Role of central histaminergic system in lorazepam withdrawal syndrome in rats.

Effects of histaminergic agonists and antagonists were investigated on withdrawal signs in lorazepam-dependent rats. Physical dependence was developed by giving lorazepam admixed with the food in the following dose schedule (in mg/kg given daily x days): 10 x 4, 20 x 4, 40 x 4, 80 x 4, and 120 x 7. The parameters observed during the periods of administration of lorazepam and after its withdrawal were spontaneous locomotor activity (SLA), reaction time to pain, foot shock aggression (FSA), and audiogenic seizures. During the withdrawal period, the rats were divided into groups of 10 each. Control-withdrawal group did not receive any drug. The drugs (in mg/kg administered intramuscularly)--L-histidine (50), histamine-N-methyl (2), promethazine (10), pheniramine (10), astemizole (10), and thioperamide (1)--were given separately in other groups daily during the withdrawal period. The withdrawal signs in control group were hyperkinesia, hyperaggression, and audiogenic seizures. L-Histidine, precursor of histamine, and thioperamide, antagonist of H3 receptor, potentiated hyperkinesia, hyperaggression, and audiogenic seizures. Histamine-N-methyl, agonist of H3 receptor, and H1 receptor antagonists, promethazine and pheniramine, blocked all the withdrawal signs. Astemizole, a peripheral antagonist of H1 receptor, could not affect any withdrawal sign. It may be concluded that histamine H1 receptors are facilitatory and H3 receptors are inhibitory for benzodiazepine (BZD) withdrawal syndrome.     

Effect of dopamine agonists and antagonists on the lorazepam withdrawal syndrome in rats

1. The effects of dopaminergic agonists and antagonists were investigated on withdrawal signs in lorazepam-dependent rats. Physical dependence was developed by giving lorazepam admixed with food in the following dose schedules: 10 x 4, 20 x 4, 40 x 4, 80 x 4 and 120 x 7 mg/kg, daily for x days. 2. The parameters observed during the periods of administration of lorazepam and after its withdrawal were spontaneous locomotor activity (SLA), reaction time to pain, foot shock aggression (FSA) and audiogenic seizures. 3. During the withdrawal period, rats were divided into groups of 10 rats each. One group did not receive any drug and served as the control withdrawal groups. Three other groups received, separately, one of the following dopamimetic drugs: (i) 200 mg/kg per day, i.m., L-dihydroxyphenylalanine (DOPA; +50 mg/kg per day, i.m., carbidopa); (ii) 2 mg/kg per day, i.m., amphetamine; or (iii) 1 mg/kg per day, i.m., apomorphine. The remaining groups received one of the following dopamine antagonists: (i) 0.1 mg/kg per day, i.m., SCH 23390; (ii) 0.5 mg/kg per day, i.m., haloperidol; (iii) 0.5 mg/kg per day, i.m., centbutindol; and (iv) either 1 or 20 mg/kg per day, i.m., clozapine. 4. The withdrawal signs observed in the control group were hyperkinesia, hyperaggression and audiogenic seizures. 5. L-Dihydroxyphenylalanine (+ carbidopa), amphetamine and apomorphine potentiated hyperaggression and audiogenic seizures. The dopamine D2 receptor antagonists haloperidol, centbutindol and clozapine (at 20 mg/kg, i.m.) blocked all withdrawal signs. The D1 receptor antagonist SCH 23390 inhibited hyperkinesia and hyperaggression. The D4 receptor antagonist clozapine (at 1 mg/kg, i.m.) had no effect on any of the withdrawal signs. 6. It may be concluded that dopamine D2 receptors exert a dominant facilitatory influence, with partial contribution of D1 receptors, on the benzodiazepine withdrawal syndrome.     

Dextromethorphan attenuates ethanol withdrawal syndrome in rats

The effects of dextromethorphan (DM), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors, have been investigated on ethanol withdrawal signs in rats. Ethanol (7.2% v/v) was given to rats in a liquid diet for 16 days. DM (10, 20, and 40 mg/kg) and saline were injected intraperitoneally at the third hour of ethanol withdrawal. DM (40 mg/kg) and ethanol dependent saline were also administered to ethanol naive rats. DM (40 mg/kg) did not produce any significant change in locomotor activity in ethanol naive rats. The effects of DM on locomotor activity and total ethanol withdrawal score were evaluated at the fourth and sixth hours of ethanol withdrawal. DM inhibited locomotor hyperactivity at these periods. DM also reduced total ethanol withdrawal score from the fourth hour to the sixth hour, and it significantly decreased audiogenic seizures. Seizure susceptibility after chronic ethanol exposure may be dependent upon sensitization or upregulation of NMDA processes and NMDA receptors. Our results suggest that inhibition of NMDA receptors by DM alleviates signs of ethanol withdrawal.     

Effect of pharmacological interference with various neuropathways on blockade of morphine-withdrawal hypothermia by morphine and by conditional stimulus

Rats were given two equally spaced injections of morphine sulphate daily, each injection being paired with a bell sound. The morphine dose was gradually increased to 200 mg/kg per day. At 24 hr after withdrawal, all rats showed hypothermia which was reversed by either the bell sound or morphine. Morphine alone also produced an overshoot hyperthermia. The bell sound-induced alleviation of withdrawal hypothermia was blocked by pretreatment with mecamylamine (2.5 mg/kg). phenoxybenzamine (2 mg/kg), haloperidol (0.2 mg/kg) and benztropine (0.625 mg/kg) but was not blocked by cyproheptadine (2 mg/kg) or propranolol (2 mg/kg). In contrast, morphine-induced hyperthermia during withdrawal was blocked by pretreatment with mecamylamine, phenoxybenzamine and cyproheptadine but was not blocked by haloperidol, benztropine, or propranolol.     

Precipitated and spontaneous withdrawal in baboons after chronic dosing with lorazepam and CGS 9896

In order to assess the ability of lorazepam (20 mg/kg/day) and CGS 9896 (100 mg/kg/day) to produce physical-dependence in baboons, the occurrence of Ro 15-1788 precipitated withdrawal signs and spontaneous withdrawal signs were determined. Lorazepam-treated baboons displayed precipitated withdrawal signs following the administration of Ro 15-1788 (5 mg/kg), and displayed mild to moderate spontaneous withdrawal signs following termination of drug treatment. CGS 9896-treated baboons did not display Ro 15-1788 precipitated withdrawal signs and displayed either no or only mild spontaneous withdrawal signs.     

Effect of thyrotropin-releasing hormone on the time course of neurologic recovery after spinal cord injury in the rat

Spinal cord injuries in rats were experimentally produced by compressing the cord at the eleventh thoracic vertebral level for 60 minutes with stainless steel screws (2 mm in diameter and 2.8 mm in length). The main neurologic signs produced by cord compression were motor as well as sensory deficits and urinary incontinence. Rats with a neurologic score, based on both motor and sensory deficits, of 1 (complete paraplegia but responsive to tail pinching) 24 hours after injury were used to study the relative effect of subcutaneous treatment with TRH once or twice daily for 7 consecutive days on the time course of recovery after spinal cord injury and the dose-dependency of this effect. Once daily (5, 15, or 45 mg/kg/day) or twice daily (2.5, 7.5, or 22.5 mg/kg x 2/day) treatment with TRH starting 24 hours after injury improved the neurological signs and reduced the incidence of urinary incontinence, dose-dependently. The minimum effective doses for once and twice daily treatments were 45 mg/kg/day and 7.5 mg/kg x 2/day. These results indicate that the neurologic recovery-accelerating effect of TRH administered 24 hours after cord injury for 7 days is dose-dependent and that a twice daily dosage schedule tends to produce better improvement in the neurologic state than a once daily schedule dose.     

Effect of acetyl-L-carnitine on ethanol consumption and alcohol abstinence syndrome in rats

The effect of acetyl-L-carnitine on alcohol consumption and its possible ability to alleviate all symptomatology of ethanol withdrawal syndrome has been investigated in rats. Alcohol-dependence was induced in animals (9-15 g/kg ethanol solution at 20% for a period of 4 days) in order to measure the effects of acetyl-L-carnitine on ethanol abstinence syndrome. The ethanol dependence phase was characterized by the onset of signs and responses of progressive severity: hyperactivity, tremors, spastic rigidity and spontaneous convulsive seizures. After 4 days, 8 h after the last ethanol administration, two groups of animals received acetyl-L-carnitine (125 mg/kg and 250 mg/kg intraperitoneally, respectively) and the intensity of the withdrawal syndrome was assessed on the basis of the appearance of tremors. The effect of acetyl-L-carnitine on voluntary alcohol consumption was investigated in a rat line selected for innate ethanol preference. For 15 days the animals could freely choose both water and/or a hydroalcoholic solution (10% p:v). Acetyl-L-carnitine was given intraperitoneally at a dose of 200 mg/kg twice daily. The water and the hydroalcoholic solution levels were checked at the same time daily. Acetyl-L-carnitine treatment significantly reduced the onset of tremors in ethanol withdrawal syndrome as well as the level of ethanol intake in alcohol-preferring rats. These results suggest a possible pharmacological role of acetyl-L-carnitine in the treatment of alcohol dependence.     

Activators of potassium M currents have anticonvulsant actions in two rat models of encephalitis

Opioid systems in hippocampus regulate excitability and kappa opioids have a role in anticonvulsant protection, but their mechanisms of action are incompletely understood. We examined the ability of opioid and nonopioid agents with overlapping ionic mechanisms and actions similar to kappa opioid agonists, to block seizures in rat models of encephalitis due to Borna Disease virus and Herpes Simplex Virus Type-1. Naltrindole, a delta antagonist and thus a kappa opioid sparing agent, (10 mg/kg s.c.) blocked spontaneous and naloxone (opioid antagonist)-induced seizures in the models, but produced somatic signs similar to opioid withdrawal. Given that delta antagonists as well as kappa opioid agonists in hippocampus enhance potassium M currents (I(M)), we tested the effect of the I(M) augmenter flupirtine. Flupirtine (20 mg/kg i.p.) prevented seizures in Borna and herpes infected rats, without signs of withdrawal, hypotonia or sedation. The results support the efficacy of opioid and nonopioid drugs in modulating naloxone-induced seizures in critical illness due to viral encephalitis and by analogy, opioid withdrawal seizures.     

The role of group I mGlu receptors in the expression of ethanol-induced conditioned place preference and ethanol withdrawal seizures in rats

In animal models, N-methyl-d-aspartate (NMDA) receptors antagonists inhibit physical dependence and the reinforcing effects of ethanol. The group I metabotropic glutamate (mGlu) receptors antagonists (mGlu1 and mGlu5) attenuate excitatory effect of glutamate by functional modulation of the glutamate/NMDA receptors. The objective of the present study was to evaluate the effects of a selective mGlu5 receptors antagonist—MTEP, and mGlu1 receptors antagonist—EMQMCM, on two processes relevant to alcohol addiction: the expression of ethanol-induced conditioned place preference (CPP) paradigm, and ethanol withdrawal audiogenic seizures in rats. Our experiments indicated that EMQMCM at the doses of 5 and 10 mg/kg, and MTEP at the doses of 2.5 and 5 mg/kg, significantly attenuated the expression of ethanol CPP. Furthermore, both group I mGlu receptor antagonists, i.e. EMQMCM at the dose of 10 mg/kg and MTEP at the dose of 5 mg/kg, attenuated audiogenic seizures induced by the sound stimulus 12 h after withdrawal of ethanol in dependent rats. Our study shows the importance of mGlu5 and mGlu1 receptors for the expression of ethanol-induced CPP and withdrawal seizures, although mGlu5 receptors antagonist (MTEP) was more potent than the antagonist of mGlu1 receptors (EMQMCM).     

Comparison of simultaneous administration of lithium with L-NAME or L-arginine on morphine withdrawal syndrome in mice

Due to the claim that chronic administration of lithium or L-N(G)-nitroarginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor reduces morphine withdrawal syndrome, the effects of chronic administration of lithium, L-NAME, or L-arginine (L-Arg), a precursor of NO, alone or co-administration of lithium with L-Arg or L-NAME, on naloxone-precipitated withdrawal syndrome and physical dependence development to morphine in mice chronically treated with morphine, were evaluated. Morphine dependency was induced by the intraperitoneal injection (i.p.) of morphine (10 mg/kg), once daily for 7 days. Physical dependence to morphine was observed by precipitating an abstinence syndrome with naloxone (2 mg/kg, i.p.). Chronic administration of L-NAME (10 mg/kg, i.p., once daily, for 7 days after 10 days of receiving only tap water and food prior to naloxone), decreased all withdrawal signs significantly, while L-Arg (200 mg/kg, as above) increased only some withdrawal signs significantly in morphine-dependent mice. Chronic administration of lithium (600 mg/kg, in drinking water) alone or co-administration of lithium (as above) with L-NAME (10 mg/kg) or L-Arg (200 mg/kg, i.p., once daily) for 7 days after 10 days of receiving only lithium (as above) and food, decreased all withdrawal signs and physical dependence significantly in morphine-dependent mice. The results obtained indicate that co-administration of L-NAME with lithium increases the effect of lithium or L-NAME alone, on withdrawal signs, but this increase is not significantly different as compared to chronic lithium or L-NAME administration alone; while co-administration of L-Arg with lithium decreases the effects of lithium on withdrawal signs and this decrease is not significant as compared to chronic lithium administration alone. These findings indicate that nitric oxide may be involved in modulation of naloxone-induced withdrawal syndrome, and treatment with lithium could have some effect on this system. Copyright 2000 John Wiley & Sons, Ltd.     

Dipyrone inhibits ethanol withdrawal and pentylenetetrazol‐induced seizures in rats

The effects of dipyrone, a nonnarcotic analgesic drug, on ethanol withdrawal and pentylenetetrazol (PTZ)‐induced seizures in male Wistar rats were investigated. Ethanol (7.2%) was given to rats by a liquid diet for 21 days. After 6 h of ethanol withdrawal, rats were exposed to an audiogenic stimulus (100 dB) for 60 sec for induction of seizures. Dipyrone (50, 100, and 200 mg/kg ip) and saline were administered to rats 30 min before audiogenic stimulus, and the effects of dipyrone on the seizures induced by audiogenic stimulus were evaluated. The effects of dipyrone on PTZ‐induced seizures were also evaluated in other individual groups of the rats. The same doses of dipyrone were injected in the rats ip 30 min before PTZ (50 mg/kg) injections. Immediately after PTZ injections, onset time and severity of the convulsions were recorded. Dipyrone significantly and dose‐dependently reduced both incidence and intensity of the ethanol withdrawal‐associated audiogenic seizures. It also inhibited significantly and dose‐dependently intensity but not onset time of the PTZ‐induced seizures. Dipyrone (50–200 mg/kg) did not produce any significant change in locomotor activity in naive rats. Our results suggest that dipyrone has some prominent anticonvulsant activities on both ethanol withdrawal and PTZ‐induced seizures in rats, and that using dipyrone may be a new and effective therapeutic approach in the treatment of seizures. Drug Dev. Res. 53:254–259, 2001. © 2001 Wiley‐Liss, Inc.     

Role of nitric oxide in catalepsy and hyperthermia in morphine-dependent rats

The possible involvement of nitric oxide (NO) in morphine-induced catalepsy and hyperthermia was studied in morphine-dependent rats. Four days repeated injection regimen was used to induce morphine dependence, which was assessed by naloxone challenge (0.5 mg x kg(-1), s.c.). Pretreatment of rats with the NO synthase inhibitor, N(G)-nitro-L-arginine (L-NA, 8 mg x kg(-1) twice daily, i.p.) potentiated the cataleptic response of morphine as shown by a rightward shift in the morphine-log dose-response curve. Prior treatment of rats with the NO precursor, L-arginine (200 mg x kg(-1), twice daily, i.p.) abolished the potent effect of L-NA and restored the cataleptic scores to levels similar to those of morphine-dependent rats. The same dose of L-NA significantly blocked morphine-induced hyperthermia at the dose levels of morphine (15-105 mg x kg(-1)) and this effect was reversed by L-arginine. These data provide the first experimental evidence that NO is involved in morphine induced catalepsy and hyperthermia and demonstrated that blockade of NO synthesis may suggest a dangerous interaction with opioids in the control of motor function.     

Effects of olanzapine on ethanol withdrawal syndrome in rats

The present study was designed to investigate the effects of olanzapine, a serotonin-dopamine antagonistic atypical antipsychotic agent, on ethanol withdrawal syndrome in rats. Adult male Wistar rats were subjects. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 21 days. Control rats were pair fed with an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. After 2nd, 4th and 6th h of ethanol withdrawal, rats were observed for 5 min, afterwards withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behavior, tremor, wet dog shakes, abnormal posture and abnormal gait were recorded or rated. Olanzapine (0.5, 1 and 2 mg/kg) and saline were injected to the rats intraperitoneally 30 min before ethanol withdrawal assessment. A second series of injections was also given 30 min before the 6th-h-observation, and subjects were then tested for audiogenic seizures. Olanzapine (2 mg/kg) produced significant inhibitory effects on stereotyped behaviors and wet dog shakes at the 6th h of ethanol withdrawal. Contrary, the same dose caused some increases in the intensity of posture and gait impairments at the 2nd h of ethanol withdrawal. In addition, that dose was found to be ineffective on agitation, tremor, tail stiffness and audiogenic seizures. Our results suggest that acute olanzapine treatment has beneficial effects on stereotyped behavior and wet dog shakes, but it also has some adverse effects on posture and gait during ethanol withdrawal in rats. Overall, olanzapine does not seem to be an adequate and suitable drug in controlling of ethanol withdrawal syndrome.     

Comparison of development of drug dependence in naive and drug dependence-experienced rats]

Phenobarbital, chordiazepoxide, diazepam and/or morphine were repeatedly administered to both male and female rats (N equals 10) for 4 similar to 6 weeks. The drug dose was gradully increased from 5 to 10, 20, 40, 80 and 160 mg/kg once daily (p.o) at seven day intervals. In the case of morphine, the last dose was 40 mg/kg. The drugs were constantly withdrawn for 24 hr at 8 day intervvals. None of the rats were given drugs for 16 days after administration of the last scheduled dose in order to recover their initial weight (Exp. I). Onset of dependence formation, decrease in body weight and food intake, days required to reach the maximum decrease in body weight and duration of withdrawal signs were observed throughout this experiment. The rats (drug dependence-experimented rats) who survived the first stage of this experiment were continuously subjected to re-administration by the same dosage schedule as in Exp. I (seven days of drug administration, 48hr of withdrawal). The re-administered rats showed a more rapid onset of dependence formation and a longer duration of decreas in boy weight during 16 days withdrawal than did the naive rats. It is concluded, that in addition to the decrease in body weight by withdrawal plus duration of the withdrawal signs, the onset of drug dependence formation is also a specific factor.     

Investigations with the novel non-opioid analgesic flupirtine in regard to possible benzodiazepine-like abuse inducing potential

Flupirtine (D-9998, Katadolon, CAS 56995-20-1); CAS 56995-20-1), a novel non-opioid analgesic was investigated for possible benzodiazepine-like activities. In receptor binding studies flupirtine and its metabolite were found to reveal no affinity for specific 3H-flunitrazepam binding up to a concentration of 10 mumol/l. In drug discrimination studies, rats were trained to discriminate the novel analgesic flupirtine (10 mg/kg i.p.) from no drug (NaCl 0.9%) under a two-choice fixed-ratio 5 shock-termination schedule. Flupirtine yielded a dose-response curve with an ED50 of 3.9 mg/kg i.p. In generalization tests with a benzodiazepine-type compound lorazepam (0.3 mg/kg, i.p.) did not generalize to the flupirtine training dose. In physical dependence studies using rats, during and after chronic oral administration of flupirtine (2 x 80 mg/kg p.o.) over 45 days no signs of benzodiazepine- and opiate-like physical dependence were observed in rats after withdrawal of the drug. In contrast diazepam (2 x 5 bzw. 2 x 10 mg/kg p.o.) induced typical symptoms of physical dependence. A significant weight loss of the codeine treated animals (2 x 60 mg/kg p.o.) and other typical side effects were also observed after withdrawal of codeine. These results clearly demonstrate that flupirtine has no affinity for benzodiazepine receptors and is free of benzodiazepine or opiate/opioid-like abuse potential.     

Effect of peripheral administration of cinnarizine and verapamil on the abstinence syndrome in diazepam-dependent rats

The effects of two calcium channel blockers (verapamil and cinnarizine) were evaluated on diazepam withdrawal symptoms. Rats were made diazepam dependent by chronic treatment with daily injections of the drug, 20 mg/kg IP for 3 weeks. On abrupt termination of the drug, animals showed withdrawal hyperactivity that was assessed by autonomic, behavioural and motor signs. The peak effect was seen 3 days after the withdrawal of diazepam. On IP administration, verapamil and cinnarizine (10, 20 and 40 mg/kg) given on eight occasions at an interval of 12 h reversed the withdrawal-induced increase in spontaneous motor activity. Cinnarizine in higher doses (20 and 40 mg/kg) was found to be effective in suppressing the behavioural signs but verapamil did not show any protective effect against startle response and irritability. These results suggest that modulation of the calcium influx in the CNS might influence withdrawal.This study was presented in XIth International Congress of Pharmacology (IUPHAR) at Amsterdam (July 1–6, 1990)     

Antagonism of methomyl-induced toxicosis by diphenhydramine in rats

The efficacy of diphenhydramine in the prevention and treatment of methomyl-induced toxicosis was evaluated in female rats. Diphenhydramine at 10 and 20 mg/kg subcutaneously (s.c.) given immediately after methomyl increased the LD(50) of methomyl (6.29 mg/kg intraperitoneally (i.p.)) in the rats by 71 and 75% respectively. Diphenhydramine at 20 mg/kg s.c. given immediately after methomyl (6 mg/kg i.p.) decreased the occurrence of cholinergic signs of toxicosis, and prevented convulsions, gasping and death by 100% in comparison with the control (methomyl-saline) group. Diphenhydramine administration at 2.5, 5 and 10 mg/kg s.c. 20 min before methomyl (8 mg/kg i.p.) significantly and dose-dependently decreased the number of convulsion episodes in rats in comparison with the control group. This effect was similar to those of atropine and diazepam pretreatments at 20 mg/kg s.c. Diphenhydramine and atropine at 20 mg/kg i.p. given 5 min after the methomyl administration (8 mg/kg i.p.) were close to each other in reducing the signs of cholinergic toxicity as well as the severity of toxicosis induced by methomyl in rats. Methomyl at 4 and 8 mg/kg i.p. significantly decreased erythrocyte (40 and 43%) and plasma (23 and 31%) cholinesterase activities in comparison with the control group. Diphenhydramine (10 mg/kg s.c.) injected 15 min before methomyl significantly decreased the inhibitory effect of methomyl (4 and 8 mg/kg i.p.) on erythrocyte cholinesterase to 17 and 27%, respectively. The inhibitory effect on plasma cholinesterase was not affected by the diphenhydramine pretreatment. The data suggest that diphenhydramine could be of therapeutic value in reducing the toxic effects of methomyl.     

Oral administration of glycine and polyamine receptor antagonists blocks ethanol withdrawal seizures

Cessation of chronic administration of orally administered large amounts of ethanol for 7 days resulted in a markedly increased frequency of audiogenic seizures in Sprague-Dawley rats. Oral administration of the novel glycine receptor antagonist, L-701,324, produced a dose-dependent (2.5 and 5.0 mg/kg; –30 min) inhibition of ethanol withdrawal signs when measured about 12 h after withdrawal of the ethanol treatment. Similarly, using the same experimental paradigm, oral administration of the specific polyamine receptor antagonist, eliprodil, caused a dose-related (2.0 and 5.0 mg/kg; –30 min) inhibition of ethanol withdrawal-induced audiogenic seizure activity. The inhibition of ethanol withdrawal seizures produced by L-701,324 and eliprodil, respectively, was obtained at doses which by themselves did not change the locomotor activity in naive Sprague-Dawley rats. The findings that L-701,324 and eliprodil are potent inhibitors of seizure activity induced by cessation of chronic ethanol administration and the fact that they, in contrast to currently available NMDA receptor antagonists, do not produce psychotomimetic and/or sedative effects, suggest that these drugs may represent a new class of therapeutically useful pharmacological agents for the treatment of ethanol withdrawal seizures. Furthermore, since there is evidence that eliprodil produces its pharmacological actions through a specific inhibition of NMDAR1 and/or NMDAR2B subunits, these data may indicate that certain NMDA receptor subunits may be of particular importance for the mediation of seizure activity following the discontinuation of chronic ethanol exposure.     

Oral administration of glycine and polyamine receptor antagonists blocks ethanol withdrawal seizures

Cessation of chronic administration of orally administered large amounts of ethanol for 7 days resulted in a markedly increased frequency of audiogenic seizures in Sprague-Dawley rats. Oral administration of the novel glycine receptor antagonist, L-701,324, produced a dose-dependent (2.5 and 5.0 mg/kg; − 30 min) inhibition of ethanol withdrawal signs when measured about 12 h after withdrawal of the ethanol treatment. Similarly, using the same experimental paradigm, oral administration of the specific polyamine receptor antagonist, eliprodil, caused a dose-related (2.0 and 5.0 mg/kg; − 30 min) inhibition of ethanol withdrawal-induced audiogenic seizure activity. The inhibition of ethanol withdrawal seizures produced by L-701,324 and eliprodil, respectively, was obtained at doses which by themselves did not change the locomotor activity in naive Sprague-Dawley rats. The findings that L-701,324 and eliprodil are potent inhibitors of seizure activity induced by cessation of chronic ethanol administration and the fact that they, in contrast to currently available NMDA receptor antagonists, do not produce psychotomimetic and/or sedative effects, suggest that these drugs may represent a new class of therapeutically useful pharmacological agents for the treatment of ethanol withdrawal seizures. Furthermore, since there is evidence that eliprodil produces its pharmacological actions through a specific inhibition of NMDAR1 and/or NMDAR2B subunits, these data may indicate that certain NMDA receptor subunits may be of particular importance for the mediation of seizure activity following the discontinuation of chronic ethanol exposure.     

Anticonvulsant, but not antiepileptic, action of valproate on audiogenic seizures in metaphit-treated rats

1. The blocking effects of valproate (2-propylpentanoic acid), a standard anti-epileptic drug, on metaphit (1-[1-(3-isothiocyanatophenyl)-cyclohexyl]-piperidine)-induced audiogenic seizures as a model of generalized, reflex audiogenic epilepsy in adult Wistar male rats were studied. 2. Rats were stimulated using an electric bell (100 +/- 3 dB, 5-8 kHz, 60 s) 60 min after i.p. metaphit (10 mg/kg) injection and afterwards at hourly intervals. For power spectra and electroencephalograph (EEG) recordings, three gold-plated screws were implanted into the skull. Different doses of valproate (50, 75 and 100 mg/kg) were injected i.p. into rats with fully developed metaphit seizures after the eighth audiogenic testing. 3. In metaphit-treated animals, the EEG appeared as polyspikes, spike-wave complexes and sleep-like patterns, whereas the power spectra were increased compared with the corresponding controls. 4. Valproate reduced the incidence and intensity of convulsions and prolonged the duration of the latency period in a dose-dependent manner 4 h after administration. 5. The ED(50) of valproate in the first hour after injection was 63.19 mg/kg (95% confidence interval 51.37-77.71 mg/kg). 6. None of the doses of valproate applied eliminated the EEG signs of metaphit-provoked epileptiform activity. 7. Taken together, these results suggest that all doses of valproate examined acted to suppresse behavioural but not epileptic EEG spiking activity in metaphit-induced seizures.