The dopamine D1 receptor agonist and D2 receptor antagonist LEK-8829 attenuates reinstatement of cocaine-seeking in rats.

Various dopaminergic drugs have been studied for their efficacy in the treatment of cocaine addiction. Pretreatment with either selective dopamine D1 receptor agonists or selective dopamine D2 receptor antagonists prevents reinstatement of cocaine-seeking in animal models of drug craving and relapse. We tested a novel ergoline derivative with combined D1 agonistic and D2 antagonistic effects, 9,10-didehydro- N-methyl- N-(2-propynyl)-6-methyl-8beta-aminomethylergoline bimaleate (LEK-8829), for its effects on cocaine-seeking in the intravenous cocaine self-administration model in rats.

Modulation of neuroleptic activity of 9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8-aminomethylergoline bimaleinate (LEK-8829) by D1 intrinsic activity in hemi-parkinsonian rats.

Parkinsonism, a common unwanted side effect of typical antipsychotic (neuroleptic) drugs, is induced by the blockade of striatal dopamine D2 receptors. In rats with hemi-parkinsonism induced by unilateral lesion of dopaminergic nigrostriatal neurons with 6-hydroxydopamine, D2 antagonists inhibit contralateral turning induced by D2 agonists and augment the levels of neurotensin mRNA in dopaminergically intact striatum. By contrast, D1 agonists induce contralateral turning and augment neurotensin mRNA levels in dopamine-depleted striatum.

Cardiovascular physiology: simulation of steady state and transient phenomena by using the equivalent electronic circuit.

By using commercially available software it is readily possible to design electronic circuits and to analyze them. By introducing the concept of equivalent quantities a simulation of various physiological phenomena is possible. This includes the steady state as well as various complex transient phenomena.

N-tert-butyl-alpha-phenylnitrone, a free radical scavenger with anticholinesterase activity does not improve the cognitive performance of scopolamine-challenged rats.

Reversible inhibitors of acetylcholinesterase improve spatial learning and memory in animal models of cognitive impairment. Here we investigate if the beneficial effects of free radical scavenger N-tert-butyl-alpha-phenylnitrone (PBN) on cognitive performance could be explained by its recently discovered anticholinesterase activity. Morris water maze experiment was performed to examine the effect of PBN on the impairment of spatial learning and memory induced by the antagonist of cholinergic muscarinic transmission scopolamine.

Dopaminergic regulation of synaptotagmin I and IV mRNAs in hemiparkinsonian rats.

Synaptotagmins (Syts) I and IV are synaptic proteins involved in the regulation of neurosecretion. Dopaminergic drugs have been shown to modulate their expression. Here we investigate whether dopaminergic regulation of syt I and syt IV expression could play a role in the hypersensitive striatum of rats with unilateral lesions of dopaminergic nigrostriatal neurons with 6-hydroxydopamine.

Ergoline derivative LEK-8829-induced turning behavior in rats with unilateral striatal ibotenic acid lesions: interaction with bromocriptine.

LEK-8829 [9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8- aminomethylergoline bimaleinate] is an antagonist of dopamine D2 receptors and serotonin (5-HT)2 and 5-HT1A receptors in intact animals and a D1 receptor agonist in dopamine-depleted animals. In the present study, we used rats with unilateral striatal lesions with ibotenic acid (IA) to investigate the dopamine receptor activities of LEK-8829 in a model with innervated dopamine receptors. The IA-lesioned rats circled ipsilaterally when challenged with apomorphine, the mixed agonist on D1/D2 receptors.

The effects of kainic acid in rats with spontaneous recurrent seizures.

1. Rats with spontaneous recurrent seizures (SRS) were obtained by injection of kainic acid (KA; 10 mg/kg SC) to drug-naive rats that regularly developed wet-dog shakes followed by complex partial seizures and status epilepticus. Three to five weeks later, the rats with manifest SRS were selected.

Antiparkinsonian potential of interaction of LEK-8829 with bromocriptine.

The ergoline derivative, LEK-8829 (9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8-aminomethylerg oline), has been proposed as a potential atypical antipsychotic drug with antagonistic actions at dopamine D2 and serotonin 5-HT2 and 5-HT1A receptors (Krisch et al., 1994, 1996). LEK-8829 also induces contralateral turning in rats with 6-hydroxydopamine-induced unilateral lesion of dopamine nigrostriatal neurons.

The D1 receptor-mediated effects of the ergoline derivative LEK-8829 in rats with unilateral 6-hydroxydopamine lesions.

1. Previous experiments have suggested a potential atypical antipsychotic activity of the ergoline derivative LEK-8829. In vitro experiments showed a high affinity to 5-HT1A, 5-HT2 and D2 receptors (the ratio of pKi values 5-HT2/D2 = 1.

Application of the nonradioactive in situ hybridization for the localization of acetylcholinesterase mRNA in the central nervous system of the rat; comparison to the radioactive technique.

In this preliminary report nonradioactive digoxigenine-based and radioactive in situ hybridization procedures for the localization of acetylcholinesterase mRNA were tested and compared in rat brain. General patterns of Ache mRNA localization observed by both techniques did not differ significantly and were practically the same as reported in previous in situ studies on the mammalian brain. Shorter procedure time and avoidance of precautions necessary at work with radioactive materials are major advantages of nonradioactive technique.

Pharmacological studies with two new ergoline derivatives, the potential antipsychotics LEK-8829 and LEK-8841.

The pharmacological properties of 9,10-didehydro-N-methyl-N-(2-propynyl)-6-methyl-8 beta-aminomethylergoline (LEK-8829) and 9,10-didehydro-N-methyl-N-(2-propynyl)-2-bromo-6-methylergoline -8-beta-carboxamide (LEK-8841), new ergoline derivatives, were compared with those of haloperidol and clozapine by in vitro radioligand displacement assays, various behavioral tests and blood pressure measurements. Both ergolines displayed low affinity for rat striatal 3H-SCH23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pin e)- labeled dopamine (D)1 binding sites and high affinity for striatal 3H-spiperone-labeled D2 and cortical 3H-ketanserin-labeled serotonin-2 (5-HT2) sites. The ratio of pKi values 5-HT2/D2 was 1.

Comparison between the effects of botulinum toxin-induced paralysis and denervation on molecular forms of acetylcholinesterase in muscles.

Velocity sedimentation analysis of acetylcholinesterase (AChE) molecular forms in the fast extensor digitorum longus muscle and in the slow soleus muscle of the rat was carried out on days 4, 8, and 14 after induction of muscle paralysis by botulinum toxin type A (BoTx). The results were compared with those observed after muscle denervation. In addition, the ability of BoTx-paralyzed muscles to resynthesize AChE was studied after irreversible inhibition of the preexistent enzyme by diisopropyl phosphorofluoridate.

Efficacy of antidotes against soman poisoning in female physostigmine-protected rats.

Female rats have been found much more sensitive to lethal effects of soman than male rats. Therefore it was of interest to examine the efficacy of different antidotes against soman poisoning in females which are usually not being used in soman poisoning studies. The effects of acetylcholinesterase (AChE) non-reactivating antidotes atropine and diazepam were analyzed in combination with physostigmine prophylaxis against supralethal doses of soman.

Prevention of diisopropylphosphorofluoridate-induced myopathy by botulinum toxin type A blockage of quantal release of acetylcholine.

Botulinum toxin type A (BTx), which blocks quantal and partially reduces spontaneous nonquantal acetylcholine (ACh) release at neuromuscular junctions, was tested for its possible attenuating effect on diisopropylphosphorofluoridate (DFP)-induced muscle lesions. The extent of muscle lesion in extensor digitorum longus and soleus muscle of DFP injected rats with and without BTx pretreatment was evaluated using light and electron microscopic procedures. In parallel experiments, acetylcholinesterase (AChE) activity was measured and the functional state of muscles in experimental groups was determined by electrophysiological methods.

In vivo degradation of noradrenaline by MAO A in locus coeruleus of the rat.

Depletion of noradrenaline in locus coeruleus neurons after reserpinization was prevented by clorgyline, a selective inhibitor of MAO A, but not by deprenyl, a selective inhibitor of MAO B. Only MAO A is therefore responsible for the degradation of homoneuronal noradrenaline in locus coeruleus nerve cells.

Attenuation of soman-induced lesions of skeletal muscle by acetylcholinesterase reactivating and non-reactivating antidotes.

It has been reported recently that some oximes reactivating acetylcholinesterase (AChE) exhibit concomitant ganglion-blocking effects which presumably could contribute independently to their powerful antidotal action in organophosphate inhibitor (OPI) poisoning, thus mimicking some unrelated substances which are effective antidotes without reactivating AChE. This raises the question whether OPI-induced muscle lesions, like some other symptoms could also be attenuated by oximes and other antidotes in the absence of AChE reactivation. To test this possibility, the oxime HI-6 was applied at increasing time intervals after the injection of soman until and beyond the point when soman-AChE complex becomes completely "aged" and not capable of reactivation.

Iso-OMPA-induced potentiation of soman toxicity in rat correlates with the inhibition of plasma carboxylesterases.

Recently, the question was raised as to why iso-OMPA, generally known as a selective irreversible inhibitor of butyrylcholinesterase (BuChE), potentiates soman toxicity in rats but not in mice. Mice are known to have higher carboxylesterase (CarbE) and lower BuChE activity in plasma than rat. It could be hypothesized that it is the iso-OMPA inhibition of plasma CarbE, and not of BuChE, which is responsible for potentiation of soman toxicity in iso-OMPA-pretreated rats.

Effect of HI-6, applied into the cerebral ventricles, on the inhibition of brain acetylcholinesterase by soman in rats.

When applied to rats (intraperitoneally) immediately after subcutaneous injection of soman (120 micrograms/kg) HI-6 (100 mg/kg) protected about 40% of the activity of acetylcholinesterase (AChE) in the motor end plate region of the diaphragm but did not protect AChE in the brain. However, a partial protection of AChE in brain against inhibition by soman was obtained in anaesthetized, atropinized rats by the oxime injected into the cerebral ventricle 5 min before parenteral exposure to soman. The AChE activity in brain of rats pretreated with HI-6, analyzed 60 min after the injection of soman was between 10 and 19%, while that in non-protected animals did not exceed 1% of the control.

Cholinesterases in single nerve cells isolated from the locus ceruleus and from nucleus of the facial nerve of the rat: a microgasometric study.

Cholinesterase activity in single nerve cell bodies isolated from the locus ceruleus and nucleus of the facial nerve of the rat was analyzed by the microgasometric method. Acetylcholinesterase activity is about the same in both types of cells. Nonspecific cholinesterase is present in noradrenergic cells of the locus ceruleus but not in the cholinergic cells of the nucleus of the facial nerve.

Monoamine oxidase in single nerve cell bodies from locus coeruleus of the rat. A microgasometric study.

The magnetic diver microgasometer was used for determination of MAO activity in single nerve cell bodies isolated from the locus coeruleus of the rat. Tyramine was used as a substrate. Both molecular forms of MAO, MAO A and MAO B, are present in single nerve cell as shown by clorgyline, a selective inhibitor of MAO A molecular form.

Presynaptic modulation of activity and molecular forms of acetylcholinesterase in the rat superior cervical ganglion during early postnatal development.

Preganglionic nerve trunk of the rat superior cervical ganglion was transected shortly after birth in order to evaluate the influence of preganglionic nerves on the development of acetylcholinesterase and choline acetyltransferase in ganglionic neurons. In spite of an early decentralization, specific activity of acetylcholinesterase in the ganglion is increasing during the first 3 wk of life until it is about equal to the activity which remains in the superior cervical ganglion decentralized in an adult animal. Thus, the preganglionic nerves, which per se contribute the presynaptic fraction of total ganglionic AChE activity in normal innervated ganglia, apparently exert no significant regulatory effect on the specific activity of the fraction of acetylcholinesterase affiliated with the developing ganglionic cells.

[Basic phospholipase of Naja nigricollis venom].

It is confirmed that N. nigricollis venom contains several phospholipases one of these is a basic phospholipase A. This enzyme is toxic for mice when injected intravenously.