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Biomedical subjects

D Marona-Lewicka

Publications and source records attributed to D Marona-Lewicka.

34 records · Page 2Linked to original sources
PubMed1994

1-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane: a potent serotonin 5-HT2A/2C agonist.

A method was found to synthesize 1-(2,5-dimethoxy-4-(trifluoromethyl) phenyl)-2-aminopropane, 5, and its des-alpha-methyl congener 2-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)aminoethane, 6, the trifluoromethyl analogs of substituted hallucinogenic phenethylamine derivatives such as 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3, DOI) that are potent 5-HT2A/2C agonists. In our hands, 5 and 6 have proven to have affinity for [3H]ketanserin or [125I]-3-labeled 5-HT2A/2C sites in rat cortex comparable to or higher than the analogous bromo or iodo analogs. Similarly, 5 and 6 had potency comparable to or slightly greater than that of their bromo or iodo congeners in the two-lever drug discrimination assay in rats trained to discriminate saline from LSD tartrate. The agonist properties of 5 and 6 were evaluated by measuring the accumulation of [3H]inositol monophosphate in cultured cells selectively expressing either 5-HT2A or 5-HT2C receptors. In comparison to serotonin (5-HT), compounds 3 (DOI), 5, and 6 were equally efficacious and full agonists at the 5-HT2C receptor. Similarly, 3 and 5 produced equivalent responses at the 5-HT2A receptor as compared to 5-HT. In contrast, 6, the alpha-desmethyl analog of 5, was only half as potent at stimulating inositol monophosphate accumulation at the 5-HT2A receptor. In conclusion, the title compound 5 and its alpha-desmethyl congener 6 appear to be the most potent of the so-called hallucinogenic amphetamine 5-HT agonists reported to date. Further, the reduced efficacy of 6 at the 5-HT2A receptor may offer at least a partial explanation for the observed higher in vivo potencies of alpha-methyl-substituted compounds in this series.

3T3 Cells↗
PubMed1994

Behavioral effects of the highly selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan.

The behavioral effects of 5-methoxy-6-methyl-2-aminoindan (MMAI) were examined using the drug discrimination procedure and direct observation for classification of the characteristic syndrome induced by MMAI. The stimulus effects of MMAI were studied in 5 different groups of rats trained to discriminate MMAI (1.71 mg/kg; 8 microM/kg), MDMA (3,4-methylenedioxymethamphetamine; 1.75 mg/kg; 7.6 microM/kg), (+)-MBDB ((+)-N-methylamino-(1,3-benzodioxo-5-yl)-2-butanamine; 1.75 mg/kg; 7.18 microM/kg), (+)-amphetamine (1 mg/kg; 5.4 microM/kg), or LSD ((+)-lysergic acid diethylamide tartrate; 0.08 mg/kg; 186 nM/kg) from saline. In substitution tests in rats trained to discriminate MMAI from saline, all the compounds which fully mimicked MMAI were serotonin (5-hydroxytryptamine, 5-HT) releasing agents. This substitution is symmetrical for MDMA and (+)-MBDB. Nevertheless, the dose-response curve of MMAI is parallel to those of (+)-fenfluramine (m-trifluoromethyl-N-ethylamphetamine) and p-chloroamphetamine. The results also show that MMAI lacks amphetamine-like and LSD-like discriminative stimulus effects, suggesting that MMAI is neither a psychostimulant nor a hallucinogen. Tests of the discriminability of MMAI after 5-HT depletion with the selective serotonin synthesis inhibitor, p-chlorophenylalanine (2 x 200 mg/kg i.p., pretreatment 72 h before test), showed only saline appropriate responding. Prolonged block (ca. 1 week) of the MMAI cue by p-chlorophenylalanine further supports the conclusion that endogenous 5-HT is essential for MMAI discrimination. Fluoxetine (10 mg/kg) or paroxetine (2.5 mg/kg), both selective 5-HT uptake inhibitors, reduced the discriminability of MMAI to 40% and 50%, respectively. None of the antagonists (ketanserin, methiothepin, pindolol, yohimbine, haloperidol) used in antagonism tests inhibited the stimulus properties of MMAI. These results and data from radioligand binding studies support the conclusion that direct activation or inhibition of known neurotransmitter receptors did not play a significant role in the discriminative cue of MMAI. The administration of 5, 10, or 20 mg/kg of MMAI to rats induced a behavioral syndrome consisting of hypolocomotion with accompanying catalepsy-like posture, turning, Straub tail, flat body posture, and suppressed sleeping time. In general, this is qualitatively similar to what is seen after administration of 5-HT precursors or 5-HT receptor agonists. In conclusion, the data from the drug discrimination study and the behavioral syndrome induced by MMAI suggest that MMAI is a potential selective releaser of serotonin.

3,4-Methylenedioxyamphetamine↗
PubMed1994

Drug discrimination and receptor binding studies of N-isopropyl lysergamide derivatives.

Isopropyl (IPLA), N-methyl-N-isopropyl (MIPLA), N-ethyl-N-isopropyl (EIPLA), and N,N-diisopropyl (DIPLA) lysergamides were evaluated for lysergic acid diethylamide (LSD)-like activity. In rats trained to discriminate 0.08 mg/kg LSD tartrate from saline, each of the subject compounds completely substituted, with an ED50 two to three times larger than that of LSD except for DIPLA, which had an ED50 about eightfold greater. Similarly, all the compounds displaced [125I](R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ([125I]DOI) from rat cortical homogenates and displaced [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) from rat hippocampal homogenates with KI values similar to those of LSD, again with the exception of DIPLA, which had about nine- and fourfold lower affinities, respectively. Interestingly, all the compounds had four- to fivefold lower affinities than LSD in displacing [3H]ketanserin from 5-HT2 binding sites. Molecular modeling studies found that all the compounds had low energy conformations similar to LSD. No correlation between the activity of the compounds and the preferred conformation of the amide substituents was apparent. In summary, N-alkyl-N-isopropyl analogs of LSD retain LSD-like activity in drug discrimination and 5-HT1A and 5-HT2 agonist binding assays only until the N-alkyl substitution is as large as ethyl; LSD-like activity dramatically drops when the second alkyl substituent is N-isopropyl.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Synthesis and pharmacological examination of benzofuran, indan, and tetralin analogues of 3,4-(methylenedioxy)amphetamine.

Benzofuran, indan and tetrahydronaphthalene analogs of 3,4-(methylenedioxy)amphetamine (MDA) were prepared in order to examine the role of the dioxole ring oxygen atoms of MDA in interacting with the serotonin and catecholamine uptake carriers. The series of compounds was evaluated for discriminative stimulus effects in rats trained to discriminate saline from the training drugs (S)-(+)-MBDB (1c), MMAI (3), and (S)-(+)-amphetamine and for the ability to inhibit the uptake of [3H]serotonin, [3H]dopamine, and [3H]norepinephrine into crude synaptosome preparations. Behaviorally, the benzofuran and indan analogs 4-6 produced similar discriminative cues, whereas the tetralin derivative 7 did not fully substitute for the training drugs. The results in the in vitro pharmacology studies indicate that selectivity for 5-HT versus catecholamine uptake carriers may be modulated by the position and orientation of ring oxygen atoms. However, the nonoxygenated isostere 6 possessed high potency at all uptake sites examined. Enlargement of the saturated ring by one methylene unit to give the tetralin derivative resulted in a large (3-4-fold) reduction in activity at catecholamine sites.

3,4-Methylenedioxyamphetamine↗
PubMed1993

Novel serotonergic agents.

The preliminary structure-activity relationships are described for a series of substituted phenethylamines that induce the release of neuronal serotonin. Structures that also have the ability to release neuronal catecholamines are toxic to serotonin neurons, leading to long-term reductions in serotonin markers in rat brain. Conversely, compounds that are selective for the serotonin uptake carrier, and do not affect catecholamines, are not neurotoxic. It is suggested that these novel, selective serotonin releasing agents may find therapeutic utility in disorders where serotonin uptake inhibitors are currently employed.

Neurons↗
PubMed1992

p-methylthioamphetamine is a potent new non-neurotoxic serotonin-releasing agent.

p-Methylthioamphetamine (MTA), was compared to p-chloroamphetamine (PCA) in a number of pharmacological assays. MTA was about 2-fold more potent than PCA at inhibiting synaptosomal uptake of [3H]5-hydroxytryptamine ([3H]5-HT), and about 7-fold and 10-fold less potent than PCA at inhibiting synaptosomal uptake of [3H]dopamine and [3H]norepinephrine, respectively. In drug discrimination assays, MTA was nearly equipotent to PCA in animals trained to discriminate saline from 3,4-methylenedioxymethamphetamine (MDMA), or two related analogues S-(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (S-MBDB) or 5-methoxy-6-methyl-2-aminoindan (MMAI). MTA caused dose-dependent increases of tritium efflux from superfused rat frontal cortex slices preloaded with [3H]5-HT, comparable to that induced by an equal molar concentration of PCA. The potential neurotoxicity of MTA was examined by measuring monoamine and metabolite levels at one week following an acute dose. A 10 mg/kg dose of PCA caused a 70-90% decrease of cortical, hippocampal and striatal 5-HT and 5-hydoxyindoleacetic acid (5-HIAA) levels, while twice the molar dose of MTA (21.3 mg/kg) had no effect. Thus, MTA is a potent, selective, serotonin releaser, apparently devoid of serotonin neurotoxic effects. This work also supports the idea that catecholamine systems may play a critical role in the neurotoxicity of PCA-like compounds.

Amphetamines↗
PubMed1992

[Experimental model of depression: neurochemical changes and the effects of imipramine and citalopram].

A study was made of the influence of the antidepressants imipramine and citalopram (10 mg/kg, chronic administration, i.p.) on the depression-like condition in submissive male rats. The above condition developed under the effect of chronic emotional stress because of successive experience of defeat in social confrontations (Kudryavtseva, Bakshtanovskaya, 1988). Imipramine rather than citalopram exerted a remarkable antidepressive effect recorded by the Porsolt's test. Measurements of the content of serotonin, dopamine and noradrenaline in brain structures have demonstrated changes in the serotoninergic and catecholaminergic systems in males with the depressive symptomatology in relation to intact animals. It should be mentioned that at different stages of pathological process formation, the role of certain structures and mediator systems underwent definite changes.

Animals↗
PubMed1987

The effect of chronic imipramine and electroconvulsive shock treatment on [3H]DADLE binding to cortical membranes of rats pretreated with chronic reserpine or 6-hydroxydopamine.

Repetitive electroconvulsive shock treatment (for 8 days) or chronic administration of imipramine (10 mg/kg/day IP for 14 or 21 days) elevated the density of opioid delta receptors in the cerebral cortex of the rat. Electroconvulsive shock treatment produced a similar effect in rats treated subchronically with reserpine or receiving intraventricularly 6-hydroxydopamine, but these manipulations of central catecholamines prevented the action of imipramine.

Animals↗
PubMedDate not supplied

Neurochemical correlates of differences in responses to psychotropic drugs. I. Apomorphine and morphine effects on locomotor activity of C57/BL and Balb/C mice.

C57/BL mice have higher basal locomotor activity than Balb/C mice and react to apomorphine (4 mg/kg) and morphine (20 mg/kg) with motor stimulation, while in Balb/C mice this dose of apomorphine depressed the basal locomotor activity and morphine did not affect it. No differences in the characteristics of opiate mu and delta receptors in the whole brain of mice of both strains were found, but the responsiveness of the central alpha-adrenoceptor system, as measured with the accumulation of inositol phosphate in brain slices after exposure to noradrenaline was different: the low concentrations of noradrenaline (5 microM) produced stronger effect in Balb/C mice, but the maximum responses tended to be stronger in C57/BL mice.

Animals↗
PubMedDate not supplied

Stability and variability of locomotor responses of laboratory rodents. I. Native exploratory and basal locomotor activity of Albino-Swiss mice.

The exploratory and basal locomotor activities were tested in four groups of Albino-Swiss mice twice, at a 4-5 day interval, to investigate the variability of responses and correlation between the exploratory and basal locomotor activity, and their stability in individual animals. We have found that there exists only a weak correlation between the exploratory and basal locomotor activities. The repetition of tests results in a slight but significant depression of the exploratory, but not of the basal locomotor activity. The correlation between individual performances in two subsequent tests is generally low, regarding both the exploratory and the basal locomotor activity. There are no differences in the density of cerebral alpha 1-adrenoceptors between mice exhibiting extremely different exploratory or basal locomotor activities. The results suggest that preselection of mice for the tests involving locomotor activity in attempt to reduce the variability of results is pointless.

Animals↗
PubMedDate not supplied

Stability and variability of locomotor responses of laboratory rodents. II. Native exploratory and basal locomotor activity of Wistar rats.

The exploratory and basal locomotor activities were tested in four groups of Wistar rats twice, at a 4 day interval, to investigate the variability of responses and their changes on repetition of the test. The locomotor activity of rats was much lower than that of mice, particularly when the basal locomotor activity is concerned, but the individual variability was much higher. The exploratory activity declined significantly on the repeated testing. However, there was a good correlation between the individual exploratory activity in two consecutive tests, which suggests that preselection in the rat may be useful.

Animals↗
PubMedDate not supplied

A comparison of locomotor responses to some psychotropic drugs and cerebral receptors in the Acomys cahirinus and the laboratory mouse.

Comparative studies of the laboratory mouse and Acomys cahirinus have shown differences in their motor activity patterns and motor responses to morphine, apomorphine and clonidine. The two species also differed in respect of the density of cerebral alpha 2-adrenergic receptors, but no significant differences between other types of receptors (alpha 1-adrenergic, beta-adrenergic, opiate mu and delta, and spiroperidol binding sites) were found. It is suggested that the high excitability of the Acomys may be related to a deficit in the inhibitory noradrenergic transmission in the central nervous system.

Animals↗
PubMedDate not supplied

The effect of morphine dependence and abstinence on opioid receptors in the cerebral cortex and spinal cord of the rat.

The characteristics of cerebral cortical and spinal cord opiate mu, delta and kappa receptors were investigated by measuring of the specific binding of [3H]naloxone, [3H]DADLE and [3H]bremazocine in drug-free rats and in rats rendered tolerant to morphine and in those in which morphine abstinence syndrome was precipitated with naloxone. The opiate receptors in the spinal cord were less dense than those in the cortex; the difference was most pronounced in the case of delta receptors. The characteristics of the investigated opioid receptors did not change in the state of tolerance or abstinence.

Animals↗
PubMedDate not supplied

Stability and variability of locomotor responses of laboratory rodents. III. Effect of environmental factors and lack of catecholamine receptor correlates.

The exploratory locomotor activity of rats differs between groups, and the results suggest the involvement of a seasonal factor. The body weight and the state of satiety do not appear to influence the locomotor activity. The individual activities of rats are correlated in subsequent tests only if the period between the tests is not long. The foehn wind changes the locomotor activity in the second test, depending on the animals' experience. No correlation between the native locomotor activity and cortical and striatal binding sites for [3H]prazosin and [3H]spiroperidol was found.

Animals↗
PubMedDate not supplied

Stability and variability of locomotor responses of laboratory rodents. IV. The responses of rats and mice to apomorphine and amphetamine.

Both apomorphine and amphetamine produce hypermotility in mice and rats previously adapted to the measuring apparatus. The amphetamine hypermotility, induced by 1.5 mg/kg ip of the drug, began to develop after 20 min and lasted for over 1 h. The response was similar in animals tested at various times of the year. In the investigated populations approx. 20% of rats were very highly stimulated, and approx. 15% did not respond with hypermotility. The individual response was a stable feature of a given rat, as the correlation of results of subsequent tests was significant. Apomorphine (1 mg/kg sc) stimulates the locomotor activity of the rat immediately after the injection. The seasonal variability of response was high. The results of subsequent tests were correlated. The differences between animals were less distinct than those observed after amphetamine. In mice hypermotility induced by apomorphine (1 mg/kg sc) began to evolve after 10 min, the amphetamine hypermotility - after 40 min. There exist subpopulations reacting very strongly to either of the drug. The responses in subsequent tests were well correlated. In mice the second injection of amphetamine (after 4 days) produced a much higher locomotor response than the first injection, while in all other cases (apomorphine in mice, both dopaminomimetics in rats) the magnitude of responses in subsequent tests was similar. No correlations between the type of responses to the drugs and characteristics of central catecholaminergic receptors were found.

Amphetamine↗