Gabamimetic properties of anxiolytic drugs

Diazepam (5 mg/kg, ip) and tracazolate (40 mg/kg, ip), a nonbenzodiazepine anxiolytic, blocked electrically-induced head-turning without producing sedation. Bicuculline and picrotoxin, GABA antagonists, at doses not affecting head-turning (2 mg/kg, ip) antagonized the effects of diazepam and tracazolate on head-turning. However, at the same dose, bicuculline was more effective as an antagonist of diazepam whereas picrotoxin was more effective as an antagonist of tracazolate. These results suggest that benzodiazepine as well as nonbenzodiazepine anxiolytics possess GABAmimetic activity. The difference in potency between bicuculline and picrotoxin as antagonists of diazepam and tracazolate may be related to their reported differences as GABA antagonists (e.g., site of receptor interaction).     

CGS8216 noncompetitively antagonizes the discriminative effects of diazepam in rats

The benzodiazepine antagonist properties of CGS8216 were evaluated in rats trained to discriminate between saline and 1.0 mg/kg of diazepam in a two-choice, stimulus-shock termination procedure. CGS8216 (0.3 to 100 mg/kg) administered alone, either s.c., p.o. or i.p., occasioned only saline-appropriate responding. When administered concomitantly with a constant 1.0 mg/kg dose of diazepam, CGS8216 produced dose-related decreases in drug-appropriate responding. CGS8216 was most potent by the i.p. route, and approximately tenfold less potent by the oral route. CGS8216 was dermatotoxic after s.c. administration. CGS8216 i.p. had a long duration of action. A dose of 30 mg/kg completely antagonized the discriminative effects of the 1.0 mg/kg training dose of diazepam when the antagonist was administered 8 hr before the start of the test session. In order to determine the type of antagonism by CGS8216, the dose-effect curve for diazepam was redetermined in the presence of varying doses of CGS8216 (0.3 to 3.0 mg/kg, i.p.). CGS8216 produced a dose-related rightward shift in the diazepam dose-effect curve, but also decreased the slope and appeared to decrease the maximal effect. These results are consistent with the interpretation that CGS8216 antagonizes diazepam in a noncompetitive manner. It may do so because either it interacts with a subpopulation of benzodiazepine receptors, it functions as a pseudo-irreversible antagonist due to its high affinity, or because it is an antagonist with agonist properties.     

Characteristics of the abstinence syndrome induced by the administration of the benzodiazepine antagonist CGS 8216 to rats following chronic treatment with diazepam

Male rats were treated with 5 and 10 mg/kg diazepam once daily for 5-30 days. After the drug discontinuation a benzodiazepine receptor antagonist CGS 8216 (2.5-10 mg/kg) induced a behavioural syndrome that might be characterized as an abstinence syndrome. The most typical signs of abstinence were head twitches, myoclonic seizures of forepaws, emotional hyperirritability, increased muscle tone of the tail, sniffing and chewing. These behavioural changes could be observed within 1-1.5 hours after CGS 8216 injection. The abstinence syndrome was induced by repeated CGS 8216 injections for 10-15 days after diazepam discontinuation. Further analysis has shown that that the intensity of abstinence was dependent on the dose and duration of chronic diazepam, as well as on CGS 8216 dose. It is suggested that CGS 8216-induced abstinence syndrome in rats chronically treated with diazepam might be used as a tool for studying the addictive potential of benzodiazepines.     

CGS 8216, Ro 15-1788 and methyl-beta-carboline-3-carboxylate, but not EMD 41717 antagonize the muscle relaxant effect of diazepam in genetically spastic rats

Diazepam (0.4-4 mg/kg i.p.) reduced the spontaneous tonic activity in the electromyogram (EMG) recorded from the gastrocnemius-soleus muscle of spastic mutant Han-Wistar rats in a dose-dependent manner. The muscle relaxant effect of diazepam was antagonized by the benzodiazepine antagonists Ro 15-1788 (5 mg/kg i.p.), beta-CCM (2 mg/kg i.p.) and CGS 8216 (5 mg/kg i.p.), but not by EMD 41717 (50 mg/kg i.p.). These results add further support to the hypothesis that Ro 15-1788, CGS 8216 and beta-CCM do antagonize all pharmacological effects of benzodiazepines while EMD 41717 displays more selectivity in antagonizing the different actions of benzodiazepines.     

Do benzodiazepine receptors mediate the anticonflict action of pentobarbital?

The effects of the benzodiazepine antagonist CGS 8216 (2-phenylpyrazolo[4,3-c]quinoline-3(5H)-one) were examined in a thirsty rat conflict test in the presence and absence of pentobarbital. CGS 8216 (2.5-10 mg/kg i.p.) did not affect nonpunished responding, but doses of 5 and 10 mg/kg significantly reduced the rate of punished responding (i.e., the number of 3 second drinking episodes in a "shock" contingency). However, a dose of CGS 8216 which did not significantly alter punished responding (2.5 mg/kg) antagonized the anticonflict actions of pentobarbital. These observations suggest that while high doses of CGS 8216 may elicit an "anxiogenic" response in rodents, lower doses of CGS 8216 antagonize the anticonflict actions of a compound which has been shown to enhance benzodiazepine affinity in vitro. These data imply that the anticonflict actions of pentobarbital may be mediated through benzodiazepine receptors.     

Antiabstinent action of fenibut and baclofen on a model of abstinence induced by the benzodiazepine receptor antagonist CGS 8216 in rats receiving diazepam

Benzodiazepine receptor antagonist CGS 8216 (2.5 mg/kg) induced clear-cut signs of abstinence lasting 1-1.5 hours in rats after discontinuation of diazepam treatment (10-20 mg/kg/day, 20 days). Diazepam (10-20 mg/kg) and GABAB-receptor agonists: phenibut (10-100 mg/kg) and baclofen (1.25-5.0 mg/kg) abolished the signs of abstinence. Conversely, GABAB-receptor agonist THIP enhanced the signs of abstinence. It is suggested that anti-abstinence effect of phenibut and baclofen may reflect their tranquilizing activity.     

Central benzodiazepine involvement in clonidine cardiovascular actions

It is well known that the GABAergic and noradrenergic systems play an important role in blood pressure and heart rate regulation. Benzodiazepines and beta-carbolines, respectively, increase or decrease the probability of chloride-channel opening induced by GABA. The aim of this study was to determine, in conscious rats, the interaction existing between the central alpha2-adrenoceptor stimulation induced by clonidine and the facilitation or impairment of benzodiazepine receptor activity through the administration of either diazepam, a benzodiazepine receptor agonist, or methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), an inverse benzodiazepine agonist. Clonidine (5-10 microg, intracerebroventricularly) reduced heart rate and increased mean blood pressure by activation of central alpha2-adrenoceptors. Diazepam (2 mg/kg, intravenously (i.v.)) induced an increase in heart rate, while DMCM (0.3 mg/kg, i.v.) elicited a bradycardic effect. The bradycardic effects induced by both clonidine and DMCM were antagonized by the prior administration of methylatropine (1.5 mg/kg, i.v.). DMCM (0.3 mg/kg, i.v.) prevented the clonidine effects on heart rate and mean blood pressure, while diazepam (2 mg/kg, i.v.) failed to modify these effects. Our results suggest that the bradycardic effects of clonidine are mediated by a vagal stimulation and are related to the activation of a GABAergic pathway.     

Tofizopam enhances the action of diazepam against tremor and convulsions

Tofizopam, an anxiolytic 3,4-benzodiazepine, increases the affinity of benzodiazepine receptors for 1,4-benzodiazepines. In this study we investigated whether this increased affinity of the receptors alters the sensitivity of mice to tremor and to convulsions. Convulsions induced by harmane were not affected by tofizopam (50-300 mg/kg), but diazepam (15 mg/kg) increased the ED50 of harmane from 9.9 to 25.1 mg/kg. Tofizopam did not alter the threshold for electroshock-induced convulsions, while a dose of 10 mg/kg diazepam protected mice from convulsions. Low doses of tofizopam (12.5-25 mg/kg) sensitized mice to the tremorogenic effect of harmaline. Diazepam inhibited tremor: the ED50 of harmaline increased by 153% after 50 mg/kg of diazepam. In contrast to 1,4-benzodiazepines, tofizopam has no anticonvulsive effect. It sensitises mice to the tremor induced by harmaline. In combination with diazepam, however, tofizopam enhanced the anticonvulsive and antitremorogenic actions of this 1,4-benzodiazepine by 12-65%. This effect probably results from a tofizopam-induced increase in the occupation of benzodiazepine receptors.     

Effects of beta-carboline-ethyl ester on plasma corticosterone--a parallel with antagonist-precipitated diazepam withdrawal

Diazepam has been shown to produce physical dependence based on observations of behavioral stimulation or, in our laboratory, by increases in plasma corticosterone (CS) during antagonist-precipitated withdrawal. The behavioral excitation appears similar to that observed following the administration of beta-carboline esters--agents reported to interact with benzodiazepine receptors and termed "inverse agonists." The focus of the present study is to correlate the occurrence of changes in CS with behavioral excitation previously observed by others. Further, these studies are designed to show a parallel between the manifestations of benzodiazepine withdrawal and the pharmacologic effects of beta-carboline ethyl ester. Experiments were done in conscious unrestrained male Sprague-Dawley rats, with chronic i.v. catheters, using sound-attenuated one-way vision boxes. These studies compared the hormonal and behavioral changes induced by beta-carboline ethyl ester (beta CCE) with CGS-8216-precipitated withdrawal in rats treated with diazepam for 8 days. Rats treated chronically with diazepam (5 mg/kg/day), showed a significant increase in plasma (CS) following CGS-8216. Behavioral abstinence scores were also significantly elevated. beta CCE (0.5-5.0 mg/kg) showed a significant dose-related increase in plasma CS. Behavioral scores were also increased at doses of 0.5 and 2.0 mg/kg. beta CCE-induced plasma CS increases were antagonized by CGS-8216 at doses of 1.0 and 2.0 mg/kg but not by 0.5 mg/kg. In animals chronically treated with diazepam, beta CCE evoked a more prolonged plasma CS elevation than in vehicle-treated animals suggesting a dual agonist/antagonist effect. These data suggest a parallel between CS elevations and behavioral effects during withdrawal as well as similarities between the action of beta CCE and the manifestations of this withdrawal.     

3-carboethoxy-beta-carboline (beta-CCE) elicits electroencephalographic seizures in rats: reversal by the benzodiazepine antagonist CGS 8216

Intravenous administration of 3-carboethoxy-beta-carboline (beta-CCE, 10 mg/kg) to rats resulted in multiple bursts of rhythmic waves (2-4 second duration, 5-7 Hz) with amplitudes of 100-250 microV. Pretreatment of animals with the benzodiazepine receptor antagonists CGS 8216 prevented the electroencephalographic seizures elicited by beta-CCE. This dose of CGS 8216 did not produce any electroencephalographic abnormalities when administered alone. These observations suggest that the electroencephalographic seizures elicited by beta-CCE are mediated via an interaction with benzodiazepine receptors. An in vitro study of the rate of degradation of beta-CCE and 3-carbomethoxy-beta-carboline (beta-CCM) in rat plasma demonstrated that the rate of degradation of the former compound was three times more rapid than the latter. These observations, taken together with previous studies demonstrating that parenteral administration of beta-CCM elicits tonic and clonic seizures, suggests that pharmacokinetic factors may be involved in defining the pharmacologic profile of beta-carboline-3-carboxylic acid esters.     

Role of benzodiazepine-GABAA receptor complex in attenuation of U-50,488H-induced analgesia and inhibition of tolerance to its analgesia by ginseng total saponin in mice

In the present study, the role of benzodiazepine-GABAA receptor complex in the attenuation of U-50,488H (U50), a selective kappa opioid agonist-induced analgesia and inhibition of tolerance to its analgesia by ginseng total saponin (GTS) was investigated using the mice tail-flick test. The intraperitoneal (i.p.) treatment of GTS (100 and 200 mg/kg) and diazepam (0.1-1 mg/kg) dose-dependently attenuated the U50 (40 mg/kg, i.p.)-induced analgesia. GTS (0.001-10 microg/ml) did not alter binding of [3H]naloxone to mice whole brain membrane. The attenuation effect of GTS (100 mg/ kg) and diazepam (0.5 mg/kg) on U50-induced analgesia was blocked by flumazenil (0.1 mg/kg, i.p.), a benzodiazepine receptor antagonist, and picrotoxin (1 mg/kg, i.p.), a GABAA-gated chloride channel blocker. However, bicuculline (1 mg/kg, i.p.), a GABAA receptor antagonist blocked the attenuation effect of diazepam (0.5 mg/kg) but not GTS (100 mg/kg) on U50-induced analgesia. Chronic treatment (day 4-day 6) of GTS (50-200 mg/kg) and diazepam (0.1-1 mg/kg) dose-dependently inhibited the tolerance to U50-induced analgesia. Flumazenil (0.1 mg/kg) and picrotoxin (1 mg/kg) on chronic treatment blocked the inhibitory effect of GTS (100 mg/kg) and diazepam (0.5 mg/kg) on tolerance to U50-induced analgesia. On the other hand, chronic treatment of bicuculline (1 mg/kg) blocked the inhibitory effect of diazepam (0.5 mg/kg) but not GTS (100 mg/kg) on tolerance to U50-induced analgesia. In conclusion, the findings suggest that GTS attenuates U50-induced analgesia and inhibits tolerance to its analgesia and this action involves benzodiazepine receptors and GABAA-gated chloride channels.     

Modulation of the Electrically Evoked Release of 5-[3H]Hydroxytryptamine from Rat Cerebral Cortex: Effects of Alpidem, CL 218872, and Diazepam

The effect of omega (benzodiazepine)-receptor agonists, antagonists, and inverse agonists on the electrically evoked release of 5-[3H]hydroxytryptamine ([3H]5-HT) was studied in superfused slices of the rat frontal cerebral cortex. The electrically evoked release of [3H]5-HT was enhanced by nanomolar concentrations of diazepam and the selective omega 1-receptor agonists alpidem and CL 218872. The omega 1/omega 2- and omega 1-receptor antagonists flumazenil and CGS 8216, respectively, did not modify the electrically evoked release of [3H]5-HT. The omega 3-receptor agonist Ro 5-4864 and the omega 1-receptor inverse agonist ethyl-beta-carboline-3-carboxylate on their own did not affect the electrically evoked release of [3H]5-HT. On the other hand, the inverse agonist 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid methyl ester (DMCM), at micromolar concentrations, inhibited both the spontaneous and the evoked release of [3H]5-HT. The facilitation of the electrically evoked release of [3H]5-HT by diazepam, alpidem, or CL 218872 was potentiated by gamma-aminobutyric acid (GABA). Exposure to flumazenil and CGS 8216 antagonized the facilitation by diazepam, alpidem, or CL 218872 of [3H]5-HT release. The inhibition of the release of [3H]5-HT by DMCM was not modified by exposure to either flumazenil, CGS 8216, or GABA. The inhibitory effect of DMCM was not observed when monoamine oxidase activity was inhibited by pargyline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of adenosine receptor antagonists, aminophylline and caffeine, on seizure protective ability of antiepileptic drugs in rats.

Interaction of methylxanthines, aminophylline (AMP) and caffeine (CAF) on seizure protective ability of various antiepileptic drugs (AEDs), diphenylhydantoin (DPH), phenobarbitone (PB), diazepam (DZP), sodium valproate (SV) and ethosuximide (ESM) was investigated in rats. In the maximal electroshock seizure (MES) test, ED100 doses (mg/kg, ip), against hind limb tonic extension (HLTE) were DPH, 20; PB, 10; DZP, 10 and SV, 300. The interaction of AEDs with AMP (100 mg/kg, ip) reduced the seizure protection afforded by DPH, PB and DZP to 20%, while the efficacy of SV remained unimpaired. Interaction with CAF (200 mg/kg, ip) abolished the seizure protection by DPH and DZP, reduced that by PB to 20%, while the protective effect of SV was unchanged. In pentylenetetrazole (PTZ, 70 mg/kg, sc) induced seizure test, ED100 doses (mg/kg, ip) against clonic convulsions were PB, 10; DZP, 1; SV, 300 and ESM, 200. Complete seizure protection against clonic convulsions following SV or ESM was not significantly influenced by either AMP or CAF, whereas the protective effect of PB and DZP was reversed. SV and ESM showed a qualitative departure in their anti-seizure activity profiles following interaction with either AMP or CAF when compared with the other AEDs.     

Comparative study of the effect of 3-carboxy-beta-carboline methylamide and diazepam on rat behavior

The effects of benzodiazepine receptor agonist, diazepam, and inverse agonist, FG 7142, were examined. Strong antagonism between FG 7142 (10 mg/kg) and diazepam (1 mg/kg) activity was revealed in the open field test. On the other hand, both FG 7142 and diazepam inhibited isolation-induced intraspecies aggressive behaviour of rats. FG 7142 also reduced interspecies aggression of mouse-killing rats. The findings suggest that both diazepam and FG 7142 have antiaggressive properties in the isolation-induced aggression model, which are mediated by benzodiazepine receptors of the central nervous system.     

The role of benzodiazepine receptors in the discriminative stimulus properties of delta-9-tetrahydrocannabinol

Twenty male Sprague-Dawley rats were trained to discriminate 3.0 mg/kg delta-9-tetrahydrocannabinol (THC) from its vehicle. Following acquisition of this discrimination animals were tested for generalization to 3.0 mg/kg diazepam. Thirteen animals showed a generalization from THC to diazepam, whereas the remaining seven animals did not. The generalization curve for diazepam was dose-dependent from 0.1 to 10.0 mg/kg in the first group; the latter group showed no generalization from THC at any dose of diazepam in this range. No differences were found between these groups in the generalization curve for THC. The benzodiazepine antagonist Ro 15-1788 (2.0 mg/kg) antagonized the generalization to diazepam in the group that discriminated diazepam as THC. In contrast, Ro 15-1788 increased THC lever responding of 10 mg/kg diazepam in the group which did not generalize from THC. Ro 15-1788 did not alter the discriminability of THC in either group. THC also showed partial generalization to pentobarbital (1 to 10 mg/kg). The generalization was again complete in one subgroup and absent in another, but there was only a 43 percent overlap between the subgroups found with testing for generalization to diazepam. The percent THC lever responding with 3.0 mg/kg pentobarbital was increased by Ro 15-1788 in the group which generalized to diazepam, but not the other group. These data suggest that the discriminative stimulus properties of THC may have some commonality with the effects of diazepam in a subpopulation of rats trained to discriminate THC. These THC-like effects of diazepam are probably mediated by benzodiazepine receptors since they are antagonized by a specific benzodiazepine receptor antagonist.     

Reduction of inflammation in rats by diazepam: tolerance development

High doses of diazepam (10-20 mg/kg) were shown to reduce the volume of acute carrageenan-induced inflammatory paw edema in rats. This effect was not observed after adrenalectomy or long-term use of similar doses of diazepam. The present experiment was undertaken to analyze the effects of long-term (21 daily injections) treatment with diazepam (10 mg/kg) on both carrageenan-induced paw edema (CIPE) and corticosterone serum levels. For comparison, the effects of a single and acute 10 mg/kg dose of diazepam were also analyzed. Results showed that: 1- long-term diazepam treatment induced no changes in CIPE values and corticosterone serum levels; 2- acute diazepam treatment reduced CIPE values and increased corticosterone serum levels; 3- the plasmatic levels of diazepam measured 1 hour after the single treatment or 1 hour after the last dose of long-term diazepam administration were not different. These results indicate the development of tolerance to diazepam effects on both CIPE and corticosterone serum levels and suggest a relevant role for corticosterone on diazepam-induced inhibition of acute inflammation. Data were discussed in the light of peripheral benzodiazepine receptor site (PBR) activation within adrenal gland cells by diazepam, thereby increasing the serum levels of corticosterone and thus reducing CIPE. Possible actions of diazepam on HPA axis activity and/or on cytokine network were also discussed.     

Effects of GABA(A) compounds on mCPP drug discrimination in rats

Male Long-Evans rats were trained to discriminate mCPP (1.4 mg/kg, i.p.) from saline, using a two-lever, food-reinforced operant task. The GABA(A) antagonist, bicuculline (0.16-0.64 mg/kg), partially substituted for mCPP, whereas the benzodiazepine antagonist, flumazenil (1-10 mg/kg), and the benzodiazepine inverse agonist, Ro 15-4513 (0.25-2.5 mg/kg), failed to substitute for mCPP. Bicuculline produced no change in response rate, whereas Ro 15-4513 dose-dependently decreased responding. Flumazenil produced a small increase in response rates. Flumazenil (10 mg/kg), Ro 15-4513 (1.25 mg/kg), and the benzodiazepine agonists alprazolam (0.64 mg/kg) and diazepam (5 mg/kg) full agonist all failed to block the mCPP discriminative stimulus. When given in combination with mCPP, Ro15-4513 and alprazolam both produced lower response rates than did mCPP alone, whereas flumazenil and diazepam did not significantly alter response rates. These findings provide evidence that GABA(A) antagonists modulate the discriminative stimulus effects of mCPP, but that these effects are not mediated by activity at the benzodiazepine site.     

CGS 15943, a nonxanthine adenosine receptor antagonist: effects on locomotor activity of nontolerant and caffeine-tolerant rats

CGS 15943 (0.1-10 mg/kg, IP) dose-dependently increased the locomotor activity of rats to the same extent as caffeine (1.0-100 mg/kg, IP) did and was approximately 26 times more potent than caffeine. N-Ethylcarboxamidoadenosine (0.001-0.01 mg/kg, SC), an analog of adenosine, dose-dependently decreased locomotor activity; this effect was antagonized surmountably by concurrent administration of CGS 15943. The apparent pA2 value for this interaction, 6.57, was approximately 1.5 log-units (28-fold) higher than the pA2 for caffeine-NECA reported previously. Rats consuming 70 mg/kg/day of caffeine via their drinking water were tolerant to the stimulation of locomotor activity induced by both caffeine and CGS 15943. These results suggest that caffeine and CGS 15943 increase locomotor activity by a common mechanism of action possibly involving adenosine receptors or a cellular element conformationally similar to adenosine receptors.     

Discriminative stimulus properties of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), an inverse agonist at benzodiazepine receptors

Rats (N = 8) were trained to discriminate the stimulus properties of the potent benzodiazepine (BZ) receptor inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) from saline in a two-lever operant task. The initial training dose of DMCM was 0.4 mg/kg at which the discrimination developed slowly; increasing the dose to 0.8 mg/kg resulted in rapid acquisition. However, since convulsions eventually developed during further training (sensitization), the training dose was finally individualized below the convulsive threshold (0.4-0.7 mg/kg). The DMCM cue was mimicked by FG 7142 (10 mg/kg), a non-convulsant anxiogenic beta-carboline, by pentylenetrazol (20-30 mg/kg), and by the GABA antagonist bicuculline (2 mg/kg). The DMCM cue was not, or marginally, blocked by diazepam (2.5 mg/kg) or pentobarbital (10-15 mg/kg). Furthermore, the BZ receptor antagonists CGS 8216 (2.5 mg/kg), ZK 93426 (20 mg/kg), and Ro 15-1788 (20-80 mg/kg) also did not, or only marginally, block the DMCM cue. However, the receptor antagonists (alone) substituted for DMCM although Ro 15-1788 was less effective. The partial BZ receptor agonist ZK 91296 (25 mg/kg), which is structurally similar to DMCM, blocked completely the DMCM stimulus effect. THIP (4 mg/kg) did not block the DMCM cue. To explain these results, we suggest that the repeated DMCM treatment, necessary for maintaining the discrimination, shifts the balancing point ("set-point") for positive (i.e., BZ-like) agonist efficacy versus inverse agonist efficacy, towards inverse action. This hypothesis was supported by the finding of an enhanced ability of GABA to reduce 3H-DMCM binding to cortical neuronal membranes of animals treated chronically with DMCM in a regimen similar to that used to maintain the DMCM discrimination. Furthermore, this treatment did not affect baseline 3H-DMCM binding, baseline or GABA stimulated 3H-diazepam binding, or 35S-TBPS binding (to chloride channels).     

Studies on anticonvulsant actions of L-deprenyl

L-Deprenyl (Selegeline) introduced for use in parkinson's disease, is implicated to show beneficial effects in epilepsy, alzheimer's disease, cognition, depression and other age related neurological diseases. In this study, we investigated the CNS effects of L-deprenyl with special reference to epilepsy, anxiety and cognition and memory in mice. L-deprenyl (10, 20 and 40 mg/kg) showed a significant anticonvulsant activity against pentylenetetrazole (PTZ)-induced convulsions. Combination of L-deprenyl (10 mg/kg) with the sub-protective dose of diazepam (1 mg/kg) showed potentiation of the anticonvulsant effect. In the maximal-electroshock (MES)-induced convulsions, L-deprenyl (10 mg/kg) significantly delayed the onset and decreased the duration of extensor phase. Its combination with the lower dose of phenytoin (10 mg/kg) showed potentiation in response compared to the per se effect of both the drugs. However, L-deprenyl did not show any protective effect in lithium-pilocarpine induced status epilepticus. Acute treatment with L-deprenyl had no effect on learning and memory. In chronic treatment, L-deprenyl per se showed no effect on learning and memory but did improve the condition in mice with scopolamine induced memory deficit. L-Deprenyl per se was anxiogenic though in combination with diazepam (1 mg/kg) it potentiated the antianxiety effect of the latter. The above observations suggest that in epilepsy, L-deprenyl might be acting partially by influencing the GABAA/benzodiazepine mechanism in the brain (similar to diazepam and phenytoin), and in cognition enhancing effect, the cholinergic system might be playing a role. Thus, L-deprenyl could prove to be an adjuvant in the antiepileptic therapy and beneficial in dementia associated with epilepsy.