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Biomedical subjects

J Knoll

Publications and source records attributed to J Knoll.

At least 217 records · Page 12Linked to original sources
PubMedDate not supplied

Serotonin-mediated behavior in rats chronically treated with (-) deprenyl.

(-) Deprenyl given in small (0.25 mg/kg) daily doses for 30 days to rats left the serotonin (5-HT) and the 5-hydroxyindoleacetic acid (5-HIAA) levels in the striatum unchanged. The postsynaptic 5-HT receptor responsiveness, as measured with 5-methoxy-N,N-dimethyl-tryptamine (5-MeODMT), remained also unaltered. In (-) deprenyl-treated rats the p-chloroamphetamine (PCA)-induced 5-HT syndrome was significantly increased and this enhancement of the PCA effect was not abolished by the reserpine-induced depletion of the 5-HT stores.

Animals↗
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Azidomorphines and heterogenous opiate receptors.

The N-cyclopropylmethyl derivative of azidomorphine (CAM) was found to have strong opiate agonist and antagonist activity, in various in vitro and in vivo animal tests. The derivatives of azidomorphine were not only more potent analgesics than the corresponding members of the morphine family but their lipid solubility was also markedly improved: the ratios of the median effective subcutaneous/intracerebroventricular doses are between 6.2-22.0 in the azido-group, while that of morphine is 381. The antagonist potencies of N-cyclopropyl-N-allyl azidomorphine derivatives were also quantitatively estimated in oxymorphone righting test, and were found to possess antagonists activity as potent as naloxone and more potent than other opiate antagonists (nalorphine, pentazocine Mr-1452 etc.). CAM also has been shown to produce depression of acetylcholine release from the cat lateral cerebral ventricle similarly to morphine, in a naloxone reversible manner, regardless the applied stimulus (electrical stimulation of sciatic nerve, or ouabain perfusion). CAM, similarly to bremazocine, the reported kappa opioid agonist drug, markedly increased the urinary output in normally hydrated rats. This effect was reversed by high dose of naloxone, suggesting the kappa agonist action of CAM.

Acetylcholine↗
PubMedDate not supplied

A new sensitive method which unlike the Vogel test detects the anxiolytic effect of tofisopam.

A new, more sensitive than previously used anxiolytic test is described. The test consists in measuring of inhibition by punishment of drinking water necessary to swallow dry food by very hungry rats. This test reveals the anxiolytic properties of tofisopam, a clinically effective benzodiazepine anxiolytic, and of very low doses of chlordiazepoxide, both ineffective in the Vogel test, as well as anxiolytic properties of high doses of chlordiazepoxide and other anxiolytics, and confirms the lack of anxiolytic effects of major tranquilizers. The results suggest that chlordiazepoxide (and possibly other benzodiazepines) acts on two subgroups of benzodiazepine receptors, named BRI (high affinity) and BR2 (low affinity), while tofisopam acts specifically on BRI receptors. The new test is proposed as a tool for a search for drugs specifically acting on high affinity benzodiazepine BRI receptors.

Animals↗
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The effect of (-) deprenyl (selegiline) on different behavioral changes induced by dopamine agonists in the rat.

The effect of (-) deprenyl was investigated both on the stereotyped behavior and on other types of activities induced by various dopamine (DA) agonists. (-) Deprenyl was given in a single dose, 1 h prior to the DA agonists. 1-2 mg/kg sc (-) deprenyl decreased the stereotypy induced by amphetamine (AMPH, 2.5 mg/kg sc), but 20 mg/kg was needed to reduce the stereotypy-inducing effect of apomorphine (APO, 0.3 mg/kg sc). The stereotypy-inducing effect of phenyl-ethyl-amine (PEA, 40 mg/kg sc) was significantly enhanced by 0.25 mg/kg sc (-) deprenyl pretreatment. The PEA or AMPH-induced increase in the horizontal activity (locomotion) and the vertical activity (rearing) remained unchanged after a single dose of (-) deprenyl, showing that this drug acts primarily on the nigro-striatal dopaminergic system.

Amphetamine↗
PubMedDate not supplied

The effect of repeated doses of (-) deprenyl on the dynamics of monoaminergic transmission. Comparison with clorgyline.

The action of clorgyline and (-)deprenyl on the dynamics of dopaminergic and serotonergic transmission in the rat brain was compared. It was found, that daily administration of 0.25 mg/kg sc clorgyline, a specific MAO A inhibitor, reduced the turnover rate of both dopamine and serotonin after two weeks of injections. The treatment for two or four weeks with 0.25 mg/kg sc (-)deprenyl, a specific MAO B inhibitor, enhanced the turnover rate of dopamine and the fractional rate constant of dopamine efflux, reflecting an increased utilization rate of this amine in the striatum. Beside the augmentation of the dopamine turnover rate, the dopaminergic tone was also elevated by the reduction of the dopamine uptake in the striatum. Two week injections with the same dose of (-)deprenyl did not change the dynamics of serotonergic transmission.

Animals↗
PubMedDate not supplied

The ejaculatory behavior of sexually sluggish male rats treated with (-)deprenyl, apomorphine, bromocriptine and amphetamine.

Bromocriptine (0.5 mg/kg) and apomorphine (0.03 mg/kg) exert moderate aphrodisiac effect in sexually sluggish rats. This effect appears rapidly and reaches its peak within 24 h. Amphetamine (2 mg/kg) acts similarly but with a more rapid onset and offset of the effect. A single dose of (-)deprenyl, a selective inhibitor of MAO-B, exerts a much more potent effect in this test.

Amphetamine↗
PubMedDate not supplied

The effect of various MAO-B inhibitors on rabbit arterial strip response to tyramine.

Studies on the response to tyramine of the rabbit pulmonal artery strip have revealed that several specific MAO-B inhibitors (TZ-650, J-580, AGN-1135, U-1424 MDL-72165 and Ro 16-6491) potentiated the responses in a dose-dependent manner, similarly as a semi-selective MAO-B inhibitor pargyline and a nonselective MAO inhibitor tranylcypromine did. Only (-)deprenyl inhibited the response. Thus the inhibition of noradrenaline-releasing effect of tyramine, a property favorable from the point of view of safety in clinical practice, is a specific feature of (-)deprenyl and not a more general characteristics of MAO-B inhibitors.

Animals↗
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Effects of selective monoamine oxidase (MAO) inhibitors on conditioned avoidance responses (CAR) of rats.

Dopamine (DA) insufficiency in the ipsilateral corpus striatum produced by unilateral electrolytic lesion of the substantia nigra (SN) resulted in an impairment in rats' behavior as tested by one-way and two-way avoidance techniques. Selective MAO-A inhibitor, clorgyline (1 mg/kg sc daily for 7 days), improved the reduced learning capacity of SN lesioned animals, restored the decreased DA content in the corpus striatum, and caused significant hyperactivity as tested in the open field. At the same time the selective MAO-B inhibitor (-)deprenyl (injected the same way) proved to be ineffective. J-508, a selective MAO-B inhibitor, used in a non-selective dose (1 mg/kg), acted like clorgyline. The results support the hypothesis that in the rat nigrostriated system (but not in human beings) DA is preferentially deaminated by the A form of MAO.

Animals↗
PubMedDate not supplied

Inhibition by deprenyl of dopamine uptake in rat striatum: a possible correlation between dopamine uptake and acetylcholine release inhibition.

Optical isomers of deprenyl inhibit the resting and ouabain induced release of acetylcholine (ACh) in isolated striatal slices of the rat and this effect correlates with the capability of deprenyl to inhibit the uptake of 3H-dopamine in striatal homogenate in a concentration of 10(-4)--10(-4) M. The release of ACh is significantly increased in striatal slices taken from rats pretreated with a single dose of 250 micrograms of 6-hydroxydopamine. 5 mg/kg of deprenyl given 30 min prior to 6-hydroxydopamine treatment prevented completely the chemical destruction of the dopaminergic neurons. In contrast to deprenyl, clorgyline potentiated the effect of 6-hydroxydopamine.

Acetylcholine↗
PubMedDate not supplied

The aphrodisiac effect of low doses of (-) deprenyl in male rats.

The effects of single doses of (-)deprenyl, in comparison to J-508, U-1424, pargyline and clorgyline, on the sexual performance of male rats were tested. (-)Deprenyl (0.25 and 1 mg/kg, respectively) exerted a true, long-lasting aphrodisiac effect, on sexually sluggish male rats, whereas clorgyline, U-1424 and J-508 failed to act similarly. Pargyline facilitated the sexual performance of the rats, but only transiently.

Animals↗
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Synthetic tripeptides with anorexogenic effect.

Thirty two synthetic tripeptides structurally related both to thyrotropin releasing hormone (TRH) and anorexogenic tripeptide (Glp-His-Gly-OH) were investigated for anorexogenic effect in rats. While the two endogenous peptides, TRH and Glp-His-Gly-OH, were ineffective in rats deprived of food for 96 hours when they were administered intracerebroventricularly, some of the synthetic analogues showed significant food intake reducing effect under the same conditions. This anorexogenic effect of the tripeptides is similar--though much weaker--to that of satietin, a highly potent anorexogenic glycopeptide in human and mammalian serum. These tripeptides were ineffective when they were administered intravenously.

Animals↗
PubMedDate not supplied

Multiple, small dose administration of (-)deprenyl enhances catecholaminergic activity and diminishes serotoninergic activity in the brain and these effects are unrelated to MAO-B inhibition.

As a measure of the basic activity of the catecholaminergic and serotoninergic systems, the biogenic amines released from freshly excised brain tissue were measured by means of HPLC with electrochemical detection. Rats of both sexes were injected subcutaneously, daily for 21 days, either with saline or with a dose of one of the enantiomers of the following compounds: deprenyl; p-fluorodeprenyl; 1-phenyl-2-propylaminopentane, a deprenyl analogue free of MAO-B inhibitory potency; methamphetamine, the parent compound of deprenyl; and amphetamine, the parent compound of 1-phenyl-2-propylaminopentane. The release of the biogenic amines from brain tissue was measured 24 hours after the last injection. The effect of the two enantiomers of deprenyl was studied in five doses (0.01, 0.025, 0.05, 0.1 and 0.25 mg/kg), that of (-)1-phenyl-2-propylaminopentane in two doses (0.05 and 0.1 mg/kg), others in 0.05 mg/kg. Treatment with (-)deprenyl enhanced the release of dopamine from striatum, substantia nigra and tuberculum olfactorium (significant in 0.01-0.25 mg/kg) and the release of noradrenaline from the locus coeruleus (significant in 0.05-0.25 mg/kg), whilst the release of serotonin from the raphe was diminished (significant in 0.05-0.25 mg/kg in males and 0.25 mg/kg in females). (+)Deprenyl was slightly less potent than (-)deprenyl. Both p-fluorodeprenyl and 1-phenyl-2-propylaminopentane acted like deprenyl; the (+)enantiomers were more active than the (-)forms. (-)Methamphetamine was as potent as (-)deprenyl in enhancing the catecholaminergic activity and more potent than (-)deprenyl in diminishing the serotoninergic activity. (+)Methamphetamine was substantially less potent than (-)methamphetamine. (-)Amphetamine was as potent as (-)methamphetamine and (+)amphetamine was more potent than (+)methamphetamine in enhancing the catecholaminergic activity but neither (-)amphetamine nor (+)amphetamine diminished the serotoninergic activity. On the one hand, the results prove that the described effects of deprenyl are unrelated to MAO-B inhibition, on the other hand, they indicate the existence of hitherto unknown catecholaminergic and serotoninergic activity enhancer mechanisms in the brain, of which the former is stimulated and the latter inhibited by multiple, small dose administrations of deprenyl and related substances.

Amphetamine↗