Effects of GABA(B) receptor antagonists on spontaneous and on GABA-induced mechanical activity of guinea-pig smooth muscle preparations.

The majority of GABA(B) receptor antagonists have been based on alterations of the acidic moiety of gamma-aminobutyric acid (GABA) or baclofen, such as the first selective antagonist phaclofen. More recently, a new structural class of compounds derived by p-alkyl substitution in the phosphinic analog of GABA, such as CGP35348 (3-amino-propyl-(diethoxymethyl)-phosphinic acid), have been introduced as GABA(B) receptor antagonists. The present study examine the influence of a series of structurally related phosphinic acid analogues on mechanical activity and their effect on GABA-induced reactions in ileal smooth muscle. In our experiments, GABA exerted a biphasic contractile-relaxation effect with pronounced dose-dependent characteristics. 3-[[1-(S)-(3,4-Dihydrophenyl) ethyl]amino]-2-(S)-hydroxy-propyl]-(phenylmethyl)-phosphinic acid hydrochloride (CGP55845A) induced prolonged relaxation without changing the phasic activity of the ileum preparations. [3-[1-R-[[2-(S)-hydroxy-3-[hydroxy-4-methoxyphenyl]-methyl]-phosphinyl]-propyl]-aminoethyl]-benzoic acid (CGP62349) did not change the mechanical activity of smooth muscle preparation. Trans 3-[6-[[Cyclo hexylmethyl-hydroxy-phosphinyl]-methyl]-3-morpholinyl]-benzoic acid (CGP71982) itself induced smooth muscle contractions. GABA(B) receptor antagonists decreased concentration-dependently the relaxation phase of the action of GABA from 50% to 90%. Their effect on the contractile phase of the action of GABA was quite different-CGP55845A decreased it dose-dependently, whereas CGP62349 and CGP71982 did not change it significantly. These findings prompted us to assume that the GABA(B) receptor antagonists studied, being phosphinic analogues, probably act on GABA(B) receptors in guinea-pig ileum smooth muscles.

Effects of high-affinity GABAB receptor antagonists on active and passive avoidance responding in rodents with gamma-hydroxybutyrolactone-induced absence syndrome.

RATIONALE: Absence seizures in man are behaviourally manifested as arrest and mild jerks mainly of facial muscles, associated in the electroencephalogram with synchronous spike and wave discharges. Gamma-hydroxybutyrolactone (GHBL) administration is currently used as an experimental model of absence seizures in rats and mice. OBJECTIVE: The aim of the present study was to examine the effects of three potent gamma-aminobutyric acid (GABA)B receptor antagonists CGP55845A, CGP62349 and CGP71982 (0.01 mg/kg) on the development of GHBL-induced absence epilepsy and in learning paradigms of active and passive avoidance tests in GHBL-treated mice and rats. METHODS: After 4 weeks of development of the absence syndrome, active and passive avoidance tests with negative reinforcement were performed. In both animal species, the absence syndrome was observed after 3 weeks of treatment in the saline group. RESULTS: The GABAB receptor antagonists CGP55845A and CGP62349 appeared to suppress the development of the absence syndrome to a greater degree in mice than in rats. CGP71982 suppressed it later than the other two antagonists (fifth week). In an active avoidance test in GHBL-treated mice, the GABAB antagonists had different effects - CGP62349 improved learning and memory retention to a greater extent than CGP55845A, whilst CGP71982 had no influence on it. In a passive avoidance test in GHBL-treated mice, the GABAB antagonists also had different effects - CGP71982 improved both learning and memory retrieval, whereas CGP55845A and CGP62349 had no effect. In the active avoidance test in GHBL-treated rats, the GABAB antagonist CGP55845A improved learning, whereas the other two, CGP62349 and CGP71982, had no effect. In the passive avoidance test the GHBL-treated rats showed an improvement in short memory retrieval. CGP55845A and CGP71982 improved this further, whilst CGP62349 had no effect. CONCLUSIONS: GHBL appeared to influence mice and rats in a different manner - rats learned the active avoidance task better than the GHBL-treated mice. The present study confirms previous data that GABAB antagonists suppress absence behaviour.

Effects of ACE-inhibitors on learning and memory processes in rats.

INTRODUCTION: Besides their well known effect on systemic blood vessels and heart, ACE inhibitors are supposed to have an effect on CNS by changing the local peptide-protein system. AIM: To study the effect of ACE-inhibitors on learning and memory processes using active and passive avoidance. MATERIAL AND METHODS: Male Wistar rats were used; the animals were divided into 4 groups of 20 animals each. Distilled water (group C), captopril 1.5 mg/kg (group E1), trandolapril 2 mg/daily (group E2), and oxiracetam 0.1 mg/kg (group E3), respectively, were given orally 60 minutes before the test. Active (shuttle box) and passive (step-through) avoidance tests with standard configuration were used. RESULTS: The experimental and control animals increased the number of avoidances during the learning session of the active avoidance test; groups C, E1 and E2 showed no change in the number of escapes and intertrial crossings; in group E3 animals both variables were decreased. In memory retention test the experimental animals increased the number of avoidances in comparison to the controls. No difference was found in the number of escapes and intertrial crossings. In passive avoidance test all animals showed prolonged latencies during the learning session. In the early and late retention test prolonged latencies were found only in the experimental animals. CONCLUSION: The ACE inhibitors captopril and trandolapril improve learning and memory in active and passive avoidance tests comparable to the effect of the nootropic drug oxiracetam.

Effects of the anticholinesterase drug tacrine on the development of PTZ kindling and on learning and memory processes in mice.

INTRODUCTION: The anticholinesterase drug tacrine (Tac) is known to have a beneficial effect on memory deficit in mice involving in the process the cholinergic system in the brain. Chemically induced kindling is a well-known model of petit mal epilepsy. Kindling develops after repeated administration of subconvulsant doses of pentylenetetrazole (PTZ). This model is suitable for studying the two CNS disturbances associated with epilepsy, i.e. seizure attacks and memory impairment. OBJECTIVE. The aim of the present study was to examine the effect of the anticholinesterase drug Tac on the model of PTZ kindling and on active avoidance in mice. METHODS. Kindling was induced by repeated administration of PTZ (40 mg/kg) s.c. at 48-hour intervals. Tac (at doses of 0.1, 0.5 and 1 mg/kg) was injected 40 minutes before PTZ over an 8 - week period in 4 experimental groups of mice. Seizure intensity was scored using a 5-grade scale. Kindling was defined as 3, 4 or 5 grade seizures evoked by 3 consecutive doses of PTZ and treatment was discontinued. The active avoidance method (training session consisting of 50 trials) was used to test learning and memory functions. On day 7 following the learning session a memory retention test was performed. The challenge dose of PTZ was given after a 15-day discontinuation of treatment. RESULTS: In control mice, kindling was developed over a 7-week period of treatment. Mice injected with Tac (in 3 consecutive doses) showed increased seizure intensity from week 1 through week 7 of the study. On learning and memory retention tests kindled mice showed a reduced learning capabilities whereas a statistically significant upward tendency in the number of conditioned responses (avoidances) was recorded in mice treated with Tac (1 mg/kg), when compared with the controls. Mice treated with Tac (in doses of 0.1 and 0.5 mg/kg) also exhibited an increased number of avoidances on learning and memory retention tests. CONCLUSIONS: 1. The anticholinesterase drug Tac increased the seizure intensity and facilitated the development of PTZ kindling in mice. 2. On the basis of well-developed kindling Tac did not impair the memory of the experimental animals, which is possibly due to its CNS stimulating effect.

Influence of carbamazepine-10,11-epoxide on the serum level of valproic acid in epileptic patients on combined treatment with carbamazepine and valproic acid.

INTRODUCTION: Possible drug interactions in comedication have been the focus of intensive studies in the last decade. Polytherapy is often resorted to in epilepsy, and then the effect of factors such as gender, age, and metabolism should be taken into consideration. In this country, the anticonvulsant drugs used very frequently in a combined treatment of epilepsy are carbamazepine (CBZ) and valproic acid (VPA). The effect of CBZ is determined by the presence of its active metabolite carbamazepine-10.11-epoxide (CBZ-E) in blood serum. AIM: The purpose of the study was to find whether CBZ-E has any effect on the VPA serum level and whether this effect is age-dependent. MATERIAL AND METHODS: Blood samples from 52 epileptic patients on comedication with CBZ and VPA aged 3 to 53 years were examined. The patients were allocated into four age groups: preschool age (from 3 to 6 years)--9 patients; school age (from 7 to 14 years)--8 patients; adolescence (from 15 to 18 years)--11 patients, and adults (from 19 to 53 years)--24 patients. The serum levels of CBZ, CBZ-E, VPA were determined by gas chromatography. The ratio CBZ-E/CBZ of every patient was calculated. RESULTS: The CBZ and VPA levels we found were within the limits of their respective therapeutic ranges. The mean values of the serum level of the two drugs showed no statistically significant difference in the four age groups. In the school age group the mean values of CBZ and VPA were the lowest compared to the other age groups. CONCLUSIONS: The effect of CBZ-E serum level upon VPA serum level is age-dependent. In preschool age VPA manifests itself as inhibitor of CBZ-E metabolism. The ratio CBZ-E/CBZ does not affect the VPA serum level in combined therapy with these two drugs.

Effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on convulsive seizures.

Endothelins (ET-1 and ET-3) are produced in the brain and may act as neuropeptides. The effects of two endothelins (ET-1 and ET-3) were investigated using pentylenetetrazole- (PTZ), strychnine- (STR), picrotoxin- (PIC) and bicuculline-induced (BIC) convulsions. ET-1 did not exert any anticonvulsive effect. ET-3, being more specific for the brain, showed anticonvulsive activity on PTZ and BIC seizures, but not on PIC and STR seizures. Different mechanisms underlie the action of the convulsants. PTZ, BIC and PIC realized their convulsive effects through the GABAergic inhibitory transmitter system; STR exerted an excitatory effect on the spinal cord by blocking the glycine transmitter system. The results suggest that the anticonvulsive effects of ET-3 might be due to an indirect influence on the GABAergic system in the brain.

Comparative studies on the central effects of the angiotensin II analogue (Sar1 azaVal3 Ile8) AT II.

The effects of the newly-synthesized AT II analogue (Sar1 azaVal3 Ile8) AT II were investigated in comparison with the octapeptide AT II and the analogue saralazin (Sar1 Ala8) AT II, using intracerebroventricular administration, with respect to the following parameters: the level of biogenic monoamines (DA, NA and 5-HT) and the metabolites HVA and 5-HIAA in mouse forebrain; the behaviour of the animals--cataleptogenic actions of mice, PTZ convulsive--seizure threshold in mice, apomorphine stereotypy in rats and behaviour of rats in a conflict situation. The analogue (Sar1 azaVal3 Ile8) AT II, unlike saralazin and AT II, was found to induce a rise in the NA and 5-HT levels, causing also catalepsy that is different from the catalepsy induced by saralazine, AT II and haloperidol, because of its rapid onset and decline; it increases the PTZ convulsive--seizure threshold and reduces the number of punished responses to the conflict drinking test (anxiomimetic effect) in a dose 20 times lower than the dose inducing the remaining effects. This effect was antagonized by saralazine. It is concluded that the newly-synthesized analogue (Sar1 azaVal3 Ile8) AT II induces effects similar to those caused by AT II, being at the same time different to a certain extent from the effects (quantitative and qualitative) of octapeptide AT II.