Scopolamine-induced convulsions in fasted mice after food intake: determination of blood glucose levels, [3H]glutamate binding kinetics and antidopaminergic drug effects.

The present study was performed to evaluate the role(s) of hypoglycemia, changes in [(3)H]glutamate binding kinetics and dopaminergic activity in the occurrence of scopolamine-induced convulsions in fasted mice after food intake. Plasma glucose levels and density (B(max)) and affinity (K(d)) of [(3)H]glutamate binding sites in whole brain synaptic membranes were determined in animals fed ad lib or fasted for 48 h and treated intraperitoneally (i.p.) with 3 mg/kg scopolamine or saline and allowed to eat for 5 min. Fasting for 48 h decreased plasma glucose levels. After refeeding, plasma glucose concentrations increased in saline treated animals, but remained unchanged in scopolamine treated animals which consumed less food. Fasting for 48 h also produced significant changes in the kinetics of [(3)H]glutamate binding. The B(max) and K(d) of the binding sites decreased in fasted animals. These changes were partially antagonized by scopolamine treatment and food intake. For the evaluation of the contribution of dopaminergic activity, another group of mice fasted for 48 h and pretreated (i.p.) with saline or dopamine antagonists, 2 mg/kg chlorpromazine or 2 or 4 mg/kg haloperidol, were treated 10 min later with either saline or 3 mg/kg scopolamine. Then 20 min later, they were allowed to eat ad lib and were observed for 30 min for the incidence and onset of clonic convulsions. Pretreatment of both 2 mg/kg chlorpromazine and 4 mg/kg haloperidol markedly suppressed the convulsions. These results indicate that the decrease in the [(3)H]glutamate binding induced by fasting, its antagonism by scopolamine treatment and food intake, and the dopaminergic hyperactivity may be possible factors contributing to the occurrence of convulsions.

Therapeutic drug monitoring in Turkey: experiences from Istanbul.

Therapeutic drug monitoring (TDM) has assumed an important place in patient management in the last few decades. In this study, serum drug levels determined in 7759 specimens sent to the Department of Pharmacology and Clinical Pharmacology in 1994 and 1998 for TDM were retrospectively evaluated. Monitored drugs were carbamazepine, valproate, phenytoin, phenobarbital, digoxin, theophylline, and salicylate. The comparison of the results obtained for the relevant 2 years showed that there was a remarkable increase in the number of requests for TDM per year and in the rate of serum drug levels that were within therapeutic range. Serum antiepileptic drug level monitoring accounted for a major part of the data. Overall data suggest that the use of TDM in antiepileptic drugs is improving; conversely, digoxin and theophylline are still not being properly monitored. In this study, the results are discussed in the light of rational TDM criteria.

Scopolamine-induced convulsions in food given fasted mice: effects of clonidine and tizanidine.

We recently reported that scopolamine pretreated mice fasted for 48 h developed clonic convulsions soon after they were allowed to eat ad libidum. Pretreatment with MK-801, the non-competitive NMDA antagonist, decreased the incidence of these convulsions. We suggested that a possible scopolamine-induced glutamatergic hyperactivity could account for these convulsions. Using alpha2-agonists, clonidine, which has been shown to inhibit glutamate release, and tizanidine, the present study was performed to find some additional data for the role of glutamate in the underlying mechanism of scopolamine-induced convulsions in food given fasted mice. Animals fasted for 48 h and pretreated (i.p.) with saline, clonidine (0.05, 0.10, 1 mg/kg) or tizanidine (0.10, 0.15, 0.30, 0.45 mg/kg) were treated (i.p.) with either saline or scopolamine (3 mg/kg). Then 20 min later, they were allowed to eat ad libidum and were observed for 30 min for the incidence and onset of clonic convulsions. All doses of clonidine pretreatment completely suppressed (0%) scopolamine-induced clonic convulsions (75%). On the other hand, only 0.15 mg/kg tizanidine pretreatment significantly decreased (15%) the incidence of convulsions; however as well as 0.15 mg/kg, both 0.30 and 0.45 mg/kg tizanidine pretreatments significantly increased latency to the onset of convulsions.

The importance of the number of NMDA receptors in the development of supersensitivity or tolerance to and dependence on morphine.

Opiate or NMDA receptor antagonists given during and/or after the development of tolerance and dependence have been reported to prevent these developments. In the present study, MK801 (dizolcipine) and naltrexone (NX), two antagonists of NMDA and opiate receptors, respectively were used in rats to find any correlations between changes in NMDA receptor kinetics, and the intensity of tolerance and dependence. Thus, six different groups of rats were formed. The rats in the groups were given saline (S)+S, S+morphine (M), NX+S, NX+M, MK801+S and MK801+M, respectively, once per day for 8 days. On day 9, the rats from each group were divided into four subgroups. The rats of the first subgroup were subjected to the determination of tail-flick latency. The rats of the second subgroup were administered 1 mg kg-1 naloxone (NL) 2 h after administration of 3 mg kg-1M. The rats of the third subgroup were implanted with two M pellets and after 72 h they were challenged with NL. The remaining rats received drugs also on day 9 according to the previous administration paradigm. Two hours after the administrations, their brains were utilised for the determination of NMDA receptor kinetics, employing [3H]glutamate. The measurement of tail-flick latency showed the prevention by NX or MK801 of the development of tolerance to M. The rats, which were administered 3 mg kg-1M 2 h before 1 mg kg-1 NL injection, on day 9 showed that only NX given previously along with M attenuated the intensity of the development of M dependence. NX administered alone intensified the development of dependence on a single dose of M. The development of M dependence upon the M pellet implantation was intensified by the previous administration of NX or MK801 concomitantly with M. The administration of M or MK801 alone, or NX together with M, caused significant upregulation of NMDA receptors. NX alone, and MK801 given concurrently with M led to a significant downregulation. So, in light of the previous findings and the present experimental data it can be said that: (1) supersensitivity to opioids may be a downregulation of NMDA as well as an upregulation of the opioid receptor; (2) either upregulation or downregulation of NMDA receptors may facilitate subsequent development of opioid dependence; (3) tolerance to opioid may necessitate both upregulation of NMDA receptors and downregulation of opioid receptors; and (4) beneficial effects of opioid antagonists in the treatment of opiate dependence and CNS injuries may be strongly related to the down regulation of NMDA receptors.

N-methyl-D-aspartate antagonists, glutamate release inhibitors, 4-aminopyridine at neuromuscular transmission.

It is thought that glutamate (GLU) and acetylcholine (ACh) are co-released in the neuromuscular junction (NMJ). Consequently, GLU is also a mediator or modulator of neuromuscular transmission (n-m) together with ACh. Therefore we decided to investigate the role of GLU in n-m by using isolated rat phrenic nerve-hemidiaphragm preparations. Since the GLU receptors present at NMJ have been reported to be predominantly N-methyl-D-aspartate (NMDA) subtype, some non-competitive and competitive NMDA receptor blockers, MK801, ketamine, dextromethorphan and CGP 37849, and GLU release inhibitors, clonidine, guanfacine, tizanidine were used at their optimum concentrations in medium after having found them from dose-response curves. The preparations were first stimulated indirectly in the presence of the optimum concentrations of the drugs used and tensions developed were recorded isometrically through a force displacement transducer on a polygraph linked to a computer + Math coprocessor by an analog converter. All drugs at their optimum concentrations suppressed contractions significantly. Prolyl-glycinamide (PLG) or phenyl-succinate, both of which are the inhibitors of GLU production also suppressed the contraction significantly, following depletion of GLU stores by tetanic contraction in nerve endings. 4-Aminopyridine, which has been shown to release GLU augmented the contractions which were also completely abolished by the NMDA receptor antagonists or GLU release inhibitors at their higher concentrations than their optimum ones. The direct stimulation of the muscles elicited statistically insignificant but higher contractions than controls at the optimum concentrations of the antagonists or inhibitors in medium. The results were discussed and it was concluded that blockade of NMDA receptors, the inhibition of GLU released or the suppression of GLU production inhibit the contractions of the rat-isolated hemidiaphragms elicited by indirect electrical stimulation, without altering acetylcholinergic part of the contraction cascade.

Scopolamine-induced convulsions in food given fasted mice: effects of physostigmine and MK-801.

We recently reported that scopolamine pretreated mice fasted for 48 h developed clonic convulsions soon after they were allowed to eat a small amount of food for 30 s. The present experiments were performed to determine whether animals also develop convulsions when they were allowed to eat ad libitum and to find some evidence for the contribution of the cholinergic and/or glutamatergic systems in the underlying mechanism(s) of convulsions. Animals fasted for 48 h were treated with 3 mg/kg scopolamine or saline. Twenty minutes later, they were allowed to eat either ad libitum or a small portion of food for 30 s. Scopolamine pretreated animals after starting to eat ad libitum or a small amount in a restricted time developed convulsions in a few minutes, the incidence being 76 and 54%, respectively. Pretreatment of 0.17 mg/kg MK-801, the noncompetitive NMDA antagonist, decreased the incidence of scopolamine-induced convulsions (22%) without affecting latency to the onset of seizures. Pretreatment of 0.1 mg/kg physostigmine, the cholinesterase inhibitor, changed neither the incidence (90%) nor latency to the onset of scopolamine-induced convulsions.