Acute and chronic effects of the synthetic neuroactive steroid, ganaxolone, against the convulsive and lethal effects of pentylenetetrazol in seizure-kindled mice: comparison with diazepam and valproate

A high-affinity positive modulator of the GABA(A) receptor complex, ganaxolone, is a 3beta-methylated analog of the naturally occurring neuroactive steroid allopregnanolone. In the present study, ganaxolone was tested for its ability to (1) suppress seizures (clonic and tonic) and lethality induced by pentylenetetrazol (PTZ) in PTZ-kindled mice (anticonvulsive effect) and (2) to attenuate the development of sensitization to the convulsive and lethal effects of PTZ in kindled mice (anti-epileptogenic effect) when given as a pretreatment prior to each PTZ injection during kindling acquisition. Two classical antiepileptic drugs, diazepam and valproate, were tested for comparison. All three drugs dose-dependently suppressed tonic seizures and lethality induced by PTZ in kindled mice; only ganaxolone was effective against clonic seizures. Ganaxolone showed anti-epileptogenic properties as it reduced the sensitivity of kindled mice to the convulsive (clonic and tonic seizures) and lethal effects of PTZ. Diazepam showed anti-epileptogenic effects against tonic seizures and lethality, but not clonic seizures; valproate was ineffective in preventing development of any of these effects. Sensitivity to PTZ-induced seizures and lethality was not affected in mice with a history of repeated treatment with ganaxolone, diazepam, or valproate. The drugs had effects on ambulatory activity that ranged from no effect (ganaxolone) through moderate impairment (diazepam) to marked disruption (valproate). Taken together, the results of the present study add to accumulating evidence of the unique anticonvulsive/behavioral profile of neuroactive steroids.     

Protective efficacy of neuroactive steroids against cocaine kindled-seizures in mice

Neuroactive steroids demonstrate pharmacological actions that have relevance for a host of neurological and psychiatric disorders. They offer protection against seizures in a range of models and seem to inhibit certain stages of drug dependence in preclinical assessments. The present study was designed to evaluate two endogenous and one synthetic neuroactive steroid that positively modulate the gamma-aminobutyric acid (GABA(A)) receptor against the increase in sensitivity to the convulsant effects of cocaine engendered by repeated cocaine administration (seizure kindling). Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) and ganaxolone (a synthetic derivative of allopregnanolone 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) were tested for their ability to suppress the expression (anticonvulsant effect) and development (antiepileptogenic effect) of cocaine-kindled seizures in male, Swiss-Webster mice. Kindled seizures were induced by daily administration of 60 mg/kg cocaine for 5 days. All of these positive GABA(A) modulators suppressed the expression of kindled seizures, whereas only allopregnanolone and ganaxolone inhibited the development of kindling. Allopregnanolone and pregnanolone, but not ganaxolone, also reduced cumulative lethality associated with kindling. These findings demonstrate that some neuroactive steroids attenuate convulsant and sensitizing properties of cocaine and add to a growing literature on their potential use in the modulation of effects of drugs of abuse.     

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.     

Effect of theophylline on diazepam and sodium valproate protection in pentylenetetrazole - kindled seizures in rats

Theophylline is well known for its convulsant and proconvulsant action. Some experimental studies also suggest that theophylline and other methylxanthines may impair the protection of antiepileptic drugs. The interaction of theophylline and the antiepileptic drugs diazepam and sodium valproate was studied in pentylenetetrazole (PTZ) - kindled seizures in rats. Pretreatment with both diazepam 4 mg/kg and sodium valproate 300 mg/kg, i.p., showed protection against PTZ kindled seizures. Theophylline, 50 mg/kg, i.p., when given before the antiepileptic drugs, failed to reverse their protection. Since theophylline has an adenosine receptor antagonist activity which may be responsible for its convulsant potential, the results indicate non-involvement of adenosinergic mechanisms in the mechanisms of actions of these antiepileptic drugs.     

Amlodipine enhances the activity of antiepileptic drugs against pentylenetetrazole-induced seizures

Amlodipine (AML), which belongs to the 1,4-dihydropyridine calcium channel antagonists, possesses pharmacological and pharmacokinetic profile that distinguishes it from other agents of this class. Pentylenetetrazole (PTZ)-induced clonic and tonic convulsions in mice were significantly reduced by administration of AML at 10 mg/kg. At this dose AML remained without influence upon the plasma level of PTZ. The ED50 value of AML against clonic seizures induced by PTZ was 5.4 mg/kg. This calcium channel antagonist (at 2.5 mg/kg) combined with ethosuximide (ETX), valproate magnesium (VPA) or phenobarbital (PB) significantly reduced their ED50 values against clonic phase of PTZ-induced seizures. AML administered alone or in combination with antiepileptic drugs (AEDs) worsened the motor performance of mice in the chimney test. However, these treatments remained without significant influence on the retention time in the passive avoidance test. Plasma levels of antiepileptics remained unchanged in the presence of AML. The results indicate that AML does not seem a good candidate for a combination therapy in epileptic patients because of its adverse potential.     

NAALADase (GCP II) inhibition prevents cocaine-kindled seizures

The prediction that inhibition of NAALADase, an enzyme catalyzing the cleavage of glutamate from N-acetyl-aspartyl-glutamate, would produce antiepileptogenic effects against cocaine was tested. Cocaine kindled seizures were developed in male, Swiss-Webster mice by daily administration of 60 mg/kg cocaine for 5 days. The NAALADase inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) produced dose-dependent protection (10-100 mg/kg) against both the development of seizure kindling and the occurrence of seizures during the kindling process without observable behavioral side-effects. It is not likely that 2-PMPA produced protection against cocaine kindling by altering the potency of the convulsant stimulus as daily administration of 2-PMPA did not alter the convulsant thresholds for cocaine. Lower daily doses of cocaine (40 mg/kg) did not increase the incidence of seizures but produced kindling, as evidenced by the increase in seizure susceptibility when mice were probed with a higher dose of cocaine. 2-PMPA was also effective in preventing the development of sensitization to this covert kindling process. In contrast to its efficacy against cocaine kindled seizures, 2-PMPA failed to attenuate the convulsions engendered by acute challenges with pentylenetetrazole, bicuculline, N-methyl-D-aspartate, maximal electroshock or cocaine. Similarly, acutely-administered 2-PMPA did not block cocaine seizures in fully-kindled mice. NAALADase inhibition thus provides a novel means of attenuating the development of cocaine seizure kindling.     

Inhibitory effect of some neuroactive steroids on cocaine-induced kindling in mice

Some neuroactive steroids which positively modulate GABAA receptor activity suppress cocaine-induced kindling but a possible involvement of other neurochemical mechanism in their antiepileptogenic effect remains to be elucidated. To this end, in the present study, we evaluated effects of allopregnanolone, a positive modulator of the GABAA receptor; its isomer without GABAergic activity--isopregnanolone and a negative-modulator of GABAergic transmission--dehydroepiandrosterone sulfate on cocaine-induced kindling in mice. Animals were pretreated daily with either vehicle or neuroactive steroid and then given cocaine (45 mg/kg) for 12 days. After a 14-day washout period in which drugs were not administered, the mice were challenged with the same 45 mg/kg dose of cocaine. Isopregnanolone (5 mg/kg) and dehydroepiandrosterone sulfate (20 mg/kg) administered daily with cocaine decreased number of mice exhibiting seizures. Allopregnanolone (5 mg/kg) also showed strong tendency to suppress cocaine kindling, however, its effect did not reach statistical significance. None of the neuroactive steroids had effect on acute cocaine (75 mg/kg ip)-induced clonic seizures. Further biochemical study showed that the veratridine- but not K+ -stimulated release of D-[3H]-aspartate in hippocampal slices was higher in cocaine-kindled mice than in the control group. Isopregnanolone (100 microM) significantly attenuated the veratridine-induced D-[3H]-aspartate release in hippocampi of cocaine-kindled group. These data indicate that positive modulation of the GABAA receptors is not a critical feature of neuroactive steroids that would determine their ability to prevent the cocaine-induced kindling.     

Pharmacological and histological characterisation of nicotine-kindled seizures in mice

The present study reports that it is possible to induce kindling by repeated injections of nicotine. The newly characterised nicotine-kindling model was compared with that of pentylenetetrazole (PTZ) kindling. Mice were kindled by repeated injection of PTZ (37 mg/kg), or nicotine (2.3 mg/kg), and the effect of the anti-epileptic drugs (AED) levetiracetam (LEV), tiagabine (TGB) and phenytoin (PHT) on seizures in kindled and naive mice were investigated. C-Fos immunoreactivity (Fos IR) was used to investigate differences in neuronal activity pattern between PTZ-, nicotine kindled and naive animals. PTZ kindled animals mainly showed increased Fos IR in limbic regions, whereas Fos IR in nicotine kindled animals was increased in the entorhinal cortex, medial habenula and the compact part of substantia nigra. Fully kindled PTZ-induced seizures were inhibited by LEV (ED50=13.6+/-7.8 mg/kg), TGB (ED50=0.3+/-0.04 mg/kg) but not PHT (ED50>40 mg/kg) whereas fully kindled nicotine-induced seizures were inhibited by LEV (ED50=1.4+/-0.4 mg/kg), TGB (ED50=0.3+/-0.06 mg/kg) and PHT (ED50=9.2+/-2.4 mg/kg). These differences in efficacy of AEDs were not due to changes in plasma levels in the various models. In conclusion, repeated administration of nicotine can induce a kindling-like phenomenon and the model showed significantly different Fos IR pattern and pharmacology to that of PTZ kindling.     

Nifedipine has paradoxical effects on the development of kindling but not on kindled seizures in amygdala-kindled rats

The effects of nifedipine, an antagonist of voltage-operated calcium channels, on the development of amygdala kindling and on the production of fully kindled seizures, stimulated from the amygdala, were investigated. Rats were treated daily with two doses (5 and 50 mg/kg, i.p.) of nifedipine during the development of kindling. Both doses of nifedipine retarded the development of kindled seizures and 50 mg/kg of nifedipine prolonged the latency to the occurrence of bilateral forelimb clonus. In contrast to these antiepileptogenic effects, however, both doses also increased the duration of afterdischarge. This resulted in a striking increase in the cumulative duration of afterdischarge, required to reach stage 4 and 5 seizures. Contrary to the results of a previous study, 50 mg/kg of nifedipine did not produce any significant effect on fully kindled seizures, regardless of the interval (5 min-24 hr) between injection and stimulation of kindling. These results suggested that although nifedipine inhibited the propagation processes of seizures during development of kindling, it appeared to increase the duration of epileptic activity at the kindling focus.     

Antiepileptic activity of Panax ginseng against pentylenetetrazole induced kindling in rats

In the present study, Panax ginseng was evaluated for its antiepileptic activity against pentylenetetrazole (PTZ) induced chemical kindling in rats. PTZ was injected at the dose of 30 mg/kg, i.p. on alternate days and the occurrence of generalized tonic clonic convulsions were considered as the end point. One group received Panax ginseng every day, at a dose of 100 mg/kg, 30 min prior to PTZ injection whereas the other group received an equal volume of distilled water to serve as control. In a separate group the rats were evaluated for motor performance tests after Panax ginseng. The rats treated with Panax ginseng showed significant protection as compared to vehicle treated PTZ injected rats. The study suggests to potential of Panax ginseng against seizures.     

Antiepileptic effects of two Rho-kinase inhibitors, Y-27632 and fasudil, in mice

BACKGROUND AND PURPOSE: Rho/Rho-kinase signalling is involved in many cellular events, including some in the CNS. However, the role of this pathway in epilepsy has not yet been assessed. Therefore, we determined the effects of two Rho-kinase inhibitors, Y-27632 and fasudil, on seizures induced by pentylenetetrazole (PTZ) or maximal electroconvulsive shock (MES). EXPERIMENTAL APPROACH: Effects of Y-27632 (5-10 mg kg(-1)) and fasudil (5-25 mg kg(-1)) on duration of myoclonic jerks, clonic and tonic convulsions, tonic hindlimb extensions and percentage of tonic convulsion index, as well as recovery latency for righting reflex were investigated in mice stimulated with PTZ (65 mg kg(-1)) or MES (50 Hz, 50 mA and 0.4 s). These inhibitors were also tested on a model of kindling induced by PTZ (35 mg kg(-1), for 11 days). Membrane and cytosolic levels of RhoA protein were measured in brain homogenates from kindled mice. KEY RESULTS: Y-27632 and fasudil diminished onset of myoclonic jerks, clonic convulsions and tonic hindlimb extensions in mice given PTZ. These inhibitors suppressed the percentage of tonic convulsion index and recovery latency for righting reflex in the mice excited with MES. Western blotting demonstrated that Rho translocation to plasma membrane increased in the brain homogenates obtained from PTZ-kindled mice. However, the Rho-kinase inhibitors at the given doses did not change motor coordination of the mice. CONCLUSIONS AND IMPLICATIONS: Rho/Rho-kinase signalling may play a role in epilepsy induced by PTZ and MES. Furthermore, Rho-kinase inhibitors could be novel important antiepileptic agents.     

Effect of anticonvulsants on seizures developing in the course of daily administration of pentetrazol to rats

Progressive behavioral and electroencephalographic (EEG) changes were examined following daily administration of pentetrazol (PTZ) to rats. A dose (40 mg/kg/day i.p.) of PTZ which, on the first day, induced clonic convulsions with spike and wave complexes, over several days progressively increased its effect and finally induced ‘violent convulsions’ with EEG seizures of high frequency components. In rats showing these violent convulsions, the PTZ convulsive threshold was decreased and, even after a 4- to 10-month resting period, the violent convulsion was elicited with the same dose of PTZ. Trimethadione and phenobarbital in doses blocking clonic convulsion in normal rats, did not suppress these violent convulsions. Higher doses of the two drugs were necessary to suppress the violent convulsion. Diphenylhydantoin did not suppress either type of convulsions. It is suggested that the progressive development of seizure by PTZ is a kindling effect and that a part of the neuronal mechanisms by which the violent convulsion occurs is involved in the mechanisms underlying the clonic convulsion.     

Gabapentin-lactam, a close analogue of the anticonvulsant gabapentin, exerts convulsant activity in amygdala kindled rats

The cyclic GABA analogue gabapentin (GBP), which recently has been marketed for treatment of epilepsy, is particularly effective against complex-partial seizures as occurring in temporal lobe epilepsy. In the present study, we compared the effects of GBP and its lactam analogue (GBP-L) in the amygdala kindling model of temporal lobe epilepsy. In fully kindled rats, GBP (50 mg/kg and 100 mg/kg i.p.) dose-dependently increased the threshold for focal seizures and inhibited the progression from focal to generalized seizures. This effect was not associated with any marked adverse effects. In contrast, GBP-L (10-50 mg/kg) induced myoclonic activity and generalized clonic seizures in kindled rats, demonstrating a striking qualitative difference between the two compounds. By comparison with non-kindled rats it was shown that kindling markedly enhanced the sensitivity of rats to the convulsant activity of GBP-L. The finding that the anticonvulsant efficacy of GBP is lost by lactam formation indicates that GBP and GBP-L differ in their mechanism(s) of action.     

Aspirin modulates the anticonvulsant effect of diazepam and sodium valproate in pentylenetetrazole and maximal electroshock induced seizures in mice

Release of prostaglandins in brain after spontaneous and experimentally induced seizures, has been demonstrated. The possible role of prostaglandins in modulation of seizure activity is still inconclusive. In the present study, the effects of aspirin and its interaction with the anticonvulsants (diazepam and sodium valproate) were studied in pentylenetetrazole (PTZ) and maximal electroshock (MES) induced seizures in mice. Aspirin 50, 100, and 500 mg/kg, i.p. was administered 45 min before the pentylenetetrazole (60 mg/kg, i.p.) and MES (60 mA, 0.2 s duration via car clip electrodes) challenge. In MES seizures significant protection was seen with aspirin 100 mg/kg where as higher dose of aspirin 500 mg/kg was required to elicit maximum protection against PTZ seizures. Sub anticonvulsant dose of sodium valproate 150 mg/kg, i.p. and aspirin 50 mg/kg i.p. showed complete protection in MES seizures and the same dose of sodium valproate offered superior protection in PTZ seizures than either drug used alone. When mice were pretreated with combination of diazepam 0.5 mg/kg and aspirin 50 mg/kg protection was significantly enhanced in PTZ seizures. However, aspirin did not show any significant protection with subanticonvulsant dose of diazepam against MES seizures. The present study suggests that prostaglandins may have anticonvulsant potential and also may have modulatory effect on anticonvulsant effect of conventional antiepileptic drugs.     

抗痫灵对大鼠杏仁核点燃效应的拮抗作用

用大鼠杏仁核点燃模型研究了抗痫灵的抗癫痫作用。每日1次电刺激杏仁基底外侧核可在第15d产生点燃效应的5期反应,刺激后放电显著延长。抗痫灵在未产生中枢镇静的剂量就能抑制点燃效应的5期反应,ED_(50)为84.7mg/kg,对刺激后放电影响较少。丙戊酸钠抑制5期反应作用较强,并能显著缩短刺激后放电时程。实验表明抗痫灵具有对抗慢性杏仁核点燃效应的作用。     

Effect of pentylenetetrazol-induced convulsions on the development and expression of limbic kindled seizures

Male Long-Evans rats experienced three convulsions induced by intravenously administered pentylenetetrazol (PTZ) and were then kindled by electrical stimulation of the olfactory bulb or amygdala. Pretreatment with PTZ did not alter the rate of kindling in either site but did enhance the expression of kindled seizures once generalization had occurred (PTZ-treated animals had significantly longer motor seizures, measured by clonus duration, than did saline-treated controls). This suggests that PTZ-induced convulsions have selective effects on areas of the brain that are involved in the expression of the motor seizure. In addition, rats treated with PTZ after kindling had convulsions that were significantly longer in duration than any of their three pre-kindling convulsions, indicating that kindling produced an increased sensitivity to PTZ's convulsant effects. Comparison of this experiment with previous research suggests that the ability of a drug treatment to generate a kindling-like effect is related to the pattern of seizure activity that it produces.     

Cysteamine suppresses kindled seizures in pentylenetetrazol-kindled rats

Rats were kindled by intraperitoneal injection of pentylenetetrazol (PTZ) (30 mg/kg) every 48 h. Once kindled, animals received a single injection of cysteamine (200 mg/kg) and subsequent responses to PTZ were observed. Cysteamine, an agent which depletes brain somatostatin and suppresses kindled seizures in amygdaloid-kindled rats, markedly suppressed the severity of PTZ-induced seizures in PTZ-kindled rats as well. However, it did not alter the convulsive response of non-kindled rats to a submaximal convulsive dose (50 mg/kg) of PTZ. The results support a role for somatostatin in kindling.     

Antiepileptogenic effects of borneol in pentylenetetrazole-induced kindling in mice

Borneol, a bicyclic monoterpene, can easily cross the blood brain barrier and was found to possess gamma amino butyric acid (GABA) modulatory effect. The present study was aimed at investigating the antiepileptogenic effect of borneol in the pentylenetetrazole (PTZ)-induced kindling besides its ability to suppress oxidative stress and neuroinflammatory marker, glial fibrillary acidic protein (GFAP). Repeated administration of a subconvulsive dose of PTZ (35 mg/kg, i.p.) on every alternate day for 4 weeks produced kindling in mice. Borneol (5, 10, and 25 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) were given as a pretreatment prior to each PTZ injection during the progression of kindling. Oxidative stress parameters such as superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT), and lipid peroxidation (LPO) were assessed at the end of the study. Neuronal damage was assessed by hematoxylin and eosin staining technique. GFAP was also evaluated in the hippocampus region of the brain by using immunohistochemistry. Borneol significantly suppressed the process of epileptogenesis in PTZ-kindled mice. The biochemical alterations induced by PTZ kindling were ameliorated in borneol-treated animals which was indicated by decreased LPO and increased SOD, GSH, CAT levels. The distinct neuronal damage observed in the kindled group was counteracted by borneol. Furthermore, it decreased the levels of GFAP which was manifested by reduced immunostaining. The above results are suggestive of the antiepileptogenic potential of borneol in the PTZ-induced kindling model of epilepsy, and thus, it could be a prospective molecule in the treatment of epilepsy.     

Pharmacological and genetic manipulation of kappa opioid receptors: effects on cocaine- and pentylenetetrazol-induced convulsions and seizure kindling

The present study used pharmacological and gene ablation techniques to examine the involvement of kappa opioid receptors (KOPr) in modulating the convulsant effects of two mechanistically different drugs: cocaine and pentylenetetrazol (PTZ; GABA-A receptor antagonist) in mice. Systemic administration of the selective KOPr-1 agonist, U69593 (0.16-0.6mg/kg; s.c.), failed to modify cocaine-evoked convulsions or cocaine kindling. Similarly, no alteration in responsiveness to cocaine was observed in wild-type mice that received the selective KOPr-1 antagonist, nor-binaltorphimine (nor-BNI; 5mg/kg) or in mice lacking the gene encoding KOPr-1. In contrast to cocaine, U69593 attenuated the seizures induced by acute or repeated PTZ administration. Nor-BNI decreased the threshold for PTZ-evoked seizures and increased seizure incidence during the initial induction of kindling relative to controls. Decreased thresholds for PTZ-induced seizures were also observed in KOPr-1 knock out mice. Together, these data demonstrate an involvement of endogenous KOPr systems in modulating vulnerability to the convulsant effects of PTZ but not cocaine. Furthermore, they demonstrate that KOPr-1 activation protects against acute and kindled seizures induced by this convulsant. Finally, the results of our study suggest that KOPr-1 antagonists will not have therapeutic utility against cocaine-induced seizures, while they may prove beneficial in attenuating several actions of cocaine that have been linked to its abuse.     

Modification of behavioral effects of drugs in mice by neuroactive steroids

Rationale: Neuroactive steroids represent a novel class of potential therapeutic agents (epilepsy, anxiety, migraine, drug dependence) thought to act through positive allosteric modulation of the GABA_A receptor. A synthetically derived neuroactive steroid, ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), is in phase-II clinical trials for epilepsy. Unlike traditional anticonvulsants such as diazepam and phenobarbital, ganaxolone shows equipotent suppression of both the seizure activity and the behavioral effects of pentylenetetrazol (PTZ) administration. Objectives: The present study explored possible reversal by ganaxolone and related neuroactive steroids of some behavioral effects of additional pharmacological challenges. Methods: Direct behavioral observation and photocell-counted locomotor activity of male, Swiss-Webster mice were made with various compounds alone and in conjunction with ganaxolone. Results: Ganaxolone both prevented and reversed PTZ-induced locomotor depression in mice. Further, ganaxolone reversed the locomotor depression induced by other convulsant/anxiogenic stimuli: bicuculline, picrotoxin and, to a lesser extent, yohimbine. Ganaxolone failed to reverse the locomotor stimulation induced by cocaine, methamphetamine, dizocilpine, and phencyclidine. In addition to ganaxolone, the endogenous neuroactive steroids allopregnanolone and pregnanolone and the synthetic neuroactive steroid Co 2-1068 also reversed observed behaviors and locomotor depression induced by PTZ. Conclusions: The present findings support the unique pharmacological effects of neuroactive steroids as a novel class of positive allosteric modulators of GABA. Received: 19 December 1998 / Final version: 22 September 1999