold caused by 60 mg/kg APO and reversed the increase in seizure threshold 60 min after a 50 mg/kg APO challenge. Ascorbate co-administration concomitant with APO also counteracted the increase in seizure threshold 60 min after 70 mg/kg APO. Results suggest a potential model for modulation of a seizure system through dietary supplementation.     

The effects of chronic administration and withdrawal of (+)-amphetamine on seizure threshold and endogenous catecholamine concentrations and their rates of biosynthesis in mice

The i.v. pentylenetetrazol seizure threshold was increased by 2.5 mg/kg and decreased by 15 mg/kg of a single (+)-amphetamine dose. After 7 consecutive days of amphetamine administration, tolerance developed to the decrease but not to the increase in seizure threshold. At 12–48 h after the last dose of 2.5 mg/kg seizure threshold was decreased, and at 36–48 h after the last dose of 15 mg/kg seizure threshold was increased. After acute and chronic administration of (+)-amphetamine (2.5 mg/kg) endogenous concentrations of whole brain dopamine (DA) were increased and returned to normal levels during the withdrawal period (12–48 h); endogenous norepinephrine (NE) levels were unchanged by acute and chronic drug treatment and during withdrawal. The rates of DA and NE synthesis were increased by chronic amphetamine administration at 24–48 h after drug withdrawal. An acute dose of (+)-amphetamine (15 mg/kg) decreased endogenous levels of DA and NE; normal levels of DA were detected with chronic drug treatment and during withdrawal, with NE remaining slightly depressed. The rates of synthesis of DA and NE were increased by acute and chronic amphetamine treatment and returned to normal 24–48 h after withdrawal. The rebound reversal in seizure threshold after (+)-amphetamine withdrawal suggests an abstinence syndrome that may be interpreted as evidence for the development of physical dependence to (+)-amphetamine after chronic drug administration.     

Catecholaminergic involvement in the effects of amphetamine isomers on seizure susceptibility

The (+)-amphetamine (2.5 mg/kg) increase in pentylenetetrazol seizure was abolished by pretreatment with reserpine, α-methyltyrosine methyl ester (α-MT), FLA-63 or 6-hydroxydopa. All treatments except reserpine antagonized the increase in seizure threshold produced by (-)-amphetamine (4 mg/kg). Only reserpine +α-MT antagonized the decrease in seizure threshold produced by (+)-amphetamine (15 mg/kg). These results indicate that amphetamine alterations in PLZ seizure susceptibility are mediated indirectly via the release of newly synthetized and/or granular stores of catecholamines.     

Anticonvulsant actions of the putative gamma-aminobutyric acid (GABA)-mimetic, ethylenediamine.

1 Ethylenediamine, 31.6-1000 mg/kg intraperitoneally, inhibited the convulsive effects of pentylenetetrazol, 100 mg/kg (i.p.) in mice. 2 Ethylenediamine, 100-1000 mg/kg (i.p.) increased the convulsion threshold to the intravenous infusion of three convulsants in the order pentylenetetrazol greater than bicuculline greater than strychnine. 3 The benzodiazepine antagonist R0 15-1788, 10 mg/kg (i.p.), significantly inhibited the anticonvulsant action of diazepam, 50 micrograms/kg, but not ethylenediamine, 1000 mg/kg. 4 These results clearly indicate that ethylenediamine has anticonvulsant properties and are consistent with the hypothesis that ethylenediamine is a gamma-aminobutyric acid (GABA)-mimetic.     

Anticonvulsant and sodium channel blocking activity of higher doses of clenbuterol

Clenbuterol, a lipophilic beta2-adrenoceptor agonist, was investigated in various seizure models of experimental epilepsy. In the maximal electroshock seizure threshold test, clenbuterol (> or =4 mg/kg i.p.) increased the electroconvulsive threshold for tonic seizures in mice. In the traditional maximal electroshock seizure (MES) test in mice, ED50 values of 11 mg/kg i.p. or s.c. were determined. In both models, the beta2-receptor antagonist ICI 118.551 did not antagonize the anticonvulsant activity of clenbuterol. Combinations of clenbuterol with standard antiepileptics revealed additive anticonvulsant effects. Repeated administration of clenbuterol (5 mg/kg s.c., twice daily for 14 days) to mice did not significantly influence its anticonvulsant potency or the effectiveness of phenobarbital in the MES test. In various chemically-induced seizure tests with tonic convulsions, clenbuterol inhibited or tended to suppress the tonic phase. However, this drug was not effective in preventing clonic seizures in the pentylenetetrazol (85 mg/kg s.c.) seizure threshold test. In the rotarod ataxia test (mice), a minimal "neurotoxic" dose (TD50) of 41 mg/kg i.p. was determined. In unrestrained rats with chronically implanted electrodes in the dorsal hippocampus, clenbuterol (2 mg/kg and 4 mg/kg i.p.) significantly reduced the duration of electrically evoked hippocampal afterdischarges. In amygdala-kindled rats, clenbuterol (5 mg/kg and 10 mg/kg i.p.) reduced the seizure severity to stage 3. Additional studies indicated that clenbuterol (6 mg/kg i.p.) increased the heart rate and decreased the blood pressure, but this drug did not alter the plasma level of the two tested antiepileptics phenobarbital and carbamazepine. Furthermore, in whole-cell voltage-clamp experiments on cultured neonatal rat cardiomyocytes, clenbuterol (1-100 microM) depressed the fast sodium current in a concentration- and frequency-dependent manner. In conclusion, the anticonvulsant effects of higher doses of clenbuterol against generalized tonic-clonic and complex partial seizures seem to be related to the inhibition of voltage-dependent sodium channels and not to the modulation of beta-adrenoceptors.     

Effects of pentoxifylline and H-89 on epileptogenic activity of bucladesine in pentylenetetrazol-treated mice

The present study shows interactive effects of pentoxifylline (PTX) as a phosphodiesterase (PDE) inhibitor, H-89 as a protein kinase A (PKA) inhibitor and bucladesine (db-cAMP) as a cAMP agonist on pentylenetetrazol (PTZ)-induced seizure in mice. Different doses of pentoxifylline (25, 50, 100 mg/kg), bucladesine (50, 100, 300 nM/mouse), and H-89 (0.05, 0.1, 0.2 mg/100g) were administered intraperitoneally (i.p.), 30 min before intravenous (i.v.) infusion of PTZ (0.5% w/v). In combination groups, the first and second components were injected 45 and 30 min before PTZ infusion. In all groups, the control animals received an appropriate volume of vehicle. Single administration of PTX had no significant effect on both seizure latency and threshold. Bucladesine significantly decreased seizure latency and threshold only at a high concentration (300 nM/mouse). Intraperitoneal administration of H-89 (0.2 mg/100g) significantly increased seizure latency and threshold in PTZ-treated animals. All applied doses of bucladesine in combination with PTX (50 mg/kg) caused a significant reduction in seizure latency. Pretreatment of animals with PTX (50 and 100 mg/kg) attenuated the anticonvulsant effect of H-89 (0.2 mg/100g) in PTZ-exposed animals. H-89 (0.05, 0.2 mg/100g) prevented the epileptogenic activity of bucladesine (300 nM) with significant increase of seizure latency and seizure threshold. In conclusion, we showed that seizure activities were affected by pentoxifylline, H-89 and bucladesine via interactions with intracellular cAMP and cGMP signaling pathways, cyclic nucleotide-dependent protein kinases, and related neurotransmitters.     

Convulsive thresholds in mice during the recovery phase from anaesthesia induced by propofol, thiopentone, methohexitone and etomidate.

1. Convulsive thresholds were measured with intravenous pentylenetetrazol in mice during the recovery phase after intravenous anaesthetic doses of propofol (10 and 20 mg kg-1), thiopentone (30 mg kg-1), methohexitone (10 mg kg-1), and etomidate 3 mg kg-1). 2. The convulsive threshold rose after each agent, indicating an anticonvulsant action for all the drugs tested; this declined to control values with initial half times of: 1.56 min (propofol 10 mg kg-1); 1.03 min (propofol 20 mg kg-1): 1.02 min (methohexitone); 3.35 min (etomidate); 13.7 min (thiopentone). 3. At no time during the recovery phase of any agent did the convulsive threshold fall below control values, which might indicate an epileptogenic effect of the drug. 4. The threshold was depressed below control values by intravenous administration of Ro 15-4513, a partial inverse agonist at the benzodiazepine receptor, thus indicating the ability of this pentylenetetrazol test to demonstrate a proconvulsant effect. 5. We conclude that the abnormal movements or convulsions associated with recovery from anaesthesia with short-acting intravenous anaesthetics may not be the result of an intrinsic proconvulsant action of the drugs.     

Effects of 2, 4-Dichlorophenoxyacetic Acid (2, 4-D) on Open-Field Behaviour and Neurochemical Parameters of Rats *

The effects of the herbicide 2, 4-dichlorophenoxyacetic acid (2, 4-D) on the central nervous system (CNS) were studied in rats. Behavioural and neurochemical studies were performed. Results show that acute and oral administration of dimethylamine 2, 4-D was able to decrease locomotion and rearing frequencies and to increase immobility duration of rats observed in an open-field test. Treatment of rats with p-chlorophenylalanine (PCPA) was unable to change rat's open-field behaviour; 5-hydroxytryptophan (5-HTP) administration not only increased locomotion and rearing frequences but also decreased immobility duration. Pretreatment of the rats with PCPA and 5-HTP decreased and increased dimethylamine 2, 4-D effects, respectively. The herbicide was not able to change the striatal levels of dopamine and homovanilic acid but decreased the striatal levels of serotonin (5-HT), as observed for the doses of 100 and 200 mg/kg and increased those of 5-hydroxyindoleacetic acid (5-HIAA) as measured after the 200 mg/kg dose treatment. When the levels of serotonin and 5-HIAA were measured at the brain stem level, only those of 5-HIAA were modified, being increased by diethylamine 2, 4-D (60; 100 and 200 mg/kg); this increment on 5-HIAA levels was observed even 1 hr after pesticide administration. Further analysis showed that 2, 4-D concentrations chromatographycally detected both in serum and brain of the intoxicated animals were dose-dependent, being found as early as 1 hr after the smaller dose of the herbicide used (10 mg/kg). The results suggest that diethylamine 2, 4-D modify 5-HT functional activity within the CNS. Thus, the effects of the herbicide on open-field behaviour of rats could be attributed to a direct or indirect pesticide action on serotoninergic systems.     

Effect of morphine pretreatment on pentylenetetrazol-induced seizures in the rat

In several species, larger doses of systemically-administered morphine induce seizures while smaller doses potentiate chemically-induced convulsions. However, it is generally considered that morphine acts as an anticonvulsant in the rat. In the present study, the effects of pretreatment with morphine on both electrical and motor manifestations of pentylenetetrazol (PTZ)-induced seizures in the rat were examined. Morphine (60 and 120 mg/kg) significantly delayed the onset of motor seizures induced by pentylenetetrazol but also induced a significantly greater number of motor seizures, a greater percentage of deaths and a lowering of the chemoconvulsive threshold for pentylenetetrazol. Recordings from animals with chronically-implanted supracortical electrodes showed that pretreatment with morphine (60 mg/kg) both altered the onset pattern of CNS excitation induced by pentylenetetrazol and delayed the onset of electrical seizure activity. These recorded electrocortical effects were similar to the behavioral effects observed in the non-implanted animals. Larger doses of morphine (175 and 250 mg/kg) by themselves produced both motor and electrocortical seizures in rats with chronically-implanted electrodes.     

Age-dependent reduction in maximum electroshock convulsive threshold associated with decreased concentrations of brain monoamines

This study investigated modification of the tonic convulsive threshold to maximum electroshock in 15- and 30 day old rats treated with drugs which reduce steady-state concentrations of monoamines. On postnatal day 15, reduction of central catecholamine concentrations by 6-hydroxydopamine or of central serotonin concentrations by 5,7-dihydroxytryptamine or p-chloroamphetamine did not alter the tonic convulsive threshold. However, simultaneous depletion of catecholamines and serotonin by tetrabenazine was associated with a significant decrease in the tonic threshold. This effect could be reversed partially by simultaneous administration of the catecholamine and serotonin precursors, L-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively. On postnatal day 30, reduction of brain serotonin concentration, but not catecholamine concentrations, was associated with a significant decrease of the tonic convulsive threshold. In a previous study, in which 7–8 day old rats were used, a tetrabenazine-induced decrease in the tonic convulsive threshold was prevented by L-dihydroxyphenylalanine bu t not 5-hydroxytryptophan. Furthermore, intracisternal 6-hydroxydopamine, but not 5,7-dihydroxyhyptamine, decreased the threshold on postnatal day 8. Therefore, the results of the present study involving 15- and 30 day old rats, together with the earlier findings in 7–8 day old rats, [28] suggest an apparent developmental transition from catecholaminergic to serotonergic dominance in regulation of the tonic convulsive threshold during the first postnatal month.     

Effect of combined treatment with dopaminergic and GABA-ergic drugs on the threshold for maximal electroconvulsions in mice

Aminooxyacetic acid (AOAA; 20 and 40 mg/kg), baclofen (15 and 20 mg/kg), gamma-hydroxybutyric acid (GHBA; 250 mg/kg) and gamma-aminobutyric acid (GABA: 3000 mg/kg), administered intraperitoneally, increased the convulsive threshold in mice but to a relatively small degree. Bicuculline and picrotoxin were shown to reverse these anticonvulsant effects except for baclofen. Apomorphine (10 mg/kg), amantadine (100 mg/kg) and L-DOPA (62 . 5 and 125 mg/kg) potentiated the action of AOAA (20 mg/kg). Also apomorphine (5 and 10 mg/kg) and amantadine (25 and 100 mg/kg) potentiated the anticonvulsant activity of baclofen (15 mg/kg). Combined treatment with baclofen (15 mg/kg) and amantadine (100 mg/kg) resulted in about 4-fold increase in the convulsive threshold. However, the action of GABA and GHBA was poorly affected by dopaminergic agonists, amantadine even decreased the threshold in animals pretreated with these substances. The results obtained in this study suggest dopaminergic stimulation to be of importance in potentiating the anticonvulsant action of some GABA-ergic drugs.     

The effects of pentylenetetrazol, bicuculline and strychnine on the development of kindled seizures

Modification of the rate of acquisition of the kindled amygdaloid seizure by the convulsants pentylenetetrazol, bicuculline and strychnine was studied. Injections of saline, 25 mg/kg of pentylenetetrazol, 2 mg/kg of bicuculline or 1 mg/kg of strychnine were given 15 min prior to the daily electrical stimulation of the amygdala. The drug doses selected were capable of producing some behavioral and electrical epileptoid activity prior to stimulation without inducing generalized seizures. To determine whether pentylenetetrazol or bicuculline accelerated the rate of development of the kindled amygdaloid seizure or merely augmented the expression of each seizure, a crossover design was implemented. The crossover studies involved switching animals during the acquisition phase (between stimulations 3–6) from prestimulation saline to drug or drug to saline injections. It was found that pentylenetetrazol markedly augmented the expression of seizures during kindling development but the results of the crossover studies showed a less dramatic acceleration in the actual rate of the development of the fully generalized kindled amygdaloid seizure. The bicuculline-treated animals showed little augmentation in the expression of seizures during the kindling acquisition phase and in the actual rate of development of the kindled amygdaloid seizure. The strychnine treated animals showed no augmentation in expression of the seizures nor in the rate of development. The effects of prestimulation injections of bicuculline (1, 2 and 3 mg/kg) and strychnine (0.5, 1 and 2 mg/kg) on fully developed kindled amygdaloid seizures were also evaluated. Pretreatment with bicuculline minimally increased seizure afterdischarge duration at the highest dose. When fully kindled animals were pretreated with strychnine, a paradoxical decrease in afterdischarge length and an increase in severity (tonic hindlimb extension) was seen with the largest dose tested. This study emphasizes the potential importance of crossover studies in evaluating pharmacological manipulations of the rate of acquisition of the kindled seizure.