Caffeine modification of kindled amygdaloid seizures

Rats were kindled during exposure to caffeine (50 mg/kg) or saline given IP twenty minutes before daily electrical stimulation of the amygdala until 3 kindled amygdaloid seizures (KAS) occured. They were then stimulated for 3 days without drug pretreatment followed by 5 additional days with drug pretreatment. There were no significant differences between the two groups in the number of daily stimulations or in the total seconds of cumulative afterdischarge (AD) needed to reach the first KAS. During kindling, the daily average AD tended to be longer in the caffeine treated group. This difference became significant (>200% saline) when the KAS was reached. When KAS animals were stimulated without caffeine pretreatment, the average AD returned to control lengths. When put back on caffeine pretreatment, the average AD was again increased. Caffeine (6–50 mg/kg, IP) was also evaluated in previously kindled rats using suprathreshold (400 μAMP) and threshold (20 μA increments) seizures. Caffeine had no consistent effect on threshold values. However, 12–50 mg/kg of caffeine increased seizure severity and AD durations after threshold stimulation. With suprathreshold stimulation, the length of the AD was significantly increased only after the highest dose of caffeine. It would appear that caffeine lengthens induced afterdischarges both during the acquisition phase of kindling and in the fully kindled subject. Caffeine does not appear to lower seizure thresholds or increase the rate of aquisition of the KAS in the doses tested in this model. It is postulated that caffeine may modify the KAS through an inhibition of the mechanisms which terminate the elicited AD.     

The effects of various anesthetics on amygdaloid kindled seizures

The effects of various doses of cataleptic anesthetics, gamma-butyrolactone (GBL), phencyclidine (PCP), and ketamine (KET), and the depressant anesthetics, pentobarbital (PB) and chloral hydrate (CH), on amygdaloid kindled seizures were tested in the rat. The seizure activity was monitored by behavioral observation and EEG recording. Anesthetic doses of the cataleptic anesthetics with the exception of KET had minimal effects on the afterdischarge duration (AD) and behavioral ranking (BR) of the elicited seizures. On the other hand, they were more inhibitory to the AD and BR than was the convulsant pentylenetetrazol (PTZ). The only cataleptic that induced spontaneous seizure activity at anesthetic doses was PCP, although KET induced epileptoid activity at supranesthetic doses. Ketamine, PB, and CH completely inhibited elicited seizure activity at anesthetic doses. In addition, rats were kindled by repetitive electrical stimulation during GBL-induced anesthesia or catalepsy. Although both these GBL groups averaged more stimulations to reach generalized seizures than the saline controls, GBL did not block the kindling process.     

Ketamine-induced changes in kindled amygdaloid seizures

The effects of ketamine on seizures kindled by repetitive electrical stimulation of the amygdala were determined in the rat. The response of fully developed kindled amygdaloid seizures (KAS) to 20, 40, 80 and 120 mg/kg (i.p.) ketamine, administered from 5 to 60 min prior to elicitation of seizures was examined. Ketamine reduced the afterdischarge duration (AD) and behavioral response (BR) in a dose-dependent fashion. However, the effect of ketamine on the afterdischarge duration and behavioral response was not clearly time-dependent for each dose (20–120 mg/kg). A dose-dependent increase in the seizure spiking frequencies in the amygdala and cortex during kindled amygdaloid seizures was also induced by ketamine. Blood plasma and brain levels of ketamine and its metabolites were determined 15 min after 20, 40, 80 and 120 mg/kg ketamine as well as 60 min after 80 mg/kg ketamine. Brain and plasma levels of ketamine and nor-ketamine were similar to those previously reported. Low plasma levels of dehydro-nor-ketamine were seen only at 60 min after 80 mg/kg ketamine. The decrease in afterdischarge duration and behavioral response and the increase in afterdischarge duration spiking frequency seen at 15 min correlated with elevated levels of ketamine and nor-ketamine in brain and plasma. However, by 60 min plasma levels of ketamine remained high, yet the brain levels of both ketamine and nor-ketamine had decreased. This is despite the fact that afterdishcarge duration and behavioral response were still attenuated and afterdischarge duration spiking frequency was still increased. Thus, the exact contribution by ketamine and nor-ketamine to the alteration of afterdischarge duration, behavioral response and afterdischarge spiking frequency cannot be made at this time. It was apparent that inhibition of the afterdischarge duration and behavioral response along with an increase in spiking frequency was not dependent on dehydro-nor-ketamine. The possibility that an unidentified metabolite may contribute to the modification of kindled amygdaloid seizures by ketamine is discussed.     

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.     

Differential response of amygdaloid neurons to clozapine and haloperidol: effects of repeated administration

Rats were pretreated with saline or with behaviorally equivalent doses of clozapine (10.0 mg/kg) or haloperidol (1.0 mg/kg) twice daily for six consecutive days. On the following day, amygdaloid neurons in clozapine-pretreated rats responded to a challenge injection of this drug with a significantly greater increase in firing rate than saline controls. In contrast, amygdaloid neurons generally remained unresponsive to haloperidol even when pretreatment with this drug was extended to 13 days. Neither clozapine nor haloperidol pretreatment, however, altered the response of amygdaloid neurons to d-amphetamine administered after a four-day washout period. Amphetamine inhibited amygdaloid activity to a comparable extent in all rats. Taken together, these results implicate the amygdaloid complex as an important site of action of clozapine and related antischizophrenic drugs.     

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

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

A behavioural and pharmacological evaluation of the discriminative stimulus induced by pentylenetetrazole in the pig

The anxiogenic nature of the interoceptive discriminative stimulus induced by pentylenetetrazole (PTZ) was investigated by examining the discriminatory behaviour of PTZ conditioned pigs during a conditioned emotional response (CER). A CER was induced in a non-operant situation, by pairing a tone stimulus with the application of a mild, non-injurious electric shock. Subsequent presentation of the conditioned tone stimulus alone produced a generalisation to the PTZ cue. This generalisation of the conditioned emotional state (CES) to the PTZ cue was antagonised by pretreatment with diazepam (0.5 mg/kg, PO; 30 min). The PTZ stimulus was also antagonised by diazepam (0.5 mg/kg, PO; 30 min) but not by an anticonvulsant dose of ethosuximide (30 mg/kg, PO; 1–3 h), providing further confirmation of the anxiogenic nature of the PTZ cue. Our results demonstrate the validity of the PTZ discrimination paradigm in pigs as a test of anxiety.     

Quantitative evaluation of the pentylenetetrazol-anticonvulsant interaction on the EEG of the cat

The interaction of pentylenetetrazol (PTZ) with the anticonvulsants phenobarbital (PB), trimethadione (TD) and diphenylhydantoin (DPH) or saline on the EEG of the cat was examined with the aid of power spectral density analysis. Pretreatment with PB or TD effectively increased the dose of PTZ required for induction of paroxysmal activity, while some decrease in PTZ dose was seen with DPH pretreatment. A direct correlation was seen between the amplitude (normalized total power) increases and the amount of PTZ required to induce paroxysm with each pretreatment. Dominant hippocampal theta (4.0–4.5 Hz) which was induced by PTZ following saline or DPH pretreatment was reduced or eliminated following TD and PB pretreatments. The triggering of generalized and sustained bilateral seizural activity was suggested to occur because activity in multiple intermittent foci throughout the brain gradually build up to a necessary critical mass. PB and TD were suggested to act by increasing the critical mass required for triggering the paroxysm, while DPH was suggested to act by lowering the critical mass resuling in less severe ictal activity.     

Anticonvulsive properties of YM-14673, a new TRH analogue, in amygdaloid-kindled rats

Effects of YM-14673 (N alpha-[( (S)-4-oxo-2-azetidinyl]-carbonyl]-L- prolinamide dihydrate), a new TRH analogue, on the development of kindling and the duration of afterdischarge (AD) were observed in amygdaloid-kindled rats in comparison with those of TRH. The right medial amygdaloid nucleus was electrically stimulated once a day for establishment of kindling. YM-14673 and TRH were administered intraperitoneally 15 and 30 min prior to electrical stimulation from 2 days after the first stimulation, respectively, and the number of stimulations required for the development of generalized seizures was measured. YM-14673 (1 mg/kg) showed tendency to suppress the development of kindling (p less than 0.1), but TRH even at high dose (10 mg/kg) showed little effect on it. In addition, the experiment for the AD duration was conducted in full-kindled rats from one day after at least 3 reproducible generalized seizures were elicited by electrical stimulation of the medial amygdaloid nucleus once a day. Both YM-14673 (1 mg/kg) and TRH (10 mg/kg) administered 15 and 30 min prior to electrical stimulation of the amygdala, respectively, significantly shortened the AD duration in full-kindled rats. At these doses, both drugs desynchronized spontaneous cortical electroencephalogram (EEG) in normal rats. These results indicate that YM-14673 seems to possess anticonvulsive property in rats.     

Defeat engenders pentylenetetrazole-appropriate responding in rats: antagonism by midazolam

Defeat and the threat of defeat by an aggressive conspecific is stressful and may engender an anxiety-or fear-like state in animals; the present experiment investigated whether defeat generalized to the discriminative stimulus properties of PTZ and how benzodiazepine receptors were involved in this generalization. Separate groups of male Long-Evans rats (Rattus norvegicus) were trained to discriminate 20 mg/kg pentylenetetrazole (PTZ) or 0.4 mg/kg midazolam (MDZ) from saline in a two-choice drug-discrimination task. After establishing stimulus control, PTZ- and MDZ-trained rats were exposed to an aggressive conspecific which resulted in defeat, as defined by the display of defensive and submissive postures as well as audible and ultrasonic vocalizations. Administration of saline after defeat resulted in greater than 80% PTZ lever selection in 15 out of 25 PTZ-trained rats; this effect was attenuated through pretreatment with MDZ (1 mg/kg). Furthermore, short-term defeat substitution for the PTZ discriminative stimulus was not accompanied by long-term changes in the post-defeat generalization curves for PTZ and MDZ when compared to pre-defeat generalization curves. Nor did defeat alter the antagonism of PTZ by diazepam (2.5 mg/kg) or MDZ by flumazenil (10 mg/kg). In order further to characterize the necessary features for defeat substitution for the PTZ discriminative stimulus, exposure to a threatening conspecific was also attempted by PTZ-trained rats protected from physical contact with a wire mesh cage. In these tests, saline continued to engender greater than 50% PTZ lever responding in 15 of 25 rats. These results suggest that an anxiety-like state is induced during defeat and exposure to a threatening conspecific in most rats; this state, as well as the PTZ discriminative stimulus, can be reversed by benzodiazepine receptor agonists. In contrast, short-term defeat substitution for the PTZ discriminative stimulus does not appear to be related to long-term alterations in the benzodiazepine receptor. Present address: Division of Behavioral Biology, Johns Hopkins University School of Medicine, Hopkins Bayview Research Campus, Baltimore, MD 21224, USA     

Neurobehavioural study of subchronic administration of oxydemeton-methyl (insecticide and acaricide) in rats

Oxydemeton-methyl, an organophosphate insecticide and acaricide produced decrease in the exploratory behaviour and prolongation of barbitone sodium induced hypnosis in rats after intermittent aerosol spray inhalational exposure, for 1/2 hour daily for 7 consecutive days, compared to the saline control group. Further, ED50 +/- SEM value for haloperidol induced catalepsy, CD50 +/- SEM value for pentylenetetrazole induced seizure and CI50 +/- SEM value for electroshock (i.e. the dose of haloperidol, PTZ and intensity of electroshock producing catalepsy or positive seizure response in 50% of rats) were significantly decreased after 7 days exposure to oxydemeton-methyl compared to that of saline control group. The study has established the central nervous system depressant effect, extrapyramidal effect and proconvulsant potential of oxydemeton-methyl which is widely used by the agricultural workers in the form of field spray.     

Facilitation of kindling by convulsions induced by cocaine or lidocaine but not pentylenetetrazol

The effect of drug-induced convulsions on kindling was studied in male Long-Evans rats. In Experiment 1 rats experienced a single convulsion induced by the intravenous infusion of cocaine, lidocaine, or pentylenetetrazol (PTZ), or received a control infusion of saline. Beginning eight days later all animals were kindled by daily stimulation of the olfactory bulb. Animals which had been convulsed by cocaine or lidocaine kindled significantly faster than either saline controls or PTZ-convulsed animals, which did not differ significantly. Experiment 2 was conducted to determine if an effect of PTZ on kindling could be obtained with repeated convulsions. Rats experienced three convulsions induced by cocaine or PTZ at 72 hr intervals, or control infusions of saline. Kindling began on the eighth day after the last infusion. Cocaine-convulsed animals again kindled significantly faster than saline or PTZ-convulsed animals, which did not differ significantly. The cocaine animals also had significantly longer afterdischarges than the saline group at the end of kindling and when stimulated again 21 days after kindling was completed. These results suggest that the facilitating effect of cocaine-induced convulsions is not a general property of all convulsants but is a more specific effect which is apparently shared by other local anesthetics.     

Effect of cocaine and pentylenetetrazol on cortical kindling

The effect of drug-induced convulsions on subsequent cortical kindling was studied in male Long-Evans rats. Animals experienced three intravenous infusions of physiological saline at 3 day intervals, or three convulsions induced by the infusion of cocaine or pentylenetetrazol (PTZ). Beginning eight days after the last infusion, all animals were kindled by stimulation of the anterior neocortex (area 6). PTZ-induced convulsions facilitated the development of both the behavioral convulsion and the electrographic seizure during cortical kindling, while cocaine-induced convulsions facilitated only the development of the electrographic seizure. Comparison of these results with previous research indicates that convulsions induced by these two drugs have long-lasting effects on brain function which differ both in their anatomical distribution and in the nature of the effects produced. These drugs also differed in their acute effects at subconvulsant doses on the expression of cortically kindled seizures. Cocaine (and lidocaine, another local anesthetic) substantially elevated afterdischarge (AD) threshold and inhibited the focal component of the cortically kindled seizure. PTZ had no significant effect on either of these variables but significantly increased AD duration. In addition to these drug effects, a substantial inhibitory effect on seizure expression was observed, both during kindling and afterwards, when ADs were elicited daily but not when they were separated by 3 days or more. This finding suggests that the large number of ADs typically required for cortical kindling may be due in part to daily stimulation.     

Dissimilar effects of nicotinamide and inosine, putative endogenous ligands of the benzodiazepine receptors, on pentylenetetrazol seizures in four strains of mice

In adult male albino BALB/c mice inosine (INS, 100 and 200 micrograms, intraventricularly) prolonged the latency of pentylenetetrazol (PTZ) seizures while nicotinamide (NAM) exerted an opposite effect. In adult male C57BL/6 mice INS decreased lethality after PTZ while NAM increased it. In adult male albino SHR (bred from Swiss) and in adult male CC57BR mice INS and NAM did not modify the effect of PTZ. Both INS and NAM administered ICB induced short-lasting locomotor excitement in albino SHR and BALB/c mice but not in C57BL/6 or CC57BR mice. Pretreatment with INS (300 mg/kg, IP) prolonged the latency of PTZ seizures only in SHR mice. Pretreatment with NAM was ineffective in all strains tested. Chronic treatment with NAM and INS (100 mg/kg, IP, daily for 5 days) in SHR mice did not modify the effect of PTZ. The data obtained emphasize the importance of the appropriate choice of mouse strain for studies on INS and NAM as puntative endogenous ligands of the BDZ receptor (BDZR). The opposite effects of INS and NAM raise doubts that these two substances could play the same or similar roles in the function of a type of BDZR which is related to the action of PTZ on the central nervous system.     

Suppression of pentylenetetrazol-elicited seizure activity by intraosseous propranolol in pigs

The intraosseous (IO) route provides a rapid and effective alternative venous access in the pediatric population when the conventional intravenous (IV) route cannot be easily obtained. DL-propranolol, a beta-adrenoceptor antagonist, exhibits antiepileptic activity in various animal seizure models. This study assessed the efficacy of IO propranolol in suppressing pentylenetetrazol (PTZ)-induced seizure activity in pigs. Domestic swine (13-20 kg) were prepared for recordings of arterial blood pressure, ECG and electrocortical activity. Seizure activity was induced by pentylenetetrazol (PTZ; 100 mg/kg; IV). Sixty seconds after the onset of seizure activity, the animals either received no drug (control) or propranolol (IV or IO via an 18-gauge spinal needle placed in the right proximal tibia). A transient increase (16.3-50.0%) in the mean arterial blood pressure (MAP) was observed following PTZ administration. Both IO and IV propranolol significantly suppressed the seizure duration (SD) (sec/min interval) at 1 min following drug administration; SD control, 36.3 +/- 4.8; IV propranolol, 12.3 +/- 5.1; IO propranolol, 18.3 +/- 6.0. In addition, both IV and IO propranolol produced a maximal decrease of 32-38% in the basal heart rate; and reduced the transient increase in MAP elicited by PTZ, with no significant effect on the basal MAP. The data demonstrate that 1) propranolol possesses anticonvulsant activity against PTZ-induced seizure in the pig, and 2) the intraosseous route is a rapid and effective alternative venous access for propranolol administration in swine.     

国产佐匹克隆抗惊厥作用的实验研究

目的　研究国产佐匹克隆（ Ｚ Ｐ Ｌ） 的抗惊厥作用。方法　在小鼠最大电休克发作（ Ｍ Ｅ Ｓ） 和戊四唑（ Ｐ Ｔ Ｚ） 惊厥试验中记录小鼠惊厥发生率;在大鼠点燃模型中记录大鼠行为发作强度和脑后放电时程（ Ａ Ｄ Ｄ） 。结果　 Ｚ Ｐ Ｌ（２０ ,４０ ｍｇ·ｋｇ － １ ,ｉｇ） 能对抗小鼠 Ｍ Ｅ Ｓ,惊厥率分别为３５ ％ 和１５ ％ （ Ｐ＜ ００１） ;在小鼠 Ｐ Ｔ Ｚ 惊厥试验中, Ｚ Ｐ Ｌ 延长了小鼠阵挛性抽搐的潜伏期,并降低强直性发作的发生率（ Ｐ＜ ００１） ; Ｚ Ｐ Ｌ（３０ ,５０ ｍｇ·ｋｇ － １ ,ｉｇ） 减弱了点燃大鼠行为发作强度,缩短 Ａ Ｄ Ｄ（ Ｐ＜ ００１） ,尤其３０ ｍｇ·ｋｇ － １ 剂量组在无明显中枢抑制作用时就能显著地抑制点燃效应。结论　国产佐匹克隆有明显的抗惊厥作用     

Blockade of the expression of sensitization and tolerance by ondansetron, a 5-HT3 receptor antagonist, administered during withdrawal from intermittent and continuous cocaine

 The present experiment evaluated the ability of the 5-HT₃ antagonist, ondansetron, administered during withdrawal from chronic cocaine administration, to block the expression of sensitization and tolerance induced by the intermittent or continuous administration of cocaine, respectively. Rats were pretreated with 40 mg/kg/per day cocaine for 14 days by either SC injections or osmotic minipumps, or 0.9% saline, administered via osmotic minipump. During the first 5 days of withdrawal from this pretreatment regimen, all rats received a daily SC injection of 0–1.0 mg/kg ondansetron. On day seven of with-drawal from the cocaine pretreatment (2 days after the final ondansetron injection) all subjects received a 15.0 mg/kg IP cocaine challenge. Their behavior was then rated according to the Ellinwood and Balster (1974) scale for 60 min. The results indicated that daily injections of ondansetron, on days 1–5 of withdrawal from the pretreatment regimen, had no significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron, on days 1–5 of withdrawal from intermittent cocaine administration, significantly blocked the expression of sensitization. In the continuous cocaine group, ondansetron injections, on days 1–5 of withdrawal from continuous cocaine administration, also blocked the expression of behavioral tolerance. The results therefore indicate that changes in 5-HT₃ receptor function are associated with the expression of tolerance and sensitization, respectively. Received: 1 April 1997/Final version: 28 July 1997     

Nicotinic activity in the interpeduncular nucleus of the midbrain prolongs recovery from halothane anesthesia

The influence of nicotinic transmission in the interpeduncular nucleus of the ventral midbrain on recovery from general anesthesia (3% halothane in oxygen) was assessed in rats. Immediately upon withdrawal of the anesthetic, nicotine (2 μl, 10⁻⁵ to 10⁻¹ M) was injected into the interpeduncular nucleus. Larger doses of nicotine (10⁻² and 10⁻¹ M) significantly (P < 0.05) prolonged the recovery of righting reflexes (to 371 ± 55 and 362 ± 67 sec, respectively, mean ± SE), compared with injection of saline (187 ± 19 sec). Prior intramuscular administration of the nicotinic antagonist, mecamylamine (2 mg/kg) significantly reduced the effect of 10⁻² M nicotine (to 211 ± 43 sec). Injection of the nicotinic antagonist, hexamethonium (10⁻¹ M) led to a low mean recovery time (181 ± 21 sec), not significantly different from control. Prolongation of recovery by 10⁻² M nicotine was not found to be significant when sites more dorsal to the interpeduncular nucleus were injected. An observed tendency for injection of nicotine to slow the post-anesthesia rate of breathing was not statistically significant and not correlated anatomically with the injection site in the midbrain. Increased release of acetylcholine has been shown previously to occur in the interpeduncular nucleus during anesthesia. The present results suggest that nicotinic activation of the interpeduncular nucleus facilitates or sums with the mechanisms in the brain that produce anesthesia under halothane.     

Behavioral and genotoxic evaluation of rosmarinic and caffeic acid in acute seizure models induced by pentylenetetrazole and pilocarpine in mice

The goal of this study was to investigate the effects of rosmarinic acid (RA) and caffeic acid (CA) in the acute pentylenetetrazole (PTZ) and pilocarpine (PIL) seizure models. We also evaluated the effect of RA and CA on the diazepam (DZP)-induced sleeping time test and its possible neuroprotective effect against the genotoxic damage induced by PTZ and PIL. Mice were treated intraperitoneally (i.p.) with saline, RA (2 or 4 mg/kg), or CA (4 or 8 mg/kg) alone or associated to low-dose DZP. After, mice received a single dose of PTZ (88 mg/kg) or PIL (250 mg/kg) and were monitored for the percentage of seizures and the latency to first seizure (LFS) >3 s. Vigabatrin and DZP were used as positive controls. In the DZP-induced sleeping time test, mice were treated with RA and CA and 30 min after receiving DZP (25 mg/kg, i.p.). The alkaline comet assay was performed after acute seizure tests to evaluate the antigenotoxic profiles of RA and CA. The doses of RA and CA tested alone did not reduce the occurrence of seizures induced by PTZ or PIL. The association of 4 mg/kg RA + low-dose DZP was shown to increase LFS in the PTZ model, compared to the group that received only the DZP. In the DZP-induced sleeping time test, the latency to sleep was reduced by 4 mg/kg RA and 8 mg/kg CA. The PTZ-induced genotoxic damage was not prevented by RA or CA, but the PIL-induced genotoxic damage was decreased by pretreatment with 4 mg/kg RA (in cortex) and 4 mg/kg CA (in hippocampus). In conclusion, RA and CA presented neuroprotective effect against PIL-induced genotoxic damage and reduced the latency to DZP-induced sleep. Of the rosmarinic acid, 4 mg/kg enhanced the DZP effect in the increase of latency to clonic PTZ-induced seizures.     

Morphine analgesia, tolerance and addiction in the cricket Pteronemobius sp. (Orthoptera, Insecta).

The escape reaction time (ERT) of the cricket Pteronemobius sp. from the heated box begins at 48° and increases with temperature until 56°C, beyond which there is no further increase. The ERT (2.2 ± 1.39 s) from the hot box at 54°C is used as a model for studying the analgesic effects of opiates. Results of the present paper show that the ERT did not change after injecting the insect in the abdominal haemocoel with 0.9% saline solution, but ERT increased when 0.32, 0.52 or 0.69 mg/g of morphine is injected in the same place. The maximum ERT increase is reached at 90 min after drug injection, and the drug effect disappears 3 h after the injection. At 90 min after drug injections, the dose of 0.50 mg/g of morphine produces 50% of ERT increase, and it is referred to as the median analgesic dose (D₅₀). 1.05 mg/g of morphine produces an ERT longer than 30 s that results in an irreversible damage to the insect. Sixty-four μg/g of naloxone given in addition to D₅₀ of morphine fully blocked the effect of morphine during its 3-h action. However, more than 64 μg/g of naloxone alone also increase the ERT in the cricket, similar to what has been described for vertebrates. Four daily morphine injections of D₅₀ decreased ERT in such a way that, at the fourth day, the ERT is similar to the ERT produced by saline solution; i.e., tolerance is shown. The suppression of daily morphine injections of D₅₀ during the fifth day produced a hyperresponse to vibration (big jumps) not shown in the case of the injections of saline solution; i.e., addiction is shown.