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Biomedical subjects

A Carlsson

Publications and source records attributed to A Carlsson.

At least 235 records · Page 13Linked to original sources
PubMed1987

Brain neurotransmitters in aging and dementia: similar changes across diagnostic dementia groups.

Reductions of the levels of transmitter substances and of the activities of enzymes involved in their synthesis have been demonstrated in the aging brain. The sensitivity to the aging process varies for different transmitters and brain regions. Dopamine neurons are more age-sensitive than most other neurons investigated. The metabolism of monoaminergic neurotransmitters is enhanced in the aging brain, as evidenced by increased metabolite/neurotransmitter ratios, perhaps to compensate for the loss of transmitter. In various types of dementia, including Alzheimer's disease (AD) and senile dementia of Alzheimer type (SDAT), several neurotransmitter indices are reduced, as compared to age-matched controls. Moreover, a decrease in neurotransmitter metabolites suggests that compensatory mechanisms are insufficient. No correlation could be found between the neurotransmitter changes and the histological changes characteristic of AD (senile plaques and neurofibrillary tangles). Neither could any relationship between multiple infarctions and neurotransmitter indices be detected. Recently observed changes in the lipid composition of the white matter, indicating demyelinization, in the brains of patients with AD/SDAT, emphasize the multifactorial aspects of dementia. Taken together, the data underline the difficulties in drawing clear demarcation lines between normal and pathological aging and between different subgroups of dementia. Despite the obvious difficulties, future therapeutic efforts should aim at substitution for the neurotransmitter deficiencies. Preventive measures have to await the clarification of the mechanisms underlying neural degeneration. Studies of the toxicity of oxygen and of autoxidation products are among the areas of research that may help to shed light on this problem.

Aging↗
PubMed1987

Treatment of the exposed knee prosthesis.

Ten knees with early tissue breakdown after knee arthroplasty resulting in exposed prostheses were treated with different plastic surgical techniques. Six knees were successfully covered: four using a gastrocnemius musculocutaneous flap, one using a fasciocutaneous flap, and one using split-skin grafts. Four knees failed: two using local skin flaps and two using split-skin grafts. A gastrocnemius musculocutaneous flap seems to provide a reliable coverage of the exposed knee joint.

Aged↗
PubMed1986

The putatively selective dopamine autoreceptor antagonists (+)-AJ 76 and (+)-UH 232 stimulate prolactin release in rats.

The 2-aminotetralin derivatives cis-(+)-(1S,2R)-5-methoxyl-1-methyl-2-(n-propylamino)tetralin, (+)-AJ 76, and cis-(+)-(1S,2R)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin, (+)-UH 232, are novel centrally acting stimulants with a putative action as selective dopamine (DA) autoreceptor antagonists. In the present study these compounds were evaluated with respect to their effects on prolactin release in male rats. Both (+)enantiomers caused a pronounced increase in plasma prolactin levels in previously untreated animals. The effects of (+)-AJ 76 and (+)-UH 232 were virtually similar, except for a higher initial increase after the latter compound. In agreement with earlier reports, the reserpine-induced elevation of plasma levels of prolactin was strongly suppressed by the DA autoreceptor agonist B-HT 920. This effect of B-HT 920 was completely blocked by (+)-AJ 76 and by (+)-UH 232, indicating that both (+)enantiomers antagonize lactotroph DA receptors. The present findings support the notion that lactotroph DA receptors resemble DA autoreceptors rather than postsynaptic DA receptors. A possible difference between the auto-/lactotroph vs. postsynaptic DA receptors with respect to both the responsiveness to agonists and to the affinity of pure antagonists is discussed.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

Determination of dopamine and its metabolites in small volumes of rat brain dialysates using small-bore liquid chromatography with electrochemical detection.

A miniaturized liquid chromatographic system with electrochemical detection (LC-ED) was developed and applied to the analysis of dopamine and its metabolites in dialysate samples collected from the rat brain in vivo. An existing LC-ED system was down-scaled using a 1 mm I.D. small-bore column operated at a reduced flow-rate and with an injection volume of 1 microliter. With the small-bore system the limit of detection for dopamine of ca. 0.06 pg was almost 50 times less than with the conventional system, which represents a two-fold improvement in concentration sensitivity. Miniaturization was accomplished with negligible loss in resolution by using a conventional commercial amperometric detector with minor modifications. The results indicate that a number of useful advantages could be realized by the combination of this small-bore LC-ED system and the in vivo brain dialysis method.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Is pindolol a mixed agonist-antagonist at central serotonin (5-HT) receptors?

The effects of the non-selective beta-adrenergic blocking agent pindolol upon central monoaminergic neurotransmission in rats were studied by means of in vivo biochemical methods. It was found that (-)-pindolol elicited a clearcut, selective, dose-dependent and stereospecific reduction of brain 5-HT synthesis rate. The synthesis reduction was not accompanied by any change in the tissue tryptophan levels and could not be prevented by depleting the monoamine stores by means of reserpine. Furthermore, in non-pretreated animals, (-)- but not (+)-pindolol (nor the beta 1- and beta 2-selective adrenoceptor antagonists metoprolol, betaxolol and ICI 118,551) decreased the 5-HIAA level and the 5-HIAA/5-HT ratio while neither enantiomer altered the concentrations of 5-HT or NA, or DA and its metabolites. It is suggested that these effects of (-)-pindolol may be due to direct stimulation of 5-HT receptors in the CNS. The action of the compound is discussed within the context of literature data indicating its ability to act as an antagonist of certain other aspects of 5-HT receptor activation. The possibility is considered that, in addition to its beta-adrenergic properties, (-)-pindolol is a mixed agonist-antagonist at central 5-HT receptors.

Adrenergic beta-Antagonists↗
PubMed1986

(+)-AJ 76 and (+)-UH 232: central stimulants acting as preferential dopamine autoreceptor antagonists.

The biochemical and behavioral effects of the putative dopamine autoreceptor antagonists cis-(+)-5-methoxy-1-methyl-2-(n-propylamino)tetralin, (+)-AJ 76 and cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin, (+)-UH 232, were evaluated in various in vivo models in rats. Both compounds produced a marked elevation in brain dopamine synthesis and turnover with only slight effects on the synthesis and turnover of serotonin (5-HT) and noradrenaline being noted. (+)-AJ 76 and (+)-UH 232 also failed to antagonize the decrease in cortical noradrenaline synthesis rate caused by the alpha 2 agonist clonidine. The apomorphine-induced decrease in dopamine synthesis rate in gamma-butyrolactone (GBL) treated animals was completely blocked by (+)-AJ 76 and (+)-UH 232 but not by d-amphetamine or methylphenidate. In activity experiments using habituated animals, (+)-AJ 76 and (+)-UH 232 produced locomotor stimulation and weak stereotypies and antagonized the sedative effects of low doses of apomorphine. Locomotor hyperactivity induced by apomorphine or the dopamine agonist DiPr-5,6-ADTN was antagonized by (+)-UH 232 and to a lesser degree by (+)-AJ 76. The locomotor hyperactivity produced by (+)-AJ 76, (+)-UH 232 and methylphenidate was completely prevented by reserpine pretreatment and partially blocked by the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (alpha-MT), whereas d-amphetamine-induced hyperactivity was only antagonized by alpha-MT pretreatment. It is concluded that (+)-AJ 76 and (+)-UH 232 produce behavioral stimulation via a preferential antagonism on central dopamine autoreceptors, an action different from that of all known stimulants including apomorphine, d-amphetamine and methylphenidate. (+)-AJ 76 and (+)-UH 232 possess but weak antagonistic effects on postsynaptic dopamine receptors and only the latter compound is able to induce sedation in rats.

4-Butyrolactone↗
PubMed1986

Central dopaminergic properties of HW-165 and its enantiomers; trans-octahydrobenzo(f)quinoline congeners of 3-PPP.

In the further development of CNS dopamine autoreceptor active compounds related to 3-PPP, the transfused 7-hydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline HW-165 and its enantiomers were synthesised. This paper describes the basic pharmacological properties of these latter, novel "atypical" dopaminergic agents, based on an extensive series of biochemical and behavioural experiments in rats. By and large, the pharmacological activities of HW-165 - essentially, if not exclusively, residing in its (4aS,10bS)-(-)-enantiomer - were similar to those displayed by (S)-(-)-3-PPP, indicating the simultaneous presence of central dopamine (autoreceptor) agonist and weak (postsynaptic) antagonist properties in the molecule. Thus, in non-pretreated animals HW-165 and its active species monotonically suppressed the spontaneous locomotion without causing catalepsy or other appreciable motor disabilities, and at the same time selectively reduced the dopamine synthesis, release/turnover and utilisation. Some differences in these biochemical responses to HW-165 [racemate or (-)-enantiomer] were, however, noted in the limbic vs. striatal brain areas (e.g. decrease of dopamine synthesis particularly in the limbic parts). On the other hand, while failing to reverse reserpine-induced akinesia or to elicit stereotyped behaviour, the agents markedly inhibited the dopamine synthesis in either of the dopamine-dominated cerebral regions in the reserpinised as well as in gamma-butyrolactone (GBL)-treated rats. As shown for racemic HW-165 after reserpine pretreatment, the inhibition of dopamine synthesis was completely and stereoselectively blocked by (+)-butaclamol, thereby supporting direct dopamine receptor interaction. Racemic HW-165 readily antagonised the d-amphetamine-induced locomotor hyperactivity. Apomorphine-induced hyperactivity was, however, distinctly more resistant to antagonism by HW-165 [racemate or (-)-enantiomer]. Moreover, the latter agents fully prevented the apomorphine-induced inhibition of striatal dopamine synthesis in otherwise non-pretreated rats, while only partly counteracting this effect of apomorphine in the limbic regions of such animals, and in either brain area of rats treated with gamma-butyro-lactone. The findings are interpreted within the context of the mixed dopamine agonist/antagonist properties (referred above) of HW-165 and its active (-)-species in relation to the adaptive state of central dopamine receptors and possible regional variations in feedback strength and organisation.(ABSTRACT TRUNCATED AT 400 WORDS)

4-Butyrolactone↗
PubMed1986

(+)-UH 232 and (+)-UH 242: novel stereoselective dopamine receptor antagonists with preferential action on autoreceptors.

The (+)- and (-)-enantiomers of the 2-aminotetralin derivatives cis-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin (UH 232) and cis-5-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (UH 242), were pharmacologically evaluated in rats in an extensive series of in vivo biochemical and behavioral experiments. These studies showed that the (+)- and (-)-enantiomers have differential effects on central dopamine (DA) receptors. Thus, (-)-UH 242 is a DA-receptor agonist stimulating both pre- and postsynaptic receptors. (-)-UH 232 is also active as a DA receptor agonist, although with much lower potency than (-)-UH 242. In contrast, (+)-UH 242 and (+)-UH 232 are characterized as DA receptor antagonists. Both (+) forms markedly accelerated DA synthesis and turnover and reversed the biochemical and behavioral effects of apomorphine. Locomotor activity was stimulated by the (+)-enantiomers over a wide dose range; hypomotility was induced only by high doses. The pharmacological profile of the (+)-enantiomers clearly differs from that of classical neuroleptics and suggests a preferential antagonistic action on DA autoreceptors. (+)-UH 232 and (+)-UH 242 may prove useful as experimental tools and as potential therapeutic agents (selectively increasing DA-ergic neurotransmission), e.g. in geriatric practice.

4-Butyrolactone↗
PubMed1986

A homologous series of N-alkylated cis-(+)-(1 S, 2 R)-5-methoxy-1-methyl-2-aminotetralins: central dopamine receptor antagonists showing profiles ranging from classical antagonism to selectivity for autoreceptors.

N-alkylated and N,N-dialkylated cis-(+)-(1 S, 2 R)-5-methoxy-1-methyl-2-aminotetralins were tested for central dopamine receptor antagonism using in vivo biochemical and behavioral models in rats. The di-methyl analogue showed a profile similar to classical dopamine receptor antagonists. It produced a marked hypomotility including catalepsy and a pronounced increase in dopamine synthesis rate. This compound also displaced DiPr-5, 6-ADTN from striatal binding sites and antagonized the hyperactivity induced by the ligand. In contrast, the mono-propyl analogue increased locomotor activity and dopamine synthesis rate over a wide dose range. This compound failed to antagonize the hyperactivity induced by DiPr-5, 6-ADTN and to displace this in-vivo binding ligand. Thus, the mono-propyl analogue appears to lack postsynaptic dopamine receptor antagonistic properties; it seems to produce its effects via a selective dopamine autoreceptor antagonism. The di-ethyl and di-propyl, but not the dibutyl, analogues were also active in the models used. Whereas the di-ethyl compound shows a profile similar to classical dopamine receptor blockers, the di-propyl compound appears to act preferentially on autoreceptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

Rat brain concentration of administered amino acids: dependence on time of day for administration.

Several large neutral amino acids (LNAA) (e.g. L-DOPA and L-tryptophan) are used as therapeutic agents. To reach the brain they have to compete with the naturally occurring large neutral amino acids for the saturable, carrier mediated transport into the brain. Since the concentration of LNAA in plasma demonstrates a diurnal rhythm, this competition could be expected to vary accordingly. To investigate if this variation could influence the brain concentration of a certain administered amino acid we injected three groups of rats with L-DOPA, L-tryptophan or saline in the afternoon when the rat plasma concentration of LNAA is at its lowest. Three other groups of rats received the same treatments at 3 a.m., when the concentration of LNAA is reported to be at a maximal level. The brain concentrations of the administered amino acids were significantly higher and LNAA in plasma lower in the groups injected in the afternoon compared with those injected during the night. These findings support the hypothesis that the time of the day when an amino acid is administered is of importance to the concentration of the administered amino acid in the brain.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

In vivo effects of the Ca2+-antagonist nimodipine on dopamine metabolism in mouse brain.

The effects of the Ca2+-antagonist nimodipine on central dopamine (DA) neurons in mice were investigated in vivo. Nimodipine caused a dose-dependent decrease in the DA metabolite 3-methoxytyramine (3-MT) in striatum and the limbic region. If the brains were microwave radiated immediately after decapitation in order to minimize post-mortal accumulation of 3-MT, the effect of nimodipine was less pronounced and statistically not significant. Nimodipine markedly decreased the accumulation of 3-MT induced by pargyline, an inhibitor of monoamine oxidase, a phenomenon that was not attenuated by microwave radiation. Furthermore, whereas nimodipine had no effect on mouse motor activity when given alone it readily blocked the pargyline-induced increase in activity. The concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in striatum and the limbic region were also reduced by nimodipine as was the accumulation of 3,4-dihydroxyphenylalanine (DOPA) measured after inhibition of the aromatic amino acid decarboxylase by 3-hydroxybenzylhydrazine (NSD 1015). In addition, nimodipine caused decreased concentrations of DA and homovanillic acid (HVA) in the limbic region but not in striatum. Nimodipine caused an increase in the striatal concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA); these changes were not seen in the limbic region. In conclusion, nimodipine appears to reduce the release as well as the synthesis of DA in mouse brain. These effects are believed to be related to the Ca2+-antagonism of nimodipine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Effects of capsaicin on central monoaminergic mechanisms in the rat.

The acute and chronic effects of capsaicin (s.c.) on the monoamines in the preoptic region + hypothalamus (RPO-H), spinal cord, substantia nigra and striatum were studied. Levels of DOPA, DA, DOPAC, HVA, 3-MT, NA, Trp, 5-HTP, 5-HT and 5-HIAA were determined by means of liquid chromatography (HPLC-EC). In response to acute capsaicin treatment, the levels of DA, DOPAC and DA synthesis rate (DOPA formation) were increased in a dose-dependent manner in the RPO-H and spinal cord. The disappearance rate of NA was accelerated in both regions. In substantia nigra, increased DOPAC levels were found whereas the levels of 3-MT were decreased in striatum after acute capsaicin treatment. Only minor changes on the levels of 5-HT and 5-HIAA in the regions studied were noted. Neonatal or adult capsaicin treatment failed to affect the levels of NA, DA and 5-HT (measured two months or five weeks after injection, respectively) in the regions studied. A capsaicin injection to rats pretreated with the drug as adults did not affect either the monoamines in the RPO-H and spinal cord or the body temperature. In contrast, in rats pretreated with capsaicin as neonates, a second injection of the drug to adult animals elicited hypothermia and changes in monoamines similar to those observed in naive animals.

Animals↗
PubMed1986

Sexually differentiated actions of 3-PPP enantiomers on prolactin secretion.

The ability of the enantiomers of the atypical dopamine receptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) to counteract gamma-butyrolactone-induced hyperprolactinemia was compared in male and female rats. Following gamma-butyrolactone (GBL) pretreatment serum prolactin concentrations were higher in female than in male rats. In males (-)-3-PPP tended to be somewhat less effective than (+)-3-PPP in decreasing serum prolactin concentrations (levels after (+)-3-PPP and (-)-3-PPP: 21% and 33%, respectively, of levels in GBL-pretreated control(s). In females the (-)-form induced a much weaker response than did the (+)-form (levels after (+)-3-PPP and (-)-3-PPP: 8% and 74%, respectively, of levels in GBL pretreated controls). Parallel experiments replacing GBL by reserpine yielded similar results. Data are discussed in terms of sex differences in responsiveness of pituitary dopamine receptors.

4-Butyrolactone↗
PubMed1986

Occurrence and distribution of 5-S-cysteinyl derivatives of dopamine, dopa and dopac in the brains of eight mammalian species.

The 5-S-cysteinyl derivatives of dopamine, dopa (3,4-dihydroxyphenylalanine) and dopac (3,4-dihydroxyphenylacetic acid) were synthesized and used as reference compounds in high performance liquid chromatography analyses of extracts from various brain regions of eight mammalian species. All three metabolites were detected in the brains of all the species studied. The regional distribution of the metabolites was similar to that of dopamine; the metabolite concentrations ranged from less than 0.1 percent to more than 1 percent of the dopamine level, the highest ratios generally being found in substantia nigra. It is suggested that the 5-S-cysteinyl catechol metabolites have been formed after autoxidation of catechols to quinones and subsequent coupling to glutathione. The adduct thus formed is finally split by peptidases to yield the 5-S-cysteinyl derivatives.

Animals↗
PubMed1986

Anticonflict effects of low doses of the dopamine agonist apomorphine in the rat.

The effects of low, "autoreceptor" doses (3.13-100 micrograms/kg, SC) of the dopamine (DA) agonist apomorphine were investigated in a modified Vogel's conflict paradigm. The compound was found to exert a marked, dose-dependent increase in the number of shocks taken in the conflict situation (maximum: approximately 230% of control responding, obtained at 12.5 micrograms/kg), thus indicating an anxiolytic action. However, the dose-response curve was biphasic, inversely U-shaped, with the highest dose tried actually suppressing the punished response rate to below control levels. Neither low- nor high-dose apomorphine modified the rats' drinking "motivation" (glucose intake after 48 hr of water deprivation). On the other hand, while unaltered by 12.5 micrograms/kg, the pain threshold tended to be lowered by 100 micrograms/kg. It is suggested that the anxiolytic-like action of apomorphine might be due to central DA autoreceptor stimulation, possibly in limbic/cortical forebrain regions. The conflict-promoting effect seen at 100 micrograms/kg is likely related to the concomitantly elicited hyperalgesia. The possibility of developing novel DA-modulating agents for the treatment of anxiety is raised.

Animals↗