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Biomedical subjects

A Carlsson

Publications and source records attributed to A Carlsson.

At least 199 records · Page 11Linked to original sources
PubMed1988

In vivo dopamine (DA) receptor binding and behavioural effects of the putative DA autoreceptor antagonists (+)-AJ 76 and (+)-UH 232 in rats with a unilateral nigral 6-OH-DA lesion.

The in vivo dopamine (DA) receptor binding and behavioural properties of the recently characterised putative preferential DA autoreceptor antagonists (+)-AJ 76 and (+)-UH 232 were studied in rats with a unilateral 6-OH-DA lesion of the substantia nigra. The main findings were a) that (+)-UH 232 and (+)-AJ 76 per se failed to produce significant turning behaviour, b) that both agents antagonised contralateral rotation caused by the DA agonist apomorphine, including a change of the characteristic two-peak apomorphine rotation pattern into a single peak, indicating that the DA antagonist properties of (+)-UH 232 and (+)-AJ 76 are retained also at denervation-sensitised postsynaptic DA receptors and--in support of this notion--c) that (+)-UH 232 and (+)-AJ 76 were able to displace the specific in vivo binding of the DA receptor agonist DP-5,6-ADTN in the denervated as well as in the intact striata of the 6-OH-DA-lesioned animals. Interestingly, in this regard (+)-UH 232 was significantly less efficient on the lesioned as compared to the intact side. The DP-5,6-ADTN-displacing effect of (+)-AJ 76 did not, however, differ between the intact and the denervated striatum. The implications of the present findings are discussed with particular reference to DA receptor sensitivity and adaptational phenomena.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Capsaicin-sensitive vasodilatatory mechanisms in the rat substantia nigra and striatum.

Thermoregulatory and neurochemical effects of capsaicin microinjection into the substantia nigra (SN) or caudatus putamen (CPu) were studied in rats. Administration of capsaicin into these brain structures induced a peripheral vasodilatation which was associated with a decrease in body temperature. Pretreatment of the rats with capsaicin either as adults or neonates abolished the thermolytic response to the drug, indicating that the effect is executed specifically upon capsaicin sensitive structures. Analyses of the levels of monoamines and their metabolites in the striatum following injection of capsaicin into the SN or CPu revealed that dopaminergic neurons are not primarily involved in this effect. This view is also supported by our findings that neurochemical lesion of unilateral nigrostriatal dopaminergic neurons did not influence the vasodilatatory response. Since the pharmacological effect of intranigral capsaicin was not abolished by unilateral axotomy (hemisection) we presume a capsaicin-sensitive, non-dopaminergic descending vasodilatatory pathway from the SN.

Action Potentials↗
PubMed1988

In vivo receptor binding, neurochemical and functional studies with the dopamine D-1 receptor antagonist SCH23390.

A series of in vivo experiments were undertaken, relating functional (motor activity, body temperature), dopamine (DA) receptor binding and neurochemical (catecholamine synthesis and utilization, DA release) aspects of the pharmacology of SCH23390 in the rat. The compound inhibited the locomotor hyperactivity, but not the hypothermia, induced by the potent DA stimulant DP-5,6-ADTN. Interstingly, SCH23390 simultaneously failed to displace DP-5,6-ADTN from its binding sites in the rat striatum--used as a direct in vivo biochemical index of DA (D-2) receptor interaction. The spontaneous locomotion in non-pretreated rats was likewise inhibited by SCH23390. The locomotor-suppressive action, but not the DP-5,6-ADTN-displacing capacity of the D-2 blocker haloperidol was significantly enhanced by SCH23390, suggesting that motility can be suppressed by either enhanced D-1 or D-2 (postsynaptic) receptor blockade, but also that the D-1 and D-2 sites involved may be physically distinct. SCH23390 only slightly altered in vivo neurochemical of DA synthesis, release and nerve-impulse flow, indicating that, while similar in suppressing dopaminergic behaviour, the D-1 antagonist is less effective than traditional neuroleptics as an activator of DA neuronal feedback mechanisms. The weak increases of DA synthesis and release nonetheless obtained were equal in magnitude (30-40%) in the limbic vs. striatal brain areas; also in this respect, SCH23390 thus differs from classical neuroleptics, which generally display more marked effects in the striatum than in limbic tissue. No major changes in the in vivo indices of NA synthesis and utilization (or in 5-HT synthesis) were found after SCH23390 administration, by and large supporting the DA receptor specificity of the compound. In summary, the studies demonstrated that SCH23390 can offset and accentuate, respectively, behavioural consequences of D-2 receptor stimulation and blockade. Importantly, at the same time no direct interaction at the level of D-2 DA receptor sites in the striatum was detected. Only slight, D-2 antagonist-like, changes in neurochemical indices of dopaminergic activity were observed after D-1 receptor blockade by means of SCH23390. With regard to DA agonist hypothermia, SCH23390 was without effect per se, but (at a high dose) attenuated the action of the D-2 antagonist haloperidol. The observations may indicate that the complex interactions between central D-1 and D-2 receptor-controlled mechanisms that influence behaviour, neurochemistry, and possibly autonomic nervous expression, are not identical.

Animals↗
PubMed1988

Beta-adrenergic control of brain uptake of large neutral amino acids.

The amino acids tyrosine and tryptophan are precursors of physiologically active amines in the central nervous system. To reach the brain they have to compete with other large neutral aminio acids (LNAA) for the normally saturated carrier by which these amino acids are transported into the brain. The beta-adrenergic agonist isoprenaline is demonstrated to cause an increase in the brain concentration of most LNAA without a concomitant decrease in any of them. This finding indicates that the transport of LNAA into the brain is regulated by a beta-adrenergic mechanism.

Amino Acids↗
PubMed1988

Afferent and efferent nerve injury in vibration white fingers.

To study afferent pain and efferent sympathetic nerve function in vibration-induced Raynaud's phenomenon, 10 patients and 11 healthy controls were examined. Thresholds for mechanically and thermally induced pain were determined on the left side of the tip of the second finger, on the skin fold between thumb and second finger and on the ear lobe. Superficial skin blood flow was simultaneously measured by laser Doppler technique on the right third finger. The patients had higher pain thresholds than controls on the vibration-exposed index finger but not on other stimulation areas. Thus receptors or pain-mediating nerve fibres in the fingers are affected by work with vibrating tools. The controls demonstrated vasoconstriction on pain stimulation, whereas the patients showed no or weak vasoconstriction in response to the stimulation. This was true also when areas not included in the disease process were stimulated, indicating that also sympathetic vasoconstrictor nerves or receptors are affected in vibration syndrome.

Afferent Pathways↗
PubMed1988

A regional study of sex differences in rat brain serotonin.

1. Male and female rats were compared with respect to serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tryptophan, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) levels in five brain regions (brainstem, hypothalamus/preoptic area, corpora striata, limbic forebrain and cortex). Brain 5-HT synthesis rate was also studied in the two sexes. 2. There were no consistent gender differences in the dopaminergic system. 3. In contrast, the serotonergic system was more expressed in females: 5-HT levels were significantly higher in females than in males in the brainstem and limbic forebrain and tended to be so in the cortex. 5-HIAA levels were significantly higher in females in all five brain regions. The 5-HIAA/5-HT ratios were significantly higher in females in the hypothalamus/preoptic area and limbic forebrain and tended to be so in the striatum and cortex. Tryptophan concentrations were significantly higher in females in the brainstem, striatum and cortex. In no brain region were 5-HT, 5-HIAA or tryptophan levels higher in males. Following L-amino acid decarboxylase inhibition 5-hydroxytryptophan (5-HTP) accumulation was more pronounced in the female rat brain. 4. Taken together these results suggest that the brain 5-HT system has a higher potential in female than in male rats. This sex difference is not restricted to a specific region but seems to exist generally in the brain.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

The current status of the dopamine hypothesis of schizophrenia.

The dopamine hypothesis of schizophrenia is still almost entirely based on pharmacologic evidence. Even though a disturbed dopamine function has not yet been established beyond doubt in schizophrenia, recent basic research on dopaminergic mechanisms opens up possibilities for the development of more sophisticated pharmacologic tools, capable of discovering subtypes of dopamine receptors, which may turn out to be abnormal in schizophrenia. Such tools may also prove therapeutically useful. Schizophrenia is probably a heterogeneous group of disorders with mixed biopathology. To facilitate the search for nondopaminergic mechanisms of possible pathogenetic importance in subgroups of schizophrenia, a hypothetical model is presented that tries to explain the role of subcortical dopaminergic pathways for mental functions and their interaction with other systems. It is proposed that corticostriatothalamocortical negative feedback loops, also involving the mesencephalic reticular formation, are modulated by mesostriatal dopamine pathways to control a thalamic filter mechanism. The psychotomimetic actions of dopaminergic agents and phencyclidine may be due to interference with these feedback mechanisms.

Animals↗
PubMed1988

N,N-Dialkylated monophenolic trans-2-phenylcyclopropylamines: novel central 5-hydroxytryptamine receptor agonists.

N,N-Dialkylated monophenolic derivatives of trans-2-phenylcyclopropylamine were synthesized and tested for central 5-hydroxytryptamine (5-HT) and dopamine (DA) receptor stimulating activity by use of a biochemical test method in rats. A hydroxy substituent in the 2- or 3-position of the phenyl ring was required for 5-HT-receptor stimulation. N,N-Diethyl or N,N-di-n-propyl substitution gave the most potent 5-HT-receptor agonists. The 4-hydroxy and 3,4-dihydroxy derivatives of trans-2-phenyl-N,N-di-n-propylcyclopropylamine were inactive at central DA and 5-HT receptors. In contrast, the corresponding 3-hydroxy derivative 18 and some of its derivatives weakly affected both DA and NE synthesis. Two of the most potent 5-HT-receptor agonists, trans-2-(2-hydroxyphenyl)-N,N-di-n-propylcyclopropylamine (8) and the 3-hydroxy isomer 18 were resolved into the enantiomers. The 1R,2S enantiomers of 8 and 18 displayed 5-HT activity, while the 1S,2R enantiomers were inactive. Compound (1R,2S)-18, but not (1R,2S)-8, weakly affected rat brain DA and NE synthesis.

Alkylation↗
PubMed1988

Occurrence and pharmacological significance of metabolic ortho-hydroxylation of 5- and 8-hydroxy-2-(di-n-propylamino)tetralin.

Aromatic ortho-hydroxylation in the liver might be one of several possible reasons for the low bioavailabilities of the potent, centrally acting dopaminergic and serotoninergic agonists 5- and 8-hydroxy-2-(di-n-propylamino)tetralin, respectively. In vitro and in vivo experiments showed that such an oxidative metabolism did indeed take place. However, the amount of hydroxylated metabolites found in the brain was estimated to represent only 0.3% of the total amount of drug administered. The O-methylation rates of these catechols were also measured in vitro and showed that 5,6-dihydroxy-2-(di-n-propylamino)tetralin is a poor substrate for catechol O-methyltransferase (COMT) and that its 7,8-dihydroxy isomer is virtually devoid of substrate activity. No O-methylated metabolites were detected in the in vivo samples analyzed. A new synthetic strategy was applied to achieve the isomeric catechols studied. 5-Methoxy- or 8-methoxy-2-(di-n-propylamino)tetralin was lithiated in the ortho position and the metalated species was subsequently quenched in nitrobenzene, yielding the methoxy hydroxy isomers, which were heated in 48% aqueous HBr to achieve the corresponding catechols.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1988

Studies on the acute and long-term changes in dopamine and noradrenaline metabolism in mouse brain following administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Previous studies from these laboratories have revealed that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced acute profound release of dopamine together with a marked reduction in dopamine synthesis. The present study was undertaken in an attempt to further elucidate these acute alterations. MPTP produced dose-dependent marked reductions in the concentrations of dopamine and noradrenaline in mouse brain 2 hours as well as 7 days after the administration. Both the acute and long-term reductions in dopamine were most pronounced in the striatum, whereas the reductions in noradrenaline (acute and long-term) were most pronounced in the cortical region. Contemporaneous with the acute reduction in the catecholamines, MPTP increased the levels of the dopamine metabolites 3-methoxytyramine and homovanillic acid (HVA), and the noradrenaline metabolite normetanephrine. In contrast, the levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were reduced. These data are indicative of a profound release of both dopamine and noradrenaline from the storage sites into the extraneuronal space. Pretreatment with the monoamine oxidase inhibitor pargyline totally prevented the acute reduction in dopamine and partially also the reduction in noradrenaline produced by MPTP. However, MPTP increased the levels of 3-methoxytyramine and normetanephrine also in pargyline treated mice. The selective dopamine uptake inhibitor GBR 13098 antagonized the MPTP-induced reduction in dopamine and increase in 3-methoxytyramine, but had no effect on the MPTP-induced reduction in noradrenaline. MPTP produced a marked acute reduction in tyrosine hydroxylation in the dopamine predominated areas striatum and limbic region, whereas a slight increase in tyrosine hydroxylation was noted in the noradrenaline predominated cortical region. Similar effects of MPTP were observed in reserpine pretreated animals. Pargyline prevented the MPTP-induced reduction in dopamine synthesis. Recent in vitro observations indicate that MPP+, the toxic metabolite of MPTP, is capable of inhibiting the electron-transport carrier, an action which may account for the neurotoxicity of the compound. It appears possible that this effect of MPP+ could explain the currently observed acute changes in catecholamine metabolism.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

The effects of 1-methyl-4-phenylpyridinium ion (MPP+) on the efflux and metabolism of endogenous dopamine in rat striatal slices.

1-Methyl-4-phenylpyridinium ion (MPP+) was shown to accumulate concentration-dependently in slices from rat striatum. At 10 microM, MPP+, the tissue concentration was found to be 118 +/- 9 microM following 75 min of incubation. The accumulation of MPP+ was reduced in the presence of 10 microM of the selective dopamine uptake inhibitor GBR 12909 (-50%) or by destruction of the dopaminergic terminals by complete hemisection of the forebrain 4 days before the experiments (-75%). Accumulation of MPP+ in the catecholamine-poor occipital cortex and cerebellum was only 25% of that obtained in striatum. Reserpine pretreatment of the rats in-vivo did not modify the accumulation of MPP+ in the striatal slices. MPP+ (1-10 microM) increased the net efflux of dopamine and reduced the efflux of the dopamine metabolite DOPAC from the striatal slices. The effect on dopamine was readily diminished if MPP+, after a 15 min incubation, was then omitted from the medium. In contrast, the DOPAC efflux was reduced for 75 min even though MPP+ was present in the incubation medium only for the first 15 min. In the presence of the monoamine oxidase inhibitor, pargyline (350 microM), MPP+ also produced an increase in dopamine efflux. In normal medium, the presence of the dopamine uptake inhibitor GBR 12909 (10 microM), or the absence of calcium, failed to modify the MPP+-induced increase in dopamine efflux. MPP+ also increased dopamine efflux from slices from reserpinized rats.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenylpyridinium↗
PubMed1988

'On-off' phenomenon in Parkinson's disease: relationship between dopa and other large neutral amino acids in plasma.

Administration of a low-protein diet to parkinsonian patients with "on-off" syndromes consistently increased the total daily time of "on" states when compared with a high-protein diet. The clinical effect of the low-protein diet may be due to a marked decrease in the plasma concentration of large neutral amino acids that compete with L-dopa for carrier-mediated transport into the brain.

Aged↗
PubMed1988

Clinical aspects of osseointegration in joint replacement. A histological study of titanium implants.

In an experimental clinical study, 25 implants of pure titanium were inserted into the proximal tibia of 11 volunteer patients, four with rheumatoid arthritis and seven with osteoarthritis. The implants were removed from five weeks to 24 months later and detailed histological analysis was performed. The implants generally healed with direct bone-metal contact, showing so-called osseointegration. Only one of the 21 implants which had been in place for over five months did not show osseointegration, probably because of inadequate primary contact with bone. The presence of rheumatoid disease did not prevent osseointegration, but accompanying osteoporosis seemed to be a risk factor.

Aged↗
PubMed1988

Mannose-resistant haemagglutination by Campylobacter pylori.

10 Campylobacter pylori strains were screened for the presence of presumptive colonization factors by measuring cell surface hydrophobicity and haemagglutination. All 8 clinical isolates and 2 reference strains caused haemagglutination of rabbit, human and/or sheep erythrocytes in the presence of mannose. None of the strains expressed a hydrophobic cell surface. In preliminary experiments the haemagglutination could be inhibited with monosialogangliosides suggesting that these strains express sialic acid specific haemagglutinin(s) which could be involved in colonization of mucosal surfaces.

Animals↗