Cyclosporine A-increased nitric oxide production in the rat dorsal hippocampus mediates convulsions

To test whether nitric oxide (NO) participates in cyclosporine A (CsA)-induced neurotoxicity including convulsions, we examined the effect of an NO synthase inhibitor on convulsions induced by combined treatment with CsA and bicuculline in mice and the effect of CsA on NO production in the dorsal hippocampus using an in vivo microdialysis method in rats. CsA (200 mg/kg, i.p.) significantly increased the intensity of convulsions induced by an intracerebroventricular injection of bicuculline (25 pmol) in mice. This facilitation was blocked by N omega -nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, but not by N omega -nitro-D-arginine methyl ester (D-NAME), an inactive form of L-NAME (10 mg/kg, i.p.). CsA (20-50 mg/kg, i.p.) dose-dependently increased NO 2 - levels in dialysates obtained with microdialysis in the rat dorsal hippocampus. This enhanced NO 2 - formation was blocked by L-NAME but not by D-NAME (50 mg/kg, i.p.). These findings suggest that CsA stimulates NO production and induces convulsions as a result of an interaction between NO and the gamma-aminobutyric acid (GABA) system in the hippocampus.     

Anticonvulsant effects of clonazepam on chemically induced convulsions

The anticonvulsant effects of two doses of clonazepam (CZP, Rivotril Roche, 0.1 and 1 mg/kg i.p.) were studied on model motor seizures induced by strychnine, bicuculline, 3-mercaptopropionic acid and metrazol in male laboratory rats (Wistar strain). In the first part the effects of different doses of the convulsants were investigated and for interaction with CZP doses were chosen after which more than 70% of the animals displayed generalized tonic-clonic convulsions (a grand mal seizure). Strychnine induced this type of seizure only: two doses (2 and 3 mg/kg s.c.) were used. CZP reduced the incidence of convulsions only after the larger dose, but plain solvent (propylene glycol, ethanol, water) was equally effective. The other substances first induced a seizure of minimal (mainly clonic) convulsions and only later a grand mal seizure. CZP was highly effective against bicuculline (3 mg/kg s.c.) and metrazol (100 mg/kg s.c.), but was less so against 3-mercaptopropionic acid. The effect on grand mal seizures was more pronounced in every case than on minimal seizures. The decisive role in the anticonvulsant effect of CZP is played by the mechanisms by which the convulsants induce epileptic manifestations. CZP is most effective against substances acting on the supramolecular complex GABA receptor (benzodiazepine receptor) chloride ionophore (bicuculline and probably metrazol).     

Species dependent dual modulation of the benzodiazepine/GABA receptor chloride channel by dihydroergosine

Dihydroergosine (50 and 100 mg/kg) enhanced the incidence of bicuculline (3 mg/kg)-induced convulsions in female rats, while 100 mg/kg of dihydroergosine given to female mice made 45% convulsive dose of bicuculline (2.5 mg/kg) to be subconvulsive. The same dose of dihydroergosine enhanced in mice the latency of bicuculline (4 mg/kg)-induced convulsions. Although, in in vitro experiments dihydroergosine showed very weak ability to prevent the binding of 3H-muscimol, the drug was able to diminish and to augment the IC50 of bicuculline and GABA when added to crude synaptosomal pellet of the rat and mouse brain respectively. Lower concentrations of dihydroergosine stimulated and higher inhibited 3H-TBOB binding to the crude synaptosomal pellet of the rat brain. In the preparation of mouse brain dihydroergosine produced only inhibition of 3H-TBOB binding. Only slight quantitative differences were observed in bicuculline-induced stimulation and in GABA- and diazepam-induced inhibition of 3H-TBOB binding between the two species. The results suggest that the opposite species-dependent effects of dihydroergosine on bicuculline-induced convulsions are due to the ability of this drug to modulate species-dependently the benzodiazepine/GABA receptor chloride channel complex.     

Participation of GABA in mediating the effects of ethanol in rats with differing susceptibility to the development of experimental alcoholism

The influence of ethanol and of GABA receptors blocker bicuculline on recovery cycles of primary response of the sensorimotor cortex was studied in rats with strong and weak inclination to development of experimental alcoholism. It is found that in rats of the first group, inhibition in the cerebral cortex was weakened in comparison with the rats of the second group. Ethanol in non-narcotic doses intensified the inhibitory processes and its effects could be prevented or suppressed by bicuculline. The conclusion is made about GABA participation in mediation of ethanol effects on inhibitory processes in the cerebral cortex.     

Pharmacology of Acorus calamus L

Water soluble dried powder of alcoholic extract of roots and rhizomes of A. calamus L. was used. The in vivo experiments involved strychnine convulsant activity in frogs, spontaneous motor activity and amphetamine hyperactivity in mice, pentobarbitone sleeping-time in rats and local anaesthetic activity in guinea pigs and rabbits. Frog skeletal muscle and heart preparations and rat phrenic nerve diaphragm constituted the in vitro experiments. Plant extracts at 10, 20 mg/kg ip did not afford protection to strychnine (1,5,2.5 mg/kg) induced convulsions and same effect was found on acetylcholine induced contractions of rectus muscle except that it inhibited caffeine citrate contractions in frog. At 1, 10 and 100 micrograms/ml doses, it caused negative iono- and chronotropic effects in frogs. Dosages of 10, 25, 50 mg/kg ip of herbal extract antagonize spontaneous motor activity and also amphetamine induced hyperactivity in mice. It was less potent than chloropromazine, though exerts sedative and tranquilizing action. Local anaesthetic activity was found to be absent at 0.5 and 1% dose levels.     

Effect of a Ca-channel blocker, ryodipine, on focal and generalized epileptic activity

The experiments were performed on 102 freely moving Wistar rats. Epileptic foci were produced by the application of a filter paper soaked in a sodium benzylpenicillin solution (20,000 IU/ml) onto sensorimotor cortex. It was shown that an intraperitoneal administration of ryodipine (1,2 and 5 mg/kg) during a steady epileptic activity (EA) resulted in suppression of EA in most animals. Antiepileptic effect of ryodipine was manifested by a decreased frequency and amplitude of interictal discharges and a less frequent appearance of ictal discharges (ID). Prior administration of ryodipine (2 mg/kg) 30 min before producing the focus of EA resulted in an increased latency and decreased number of ID, and shortening of the duration of the focus of EA. Generalized convulsions were induced by intraperitoneal of pentylenetetrazol (60 mg/kg). Ryodipine (2 mg/kg, 30 min before pentylenetetrazol) increased latency to first convulsive episodes and delayed the development of generalized tonic-clonic seizures.     

Changes in trace reactions of sensorimotor cortex and putamen neurons as affected by haloperidol

Experiments on conscious rabbits were made to elaborate motor conditioned reflexes through pairing stimuli with electrocutaneous reinforcement applied every 30 s. Neuronal activity in the sensorimotor cortex and putamen was recorded during formation and reproduction of the conditioned reflexes before and after haloperidol injection (0.2 mg/kg i. v.). In the putamen, haloperidol increased the number of neurons exhibiting trace conditioned activity and made the intensity and duration of these processes rise. The changes seen in the sensorimotor cortex were opposite in nature. Inhibition of trace conditioned activity in the sensorimotor cortex depended mainly on the decreased amplitude of the reaction conditioned component. The role of the dopaminergic system in the interaction of the neostriatum and sensorimotor cortex and in formation and reproduction of trace conditioned activity of both the structures is discussed.     

Use of acetylcholinesterase reactivators and central cholinolytics in the treatment of experimental tetanus poisoning]

Experiments were conducted on rabbits with tetanus intoxication induced by the intravenous injection of a lethal dose of the toxin; a study was made of the therapeutic efficacy of the acetylcholinesterase reactivators--dipyroxim and isonitrosine, and also of the central cholinolytics--amizyl and diphacyl. In dose of 25 mg/kg dipyroxim produced no therapeutic effect, and in doses of 30--40 mg/kg caused the animal death. Amizyl and diphacil in a dose of 3--4 mg/kg caused elimination of tonic convulsions for 1 1/2--2 hours. As to isonitrosin--it produced the same effect for 4--5 hours. In case of combined administration of reactivators and cholinolytics convulsions were eliminated for 4--5 hours.     

Role of the central amygdala GABA-A receptors in morphine state-dependent memory

AimsIn the present experiments, the effects of bilateral microinjections of the GABA-A receptor agonist and/or antagonist into the central amygdala (CeA) on morphine state-dependent memory were examined.Main methodsIn order to assess memory retrieval, a step-through passive avoidance task was used in adult male Wistar rats.Key findingsSubcutaneous (s.c.) administration of morphine (5 and 7.5 mg/kg) immediately after training (post-training) decreased the memory retrieval. Pre-test administration of the opioid (7.5 mg/kg) also induced amnesia. The response induced by post-training morphine (7.5 mg/kg) was significantly reversed by pre-test administration of the drug (5 and 7.5 mg/kg), indicating morphine state-dependent memory. Pre-test intra-CeA microinjection of muscimol, a GABA-A receptor agonist (0.01, 0.02 and 0.03 µg/rat) reduced morphine state-dependent memory. However, the same doses of muscimol by itself had no effect on memory retrieval. Furthermore, pre-test intra-CeA microinjection of bicuculline, a GABA-A receptor antagonist by itself did not alter memory retrieval. The antagonist also did not change post-training morphine (7.5 mg/kg)-induced amnesia, but in combination with a lower dose of morphine (0.5 mg/kg), improved memory performance. Moreover, muscimol's ability to interfere with morphine state-dependent memory was reversed by co-injection of bicuculline.SignificanceThe results suggest that GABA-A receptor mechanism of the CeA may influence morphine state-dependent memory.     

GABAA receptors in nucleus accumbens shell mediate the hyperphagia and weight gain following haloperidol treatment in rats

AimsWeight gain is a common outcome of antipsychotics therapy in schizophrenic patients. However, the underlying neuronal mechanisms are unclear. The present study was undertaken to investigate the role of GABA_A receptors within the framework of nucleus accumbens shell (AcbSh) in haloperidol-induced hyperphagia and body weight gain in sated rats.Main methodsIn acute studies, GABA_A receptor agonists muscimol, diazepam or antagonist bicuculline were administered by AcbSh route, alone or in combination with haloperidol (intraperitoneal/ip). Immediately after these treatments, preweighed food was offered to the animals at commencement of dark phase. Cumulative food intake was measured at 2 and 6 h post-injection time-points. Furthermore, effects of subacute haloperidol treatment, alone or in combination with muscimol, diazepam or bicuculline, on food intake and body weight were investigated.Key findingsWhile acute treatment with haloperidol, muscimol or diazepam dose dependently stimulated the food intake, bicuculline suppressed the same. Prior administration of muscimol (20 ng/rat, intra-AcbSh) and diazepam (5 µg/rat, intra-AcbSh) significantly potentiated, whereas bicuculline (40 ng/rat, intra-AcbSh) negated the hyperphagic effect of acute haloperidol (0.005 or 0.01 mg/kg/rat, ip). Subacute administration of haloperidol (0.01 mg/kg/rat/day, ip) for 15 days produced increase in food intake and body weight. Although, concomitant administration of muscimol (20 ng/rat/day, intra-AcbSh) or diazepam (5 μg/rat/day, intra-AcbSh) markedly enhanced, bicuculline (40 ng/rat/day, intra-AcbSh) prevented the subacute haloperidol-induced hyperphagia and weight gain.SignificanceThe results of present study suggest that increased food intake and body weight following haloperidol treatment in rats, may be mediated via AcbSh GABA_A receptors.     

Effect of beta-phenylethylamine on evoked potentials of the neostriatum of rats]

The effect of intraperitoneal (70 mg/kg) and local (39 ug) administration of beta-phenylethylamine (beta-PEA) on evoked potentials (EP) in the caudate nucleus upon stimulation of substantia nigra zona compacta (SNC) and frontal cortex in rats has been studied. beta-PEA, glutamate and haloperidol were injected into the caudate nucleus by means of a system consisting of a pushpull cannule and an electrode for simultaneous registration of EP. Specificity in the effect of the drugs on EP in response to stimulation of the cortex and substantia nigra was revealed. The intraperitoneal injection of beta-PEA induced, comparatively to the application, more rapid and potent decrease in the amplitude of the component (N2-P2) as a result of the substantia nigra stimulation and slightly influenced the EP amplitude in stimulation of the frontal cortex. It was established using haloperidol that the component (N2-P2) of EP in response to the substantia nigra stimulation is of dopaminergic neuron function in the nigro-neostrital system of the rat brain.     

Acute Effects of Typical and Atypical Antipsychotic Drugs on the Release of Dopamine from Prefrontal Cortex, Nucleus Accumbens, and Striatum of the Rat: An In Vivo Microdialysis Study

In vivo microdialysis has been used to study the acute effects of antipsychotic drugs on the extracellular level of dopamine from the nucleus accumbens, striatum, and prefrontal cortex of the rat. (-)-Sulpiride (20, 50, and 100 mg/kg i.v.) and haloperidol (0.1 and 0.5 mg/kg i.v.) enhanced the outflow of dopamine in the striatum and nucleus accumbens. In the medial prefrontal cortex, (-)-sulpiride at all doses tested did not significantly affect the extracellular level of dopamine. The effect of haloperidol was also attenuated in the medial prefrontal cortex; 0.1 mg/kg did not increase the outflow of dopamine and the effect of 0.5 mg/kg haloperidol was of shorter duration in the prefrontal cortex than that observed in striatum and nucleus accumbens. The atypical antipsychotic drug clozapine (5 and 10 mg/kg) increased the extracellular concentration of dopamine in all three regions. In contrast to the effects of sulpiride and haloperidol, that of clozapine in the medial prefrontal cortex was profound. These data suggest that different classes of antipsychotic drugs may have distinct effects on the release of dopamine from the nigrostriatal, mesolimbic, and mesocortical terminals.     

The behavioural effects of systemically administered kainic acid: A pharmacological analysis

Systemic injection of kainic acid (KA), a powerful neuroexcitant and structural analogue of glutamate, induced a complex behaviour in the rat characterized by early “wet-dog-shakes” (WDS and delayed convulsions. 1) The WDS syndrome was antagonized by serotonin blockers (mianserin and cyproheptadine) and by GABAmimetic agents, which decrease serotonergic transmission; in contrast, WDS were potentiated by compounds which enhance serotonin-mediated events (fluoxetine, fenfluramine, imipramine and tranylcypromine) as well as by blockade of GABA receptors (bicuculline). In addition, WDS were antagonized by haloperidol (which possesses some anti-serotonin properties) whereas KA potentiated haloperidol-induced catalepsy, an effect which was blocked by cyproheptadine. This suggests that KA induces WDS and potentiates catalepsy via an increase in serotoninergic function. 2) KA induced convulsions were antagonized by GABAmimetic agents, in agreement with their broad anticonvulsant spectrum; in contrast, mianserine and cyproheptadine did not affect or even potentiated seizures. Thus KA seizures respond differently to pharmacological treatment than do WDS, and may me related to the nwuro-excitatory action of KA.     

Inhibition of GABA system involved in cyclosporine-induced convulsions.

In this study, we attempted to clarify the mechanisms mediating cyclosporine-evoked convulsions. Cyclosporine (50 mg/kg, i.p.) significantly enhanced the intensity of convulsions induced by bicuculline (GABA receptor antagonist), but not those induced by strychnine (glycine receptor antagonist), N-methyl-D-aspartic acid, quisqualic acid or kainic acid (glutamate receptor agonists). Bicuculline plus cyclosporine-induced convulsions were significantly suppressed by an activation of GABAergic transmission with diazepam, phenobarbital and valproate. The GABA turnover estimated by measuring aminooxyacetic acid-induced GABA accumulation in the mouse brain was significantly inhibited by cyclosporine (50 mg/kg, i.p.). When cultured rat cerebellar granule cells were exposed to 1 microM cyclosporine for 24 hr, the specific [3H]muscimol (10 nM) binding to intact granule cells decreased to 53% of vehicle controls. The present study provides the first evidence suggesting that cyclosporine inhibits GABAergic neural activity and binding properties of the GABAA receptor. These events are closely related to the occurrence of adverse central effects including tremors, convulsions, coma and encephalopathy under cyclosporine therapy.     

Blockade of N-methyl-D-aspartate induced convulsions by 1-aminocyclopropanecarboxylates

1-Aminocyclopropanecarboxylic acid is a potent and selective ligand for the glycine modulatory site on the N-methyl-D-aspartate receptor complex. This compound blocks (ED50 234 mg/kg) the convulsions and deaths produced by N-methyl-D-aspartate (125 mg/kg) in a dose dependent fashion. In contrast, 1-aminocyclopropanecarboxylic acid does not protect mice against convulsions induced by pentylenetetrazole (80 mg/kg), strychnine (2 mg/kg), bicuculline (6 mg/kg), or maximal electroshock (50 mA, 0.2 s), and does not impair motor performance on either a rotarod or horizontal wire at doses of up to 2 g/kg. The methyl- and ethyl- esters of 1-aminocyclopropanecarboxylic acid are 5- and 2.3-fold more potent, respectively, than the parent compound in blocking the convulsant and lethal effects of N-methyl-D-aspartate. However, these esters are several orders of magnitude less potent (IC50 greater than 40 microM) than 1-aminocyclopropanecarboxylic acid as inhibitors of strychnine-insensitive [3H] glycine binding, indicating that conversion to the parent compound may be required to elicit an anticonvulsant action. These findings suggest that 1-aminocyclopropanecarboxylates may be useful in the treatment of neuropathologies associated with excessive activation of N-methyl-D-aspartate receptor coupled cation channels.     

Effect of an imidazobenzodiazepine (RO 15-1788) on aggressive behavior in mice

Imidazobenzodiazepine (Ro 15-1788, 5 mg/kg) similarly to a lose dose of apomorphine (0.1 mg/kg) decreased the intensity of footshock aggression in male rats. Ro 15-1788 significantly potentiated the antiaggressive action of apomorphine. Pirenperone (0.01 mg/kg) potentiated the effect of both drugs, whereas haloperidol (0.01 mg/kg) had an opposite action. After long-term treatment with apomorphine and Ro 15-1788 the tolerance to their antiaggressive action developed. This change was in agreement with increased serotonin metabolism in the forebrain. Unlike the action on aggressive behavior, Ro 15-1788 similarly to haloperidol (0.05 mg/kg) decreased the motor depressant effect of apomorphine (0.01 mg/kg) in mice. This effect correlated with the lowered serotonin metabolism after Ro 15-1788 administration. Unlike apomorphine, Ro 15-1788 reversed catalepsy induced by haloperidol (0.25 mg/kg). Administration of pirenperone (0.03 mg/kg) and destruction of serotoninergic terminals by p-chloroamphetamine (2 X 15 mg/kg) significantly potentiated the sedative action of apomorphine. It appears that different action of Ro 15-1788 on behavioral effects of apomorphine is related to different influence of Ro-1788 on serotoninergic processes in the striatum and limbic structures.     

D2-dopamine receptor and alpha2-adrenoreceptor-mediated analgesic response of quercetin

Quercetin, a bioflavonoid (100-300 mg/kg) produced dose dependent increase in tail-flick latency, the analgesic effect being sensitive to reversal by naloxone (1 mg/kg). Prior treatment with haloperidol (1 mg/kg), D1/D2 receptor antagonist haloperidol, sulpiride (50 mg/kg), a selective D2 receptor antagonist, yohimbine (5 mg/kg), a alpha2-adrenoreceptor antagonist but not by SCH 23390 a, selective D1 receptor antagonist blocked this response. Apomorphine (1 mg/kg) a mixed D1/D2 dopamine receptor agonist, and quinpirole (0.5 mg/kg), a selective D2 receptor agonist also produced antinociception, that was reversed by haloperidol (1 mg/kg), sulpiride (50 mg/kg), but not by yohimbine (5 mg/kg). The antinociceptive action of quercetin (200 mg/kg) was potentiated by D2 agonist quinpirole (0.2 mg/kg). Dopamine D1 receptor agonist SKF38393 (10 and 15 mg/kg) failed to alter the antinociceptive effect of quercetin (200 mg/kg). Quercetin (200 mg/kg) reversed reserpine (2 mg/kg-4 hr) induced hyperalgesia, which was reversed by sulpiride but not by yohimbine. Thus, a role of dopamine D2 and alpha2-adrenoreceptors is postulated in the antinociceptive action of quercetin.     

Influence of substance P on the behavioral changes induced by haloperidol in rats

Locomotor activity and grooming behavior of rats were recorded for a period of 30 min following intraventricular injections of substance P(SP) in doses of 0.60 and 2.50 microgram/rat. The lower dose of the peptide significantly increased locomotion for 10 min and time spent grooming for 25 min. The effects of the same two doses of SP on the hypokinesia induced by various pharmacological treatments modifying catecholaminergic systems were then examined. SP did not affect the behavioral depression produced by alpha-methyl-para-tyrosine (250 mg/kg), FLA-63 (25 mg/kg) and phenoxybenzamine (20 mg/kg). However, SP, in dose of 0.60 microgram/rat, systematically reversed the decrease in locomotor activity induced by a relatively small dose of haloperidol, 0.1 mg/kg. The dame dose of the peptide significantly counteracted the rigidity but not the hypokinesia and catalepsy resulting from the previous administration of a higher dose of haloperidol, 3 mg/kg. The results support the hypothesis that SP may exert direct or indirect function in motor behavior, possible via a modulatory action on brain dopaminergic systems.     

The effect of chronic levodopa on haloperidol induced behavioral supersensitivity in the guinea pig

The effect of chronic levodopa-carbidopa administration (200 mg/kg for 21 days) on guinea pigs rendered behaviorally supersensitive by the prior administration of haloperidol (.5 mg/kg for 21 days) was examined. Animals who showed an increased behavioral response to apomorphine after chronic haloperidol administration were treated with levodopa-carbidopa and then apomorphine - induced stereotypy was reexamined. Although the chronic levodopa control groups and the chronic haloperidol control remained supersensitive to the behavioral effect of apomorphine, the haloperidol-levodopa group's behavioral response to apomorphine returned to normal. Both chronic dopaminergic antagonist and agonist administration have been demonstrated to induce heightened apomorphine-induced stereotypy and this has been interpreted as a reflection of altered striatal dopamine receptor site sensitivity. The finding that the serial administration of a chronic dopaminergic antagonist followed by a chronic dopaminergic agonist results in a return to normal of a striatal dopamine receptor-dependent behavior suggests that these chronic treatments affect dopamine receptor sites by different mechanisms of action. Since neuroleptic induced dopaminergic supersensitivity in animals is an accepted model of tardive dyskinesia, levodopa may also reverse dopaminergic supersensitivity in patients and might be a potential therapeutic agent in tardive dyskinesia.     

The effect of the antipsychotic drug mosapramine on the expression of Fos protein in the rat brain: comparison with haloperidol, clozapine and risperidone

In this study, we examined the effect of the acute p.o. administration of the antipsychotic drug mosapramine, as well as the antipsychotic drugs clozapine, haloperidol and risperidone, on the expression of Fos protein in the medial prefrontal cortex, nucleus accumbens and dorsolateral striatum of rat brain. The administration of mosapramine (1 or 3 mg/kg) significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex, but not in the dorsolateral striatum. In addition, mosapramine (1, 3 or 10 mg/kg) produced a dose-dependent increase in the number of Fos protein positive neurons in the nucleus accumbens. The acute administration of 10 mg/kg of mosapramine significantly increased the number of Fos protein positive neurons in all brain regions. The acute administration of clozapine (30 mg/kg), similarly to mosapramine at lower doses (1 or 3 mg/kg), significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex and nucleus accumbens, but not dorsolateral striatum. In contrast, haloperidol (0.3 mg/kg) significantly increased the number of Fos protein positive neurons in the nucleus accumbens and dorsolateral striatum, but not medial prefrontal cortex. The acute administration of risperidone (0.3 or 1 mg/kg) did not affect the number of Fos protein positive neurons in the medial prefrontal cortex, nucleus accumbens or dorsolateral striatum of rat brain, whereas a 3 mg/kg dose of risperidone significantly increased the number of Fos protein positive neurons in all brain regions. These results suggest that the ability of mosapramine to enhance expression of Fos protein in the medial prefrontal cortex may contribute to a clozapine-like profile with respect to actions on negative symptoms in schizophrenia. Furthermore, the lack of effect of low doses of mosapramine on Fos protein expression in the dorsolateral striatum, an area believed to play a role in movement, suggests that it may have a lower tendency to induce neurological side effects.