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Biomedical subjects

A Carlsson

Publications and source records attributed to A Carlsson.

At least 253 records · Page 14Linked to original sources
PubMed1986

Multiple biochemical deficits in both gray and white matter of Alzheimer brains.

A biochemical investigation of 21 brains from patients with dementia of Alzheimer type (AD/SDAT) and 22 brains from controls was made. In the normal brains 5-hydroxytryptamine (5-HT), noradrenaline (NA) and dopamine (DA) were reduced with age while their metabolites were not reduced. In the brains from the Alzheimer patients the examination of gray matter (caudate nucleus and hippocampus) showed a significant reduced activity of choline-acetyl transferase (CAT) and a reduction of acetylcholinesterase (AChE) that bordered significance in the hippocampus. In the brains from the Alzheimer patients a disturbance was found in the 5-HT system in the form of reduced levels of 5-HT and 5-hydroxyindolacetic acid (5-HIAA). The catecholamine systems were also disturbed but to a less extent. In the 5-HT and DA systems the active amines as well as the metabolites were reduced in the brains from patients with AD/SDAT indicating not only a possible neuronal loss but also an incapacity of the remaining neurons to compensate for the loss by an increased turnover. The lipid content was slightly reduced in gray matter of the demented brains. In white matter there was a more severe reduction of the lipids and in this tissue also the cerebrosides and sulfatides were reduced. It is concluded that in brains from patients with AD/SDAT there are multiple biochemical deficits in gray as well as in white matter. The changes in white matter may be of pathogenetic importance in subgroups of AD/SDAT.

Age Factors↗
PubMed1986

Enantiomers of 3-(3,4-dihydroxyphenyl)- and 3-(3-hydroxyphenyl)-N-n-propylpiperidine: central pre- and postsynaptic dopaminergic effects and pharmacokinetics.

This study emphasizes the importance of the metabolic conversion of the enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) into their catechol analogues, the enantiomers of 3-(3,4-dihydroxyphenyl)-N-n-propylpiperidine. These isomers are both shown to be excellent substrates for COMT, with a slight preference for the S-(-) enantiomer. Assessment of the dopaminergic activity of these catechols and the results from the determination of brain levels of the enantiomers of 3-PPP and their metabolites indicate that the metabolites probably do not alter the pharmacological profiles established for (R)-(+)- and (S)-(-)-3-PPP. The conversion of the monophenols into catecholic metabolites is only 1-5%, and the further conversion of these catecholic metabolites into methoxylated analogues is very rapid. However, the very interesting observation was made that, when inhibiting COMT by means of tropolone and subsequently treating the rats with high doses of (S)-(-)-3-PPP (ip), postsynaptic dopaminergic activity was elicited. This has never been seen for (S)-(-)-3-PPP without tropolone pretreatment and might indicate that, in this special case, the catecholic metabolite affects the in vivo pharmacological profile of (S)-(-)-3-PPP.

Animals↗
PubMed1985

An amperometric detector for use with small-bore liquid chromatographic columns.

A miniaturized electrochemical flow cell for amperometric detection in liquid chromatography has been designed to meet the requirement of low volumetric dispersion when using small-bore columns. The volume of the thin-layer cell is in the range 10-50 nl, depending on the spacer dimensions, with the electrode area being about 1 mm2. The cell is constructed from glass and designed in such a way that the working electrode can be mounted without alterations to its surface state. The flow-rate dependence, contribution to peak dispersion and linear dynamic range were investigated. After separation on a 250 X 1 mm I.D. column, a detection limit for dopamine of about 0.15 pg was achieved with a linear dynamic range of 10(6). The variance of the extra-column dispersion was determined to be less than 0.3 microliter2, including injector and connecting capillaries. The applicability of the detector is illustrated with the detection of dopamine and its major metabolites, dihydroxyphenylacetic acid and homovanillic acid, and of Met- and Leu-enkephalin in samples of biological origin.

Animals↗
PubMed1985

Lack of functional evidence for the involvement of sigma opiate receptors in the actions of the 3-PPP enantiomers on central dopaminergic systems: discrepancies between in vitro and in vivo observations.

In vitro radioligand binding and autoradiographic distribution studies have suggested the possible involvement of central sigma-opiate sites in the effects of several purportedly dopaminergic agents. Specifically, Largent et al. (Proc. Nat. Acad. Sci. 81, 4983, 1984) proposed that "actions of 3-PPP at sigma receptors may account for the effect of the drug on behavior and dopaminergic nerve function". Using the sigma-opiate- and dopamine (DA)-preferring (-)- and (+)-enantiomer, respectively, of butaclamol, and the two enantiomers of 3-PPP, the present study was undertaken to address the in vivo functional significance of this proposal. To this end we investigated various biological responses considered to reflect drug interactions with DA cell body and terminal autoreceptors and with presumed non-synaptic and postsynaptic DA receptors in the rat CNS. (+)- but not (-)-butaclamol antagonized the 3-PPP (either enantiomer)-induced DA synthesis and prolactin decreases in GBL-treated rats, the (+)-3-PPP-induced inhibition of substantia nigra DA cell firing and the (+)-3-PPP-induced reversal of reserpine akinesia. Taken together with previous findings available data suggest that DA rather than sigma-opiate receptors mediate the neurochemical, electrophysiological, behavioral and other physiological (prolactin, body temperature) effects of 3-PPP and its enantiomers. The in vivo pharmacological relevance of the claimed non-dopaminergic, proposedly sigma-opiatergic, radioligand binding demonstrated in vitro (with e.g. (+)-3-PPP) thus remains to be established.

Animals↗
PubMed1985

Dopamine receptor-mediated hypothermia induced in rats by (+)-, but not by (-)-3-PPP.

The novel dopaminergic agents (+)- and (-)-3-PPP were evaluated for their effects upon thermoregulation in rats maintained at room temperature (approximately 22 degrees C). Although approximately 30 times less potent than apomorphine, (+)-3-PPP induced a clearcut, dose-dependent and haloperidol/pimozide-reversible hypothermia. In contrast, the (-)-enantiomer per se lacked a significant effect upon rat body temperature. However, (-)-3-PPP clearly attenuated apomorphine-induced hypothermia. Simultaneous biochemical investigations confirmed the presence of central dopamine (DA) agonist and antagonist properties for (+)- and (-)-3-PPP, respectively, at the doses employed. The results are compared to the agonist and antagonist effects of the 3-PPP enantiomers in various other central DA receptors systems. Particular reference is made to the recent hypothesis by Carlsson (J. Neural Transm. 57 (1983) 309, relating agonist intrinsic activity to the DA receptor responsiveness state, in turn determined by the endogenous tone. Based on the findings with (+)- and (-)-3-PPP it is suggested that DA receptors mediating hypothermia in the rat may be more akin to 'normosensitive' postsynaptic than to highly 'agonist-responsive' autoreceptors.

Animals↗
PubMed1985

Pharmacological properties of presynaptic dopamine receptor agonists.

Selective presynaptic dopamine receptor agonists appear to offer promise as putative antipsychotic agents with a low risk of extrapyramidal side-effects, including tardive dyskinesia. However, no such agent with a reasonable degree of selectivity has yet reached the stage of clinical trial. In the present paper the particular pharmacological profile of presynaptic dopamine receptor (autoreceptor) agonists is described, and underlying mechanisms are discussed. Special attention is paid to the compound 3-(3-hydroxyphenyl-N-n-propylpiperidine(3-PPP), especially its levotatory enantiomer. This agent shows affinity for both pre- and postsynaptic dopamine receptors. Its intrinsic activity in different locations varies between virtually zero and 100%, leading to a mixture of agonist and antagonist properties. It is suggested that this variability depends on the adaptive properties of the dopamine receptor.

Animals↗
PubMed1985

An electrophysiological analysis of the actions of the 3-PPP enantiomers on the nigrostriatal dopamine system.

Extracellular single unit recording and microiontophoretic studies were carried out in chloral hydrate-anesthetized gallamine-paralyzed rats to investigate the actions of the enantiomers of the dopamine (DA) analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, on the nigrostriatal DA system. Intravenously administered (+)- or (-)-3-PPP consistently inhibited nigral DA neuronal activity; these actions were readily antagonized by haloperidol but were not affected by a pretreatment of reserpine plus alpha-methyltyrosine. In contrast to (+)-3-PPP, the (-)-enantiomer produced only partial inhibition of the majority of cells studied and was also capable of partially reversing the inhibitory action of apomorphine. A prior hemitransection of the brain did not alter the inhibitory action of either enantiomer. Whereas iontophoretically ejected (+)-3-PPP consistently reduced DA cell firing rate, similarly applied (-)-3-PPP reduced the activity of only some DA cells, while the majority were not influenced. In addition, iontophoresis of (-)-3-PPP could reduce the inhibitory effect of similarly applied DA or (+)-3-PPP. The (+)-enantiomer reduced caudate neuronal activity both after intravenous administration and iontophoresis. Intravenously administered (-)-3-PPP failed to influence or increased the activity of these neurons and reversed the inhibitory action of apomorphine. However, iontophoretically ejected drug reduced caudate cell activity and did not influence the inhibitory action of DA. The activity of non-DA zona reticulata neurons was inconsistently influenced by the 3-PPP enantiomers. It is concluded that (+)-3-PPP is a directly acting DA agonist, stimulating both DA autoreceptors and postsynaptic DA receptors. In contrast, (-)-3-PPP appears to be a partial agonist at nigral DA autoreceptors, whereas the action of the drug at putative postsynaptic DA receptors in the caudate remains to clarified.

Animals↗
PubMed1985

Detection of 5-S-cysteinyldopamine in human brain.

5-S-Cysteinyldopamine was synthesized and used as reference compound in HPLC analyses of extracts from various regions of human brain. The compound could be detected in brain regions rich in dopamine (caudate nucleus, putamen, globus pallidus and substantia nigra) but not in other regions (cerebellum, occipital cortex). The occurrence of 5-S-cysteinyldopamine in dopaminergic brain regions supports the hypothesis that dopamine in part undergoes autoxidation, leading to formation of highly reactive quinones. The newly discovered metabolite may prove useful in future studies of dopamine autoxidation and the possibly resultant cytotoxicity in aging and degenerative brain disorders.

Aged↗
PubMed1985

Rat brain serotonin: biochemical and functional evidence for a sex difference.

Male and female rats were compared with respect to brain serotonin (5-HT) levels, synthetic capacity, receptor sensitivity, and CNS functions. Levels of whole brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were higher in females. The accumulation of 5-HT after treatment with the monoamine oxidase inhibitor pargyline alone and in combination with the 5-HT precursor L-tryptophan was greater in females than in males. 5-HT increased and 5-HIAA decreased to the same extent in both sexes after administration of the 5-HT agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The temperature fall after all drug treatments was greater in females, but the "5-HT behavioural syndrome" was more pronounced in females merely after pargyline plus tryptophan; the behavioural response after 8-OH-DPAT did not differ between the sexes. These results are indicative of sex differences in the brain 5-HT neuronal systems. They are discussed in relation to differences between males and females in sexual behaviour, aggression and affective disorders.

Animals↗
PubMed1985

Dopamine receptor agonists: mechanisms underlying autoreceptor selectivity. II. Theoretical considerations.

In a companion article, we extensively reviewed the pharmacological actions of the enantiomers of the dopamine analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP. The profiles of action exhibited by transdihydrolisuride (TDHL) and the trans-fused 7-OH-1,2,3,4,4a,5,6,10-octahydrobenzo(f)quinoline (HW 165) were also described. These latter agents, along with (-)-3-PPP, exert a variety of effects at different DA receptors depending on the anatomical location of these receptor sites and the experimental conditions. In the first part of the present article, it is suggested that the intrinsic activity of these agents in different pharmacological models is dependent on the responsiveness of the relevant DA-receptors which, in turn, is related to the degree of previous agonist occupancy of these sites. In situations where these agents exhibit partial agonist activity, their pharmacological effect is also dependent on the relative concentrations of drug and endogenous DA competing for common receptor sites. A number of theoretical implications will be discussed relevant to the suggestion that DA receptors exist in various adaptational states which can influence drug action. In the second part of this review, we will consider the behavioural profile exhibited by (-)-3-PPP in relation to that observed with classical DA antagonists. In addition, the potential clinical application of (-)-3-PPP and similar-acting agents will be discussed.

Animals↗
PubMed1985

In vivo displacement by 3-PPP enantiomers of N,N-dipropyl-5,6-ADTN from dopamine receptor-binding sites in rat striatum.

The enantiomers of 3-PPP or haloperidol were injected in various doses to rats 1 hour after the established dopamine receptor ligand N,N-dipropyl-5,6-ADTN. After another 40 minutes the binding of the ligand to the striatum was measured by high performance liquid chromatography, using the level in the cerebellum as "blank". (-)-3-PPP was found to cause a maximum 71% displacement of the ligand from the striatal binding sites. Haloperidol proved to be more potent but not significantly more efficacious in displacing the ligand. However, the combined treatment with (-)-3-PPP and haloperidol caused a stronger displacement of the ligand than (-)-3-PPP alone, suggesting that the binding-site populations available for the two agents are not fully identical. (+)-3-PPP also caused displacement of the ligand but was considerably less potent than its enantiomeric twin. The results are discussed against the background of the different pharmacological profiles of the 3-PPP enantiomers and haloperidol. It is suggested that an inverse relationship may exist between receptor affinity and intrinsic activity and that such a relationship may be inherent in the mechanism underlying receptor stimulation.

Animals↗
PubMed1985

Sub-chronic administration of (-)-3-PPP and central dopamine receptor sensitivity changes.

The effects of sub-chronic treatment with (-)-3-PPP (8 mg/kg, s.c., b.i.d. for 21 days), a dopaminergic agent with mixed agonist/antagonist properties, were investigated by means of behavioural and in vivo biochemical methods. There was no change in basal locomotor activity and central dopamine (DA) synthesis after 24 hours withdrawal. A slight, though significant reduction of the locomotor suppressive effect and of the DA synthesis-stimulating effect of acute (-)-3-PPP challenge doses of 0.125 and 1.0 mg/kg (s.c.), respectively, were demonstrated in (-)-3-PPP-pretreated as compared to vehicle-pretreated rats. No change in either action was evident after acute challenge with 8.0 mg/kg (s.c.) of the drug. The plasma levels of (-)-3-PPP were virtually unchanged by pretreatment with active drug. The findings are discussed in terms of a modest down- and up-regulation of DA autoreceptors and postsynaptic receptors, respectively, induced by the subchronic (-)-3-PPP treatment.

Animals↗
PubMed1985

Dopamine-receptor agonists: mechanisms underlying autoreceptor selectivity. I. Review of the evidence.

The behavioural, biochemical, neuroendocrinological and electrophysiological actions of the enantiomers of the dopamine (DA) analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, are extensively reviewed. (+)-3-PPP acts in a fashion similar to classical direct-acting DA agonists, stimulating both DA autoreceptors and postsynaptic DA receptors, although in some situations the drug appears to exhibit partial agonist activity. (-)-3-PPP exerts a variety of actions in different pharmacological models. Either agonistic, antagonistic or both agonistic and antagonistic activity are observed depending on the anatomical location of the relevant DA receptors and the experimental conditions. The actions of transdihydrolisuride (TDHL) and the trans-fused 7-OH-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline (HW 165) are also discussed. These agents possess a similar spectrum of action to (-)-3-PPP suggesting a new generation of DA agonists which exhibit variable intrinsic activity at different DA receptors. Finally, evidence is presented indicating that the 3-PPP enantiomers display selectivity for DA receptors.

Acetylcholine↗
PubMed1985

Catecholamine-uptake inhibitors prevent the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mouse brain.

Male albino mice were injected subcutaneously with 50 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Seven days after administration, the striatal levels of dopamine(DA) and its metabolites were markedly reduced, as was the cortical level of noradrenaline (NA). Pretreatment with the selective inhibitor of DA uptake, GBR 13098, selectively and totally prevented the reduction of DA and its metabolites, whereas the selective inhibitor of NA uptake, maprotiline, selectively protected against NA depletion. The unselective inhibitors of DA and NA uptake, mazindol and nomifensine, prevented the MPTP-induced depletion of both DA and NA.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

(-)-Pindolol stereospecifically inhibits rat brain serotonin (5-HT) synthesis.

(-)-Pindolol (4 mg/kg, i.p.) stereospecifically and selectively inhibited rat brain 5-HT synthesis. The DA and NA synthesis remained unaffected by pindolol (either enantiomer) treatment, and the (-)-pindolol-induced decrease in 5-HT synthesis was not prevented by reserpine pretreatment. The results indicate that, in addition to its beta-adrenergic properties, (-)-pindolol may act as an agonist at synthesis-controlling 5-HT receptors (autoreceptors ?) in the rat CNS.

Adrenergic beta-Antagonists↗
PubMed1985

Novel dopamine receptor agonists and antagonists with preferential action on autoreceptors.

The enantiomers of cis-5-hydroxy-1-methyl-2-(di-n-propylamino)tetralin and its methyl ether have been synthesized. The compounds were tested for central dopamine (DA) receptor activity, by using biochemical and behavioral tests in rats. The (1R,2S)-(-) enantiomers of 1 and 2 are characterized as centrally acting DA-receptor agonists while the corresponding (1S,2R)-(+) enantiomers are characterized as centrally acting DA-receptor antagonists. Compounds (+)-1 and (+)-2 differ from classical neuroleptics in being able to increase DA synthesis rate in a wide dose range without reducing locomotor activity, suggesting a pronounced selectivity for DA autoreceptors. Also the (-) enantiomers seem to act preferentially on DA autoreceptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1985

Resolved monophenolic 2-aminotetralins and 1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines: structural and stereochemical considerations for centrally acting pre- and postsynaptic dopamine-receptor agonists.

A detailed structure-activity relationship is revealed for resolved, centrally acting dopamine (DA) agonists acting on both pre- and postsynaptic DA receptors. The compounds resolved are 5- and 7-hydroxy-2-(di-n-propylamino)tetralin and cis- and trans-7-hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinoline. By the superimposition of the structures of the more active enantiomers of these compounds with those of known dopaminergic agonists, apomorphine and ergolines, a new DA-receptor model is proposed as an outgrowth of current DA-receptor theories. One of the most important concepts of this receptor model is its emphasis on the possible positions taken by the N-substituents of dopaminergic compounds. One of these positions i sterically well defined while the other direction is sterically less critical. The model has been used to explain the lack of dopaminergic activity of some previously reported structures and also to predict properties of novel structures, including inherent chirality, which should be active at DA receptors. Hopefully, this heuristic DA-receptor model will lead to the discovery of more selective and potent pharmacological tools, which ultimately might lead to the development of therapeutic agents for treating diseases of dopaminergic function in the central nervous system.

Animals↗