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Biomedical subjects

A Carlsson

Publications and source records attributed to A Carlsson.

At least 109 records · Page 6Linked to original sources
PubMed1994

Substituted (S)-phenylpiperidines and rigid congeners as preferential dopamine autoreceptor antagonists: synthesis and structure-activity relationships.

A series of (S)-phenylpiperidines in which the substituents on the aromatic ring and nitrogen have been varied has been prepared. They have been evaluated pharmacologically to explore the importance of these substituents for the interaction with central dopamine (DA) receptors. On the basis of biochemical and behavioral data in rats, several of these compounds are characterized as centrally acting DA autoreceptor antagonists. (S)-Phenylpiperidines having an aromatic substituent with a high group dipole moment in the 3-position, i.e., meta with respect to the piperidine ring, and being N-substituted with a propyl group were found to be highly active in vivo on the synthesis and turnover of dopamine. However, they do not induce strong hypoactivity or catalepsy. Interestingly, the most active compounds in vivo were found to display only low affinity for DA D2 and D3 receptors in vitro. In addition, 7-triflate-substituted octahydrobenzo[f]quinolines and 6-triflate-substituted hexahydro-1H-benz[e]indoles have been prepared and pharmacologically evaluated. The trans isomers of these rigid structures were found to display a pharmacological profile similar to that of the flexible phenylpiperidines. The corresponding cis isomers were found to be inactive in vivo.

Animals↗
PubMed1994

Intracerebral infusion of (+)-AJ76 and (+)-UH232: effects on dopamine release and metabolism in vivo.

The dopamine D3- and autoreceptor preferring antagonists (+)-AJ76 and (+)-UH232 were administered locally in the striatum and the nucleus accumbens. Their effects on dialysate dopamine and 3,4-di-hydroxyphenylacetic acid (DOPAC) were measured and compared with the effects of raclopride. (+)-AJ76 and (+)-UH232 but not raclopride seem to interact primarily with dopamine receptors in the terminal regions of the A9 and A10 dopaminergic fibers to exert their maximal effect on dopamine release in vivo. Thus, (+)-AJ76 and (+)-UH232 seem to recruit different dopamine receptor populations as compared to raclopride. Though the dopamine receptor antagonist-induced effects on dopamine release seem to be mediated mainly by dopamine receptors in the terminal areas, the effects on DOPAC by the different antagonists seem to be mediated mainly via effects elsewhere, presumably at the somatodendritic autoreceptors. Thus, it is suggested that the regulation of extracellular dopamine and DOPAC after treatment with dopamine receptor antagonists are subjected to different control mechanisms.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Effects of MPP+ on catecholamine levels in adrenal glands and heart of rats.

The effects of MPP+ (2.5-20 mg/kg) on the adrenal glands and heart were investigated in rats. At various periods after s.c. drug administration the rats were decapitated and tissue catecholamine levels were determined by means of HPLC with electrochemical detection. Adrenal dopamine (DA) levels were reduced at 2-8 h after MPP+ administration, but this decrease was followed by an elevation after 16 h and return to the control values after one week. Three successive injections of MPP+ caused a statistically significant elevation in adrenal DA, one day, with a tendency to elevation four and seven days after the last injection, whereas a severe (up to 96%) decrease in heart noradrenaline (NA) was found one day after the last injection. Seven days after the last injection a 50% depletion of NA in the heart was still observed. Pretreatment with GBR 12909 (30 mg/kg, 4h) blocked the MPP+ (10 mg/kg, 2 h) induced reduction of adrenal DA levels, but at the same time GBR 12909 failed to block the effects of MPP+ in the heart. One day after three successive daily injections of MPP+ (10 mg/kg each), the DA-uptake inhibitor GBR 12909 (30 mg/kg, 6 h) could still induce an increase in adrenal DA. MPP+ appears to lack persistent cytotoxic action in the adrenal medulla but rather to cause a transient inhibition of DA synthesis followed by a compensatory stimulation. The inhibition can be blocked by specific inhibitor of the DA-uptake mechanism, suggesting a direct effect of MPP+ taken up by adrenomedullary cells.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenylpyridinium↗
PubMed1994

Effects of D-cycloserine and (+)-HA-966 on the locomotor stimulation induced by NMDA antagonists and clonidine in monoamine-depleted mice.

We have previously observed that an N-methyl-D-aspartate (NMDA) antagonist in combination with the alpha 2-adrenoceptor agonist clonidine produces a marked locomotor stimulation in monoamine-depleted mice. In this paper we report on how the partial glycine agonists D-cycloserine (high intrinsic activity) and (+)-HA-966 [(+)-3-amino-1-hydroxypyrrolid-2-one; low intrinsic activity] affect this response; the interaction with both an uncompetitive and a competitive NMDA antagonist was investigated. (+)-HA-966 was found to counteract the locomotor stimulation produced by clonidine combined with either an uncompetitive (MK-801 = dizocilpine) or a competitive [D-CPPene = 3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid] NMDA antagonist. D-cycloserine potentiated the locomotor stimulation produced by either NMDA antagonist combined with clonidine, although statistical significance was achieved only in the case of MK-801. If the present hyperactivity model has any relevance for psychosis the prediction based on the present results would be that d-cycloserine, contrary to current hopes, might not be so effective in schizophrenia, whereas (+)-HA-966 might be an interesting candidate.

Allosteric Site↗
PubMed1994

I. c. v. dopamine fails to alter adrenomedullary function in rats.

Intracerebroventricularly (i.c.v.) administered dopamine (50-400 micrograms/kg, 30 min; 400 micrograms/kg, 2 and 4 h) did not induce statistically significant changes in heart adrenaline (presumed to represent the adrenaline release from the adrenals). Only the highest dose (400 micrograms/kg, 30 min) brought about significant increase in adrenal dopamine (reflecting the catecholamine synthesis), accompanied by increase in heart dopamine, indicating leakage of dopamine into the peripheral circulation. The results did not support involvement of the central dopamine receptors in the short-term control of the adrenomedullary function in rats.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

On the roles of dopamine D-1 vs. D-2 receptors for the hyperactivity response elicited by MK-801.

The present study was aimed at clarifying to what extent the hypermotility induced by the uncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 depends on dopamine (DA) D-1 compared to D-2 receptor tone. The D-1 receptor antagonist SCH 23390 was found to reduce locomotion to a greater extent in MK-801-treated than in vehicle-treated mice, whereas the reverse appeared to be the case for the DA D-2 receptor antagonist raclopride. In other words, MK-801-induced hyperactivity was more readily antagonized by SCH 23390 than by raclopride and, thus, DA D-1 receptors seem to be more important than D-2 receptors for MK-801-induced hyperactivity. These results are in line with our previous observation that MK-801 generally interacts synergistically with a DA D-1 but not with a D-2 receptor agonist in monoamine-depleted mice. In view of the possible role of deficient glutamatergic neurotransmission in schizophrenia, our findings underline the importance of investigating the efficacy of selective DA D-1 antagonists in this disorder.

Animals↗
PubMed1994

Evidence for biochemical heterogeneity in schizophrenia: a multivariate study of monoaminergic indices in human post-mortal brain tissue.

A previously performed post-mortem study comparing monoaminergic indices in the brains of 14 schizophrenic patients and 10 patients with psychosis not diagnosed as schizophrenia, with age-matched control cases without any known neuropsychiatric illness, was re-investigated, using multivariate analysis. The monoaminergic patterns showing up in this analysis suggested the existence of at least two different forms of the disease, both of which could be distinguished from the controls as well as from each other. One of the schizophrenic groups consisted of paranoid cases, and had a relatively mild family history, whereas the other group, mainly consisting of hebephrenic cases, had a severe family history. The former group showed low levels of dopamine and high levels of serotonergic precursor and metabolite, whereas the latter group in some respects tended to show the opposite aberrations. Neuroleptic treatment did not seem to account for the different biochemical profiles, unless one assumes that this treatment can cause completely different monoaminergic aberrations in different individuals. Instead, one could argue that the different biochemical profiles found are characteristic of the disease.

Adult↗
PubMed1994

Differential effects of dopamine D2 and D3 receptor antagonists in regard to dopamine release, in vivo receptor displacement and behaviour.

To establish possible functional differences between the dopamine D2 and D3 receptor we investigated the relation between the ability, for a set of nine mixed dopamine D2 and D3 receptor antagonists, to displace N, N-dipropyl-2-amino-5,6-dihydroxy tetralin (DP-5,6-ADTN) from striatal binding sites and the subsequent behavioural consequences in vivo. Dopamine D2 receptor preferring antagonists are powerful displacers of DP-5,6-ADTN from the striatum. Maximal displacement is followed by strong hypomotility. Displacement of the agonist by the D3 preferring antagonist U99194A is only partial and results in synergistic increases in locomotor activity. Superimposing haloperidol upon GBR12909 leads to a synergistic increase in striatal dialysate dopamine concentrations. This effect is absent when combining GBR12909 with the putative D3 antagonist U99194A. These data give support for the hypothesis that the dopamine D3 receptor is functionally relevant at the postsynaptic level. Here, in contrast to the D2 receptor, it is proposed to exert an inhibitory influence on psychomotor functions.

Animals↗
PubMed1994

Influence of GBR 12909 and d-amphetamine on indices of catecholamine synthesis and release in rat adrenal glands.

Our previous results have shown that dopamine (DA) levels in rat adrenal glands could be increased by DA D2 receptor agonists and that this effect could be blocked by the DA D2 antagonists domperidone (supposed to be only peripherally active) and raclopride. The data now presented are aiming to characterize the effects of two indirect DA agonists, GBR 12909 and d-amphetamine, on adrenal DA levels (taken as an index of adrenal catecholamine synthesis rate), and on adrenaline (Ad) levels in the heart (assumed to reflect the Ad release from the adrenal medulla). After various periods of s.c. drug administration the rats were decapitated and tissue catecholamine levels were determined in adrenal glands, hearts and forebrains according to standard techniques by high performance liquid chromatography (HPLC) with electrochemical detection. GBR 12909 (15 and 3 mg/kg), a highly selective DA-uptake inhibitor, induced a pronounced dose dependent increase in adrenal DA and heart Ad, though not until 4 hr after administration; this effect persisted for at least 16 hr. However, a statistically significant decrease in forebrain DOPAC was observed already after 30 min. The GBR 12909 effects on adrenal DA and heart Ad were blocked by raclopride, but not by domperidone, suggesting a central site of action. d-Amphetamine, in both doses used (2.5 and 5 mg/kg) induced a statistically significant decrease in forebrain DOPAC between 30 min and 2 hr, and an increase in adrenal DA. Heart Ad was not significantly changed.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Purification of infectious pancreatic necrosis virus by anion exchange chromatography increases the specific infectivity.

An improved method for the isolation and purification of infectious pancreatic necrosis virus (IPNV) is described. Virions released into the clarified growth medium are adsorbed to an anion exchange resin of diethylaminoethyl cellulose at pH 8.1. IPNV together with the likewise released and accumulated excess pool of the precursor to the major capsid protein, ICP62, are eluted at a salt concentration between 100 and 125 mM NaCl. The bovine serum albumin content of the growth medium supplement also elutes close to this position. Upon one step of combined sucrose- and CsCl-gradient centrifugation the recovered viruses display lower levels of aggregation, higher specific nucleic acid contents and an approximately 350% higher specific infectivity as compared with pools of viruses processed in parallel and isolated according to the established method relying on precipitation with poly(ethylene glycol).

Animals↗
PubMed1994

Glutamatergic neurons projecting to the nucleus accumbens can affect motor functions in opposite directions depending on the dopaminergic tone.

1. Intracerebral cannulas were implanted stereotactically into the nucleus accumbens, dorsal striatum or nucleus entopeduncularis of male NMRI mice. 2. Monoamine-depleted mice were injected intracerebrally with the competitive NMDA receptor antagonist AP-5, the non-competitive NMDA antagonist MK-801 or the AMPA-kainate receptor antagonist CNQX. A marked locomotor stimulation was produced when AP-5 was injected into the nucleus accumbens, but not when injected into the dorsal striatum. Likewise, CNQX stimulated locomotor activity when injected into the nucleus accumbens. Neither AP-5 nor CNQX produced behavioral stimulation following injection into the nucleus entopeduncularis. 3. The tone in the monoaminergic systems influences the potency of competitive and non-competitive NMDA antagonists differently with regard to stimulation of locomotor activity. In the case of the competitive NMDA antagonist AP-5 the potency was higher in monoamine-depleted than in monoaminergically intact mice. In contrast, the potency of the non-competitive NMDA antagonist MK-801 was higher in monoaminergically intact than in monoamine-depleted animals. 4. A unilateral injection of AP-5 into the nucleus accumbens caused the animals to rotate: The rotation was predominantly ipsilateral in monoaminergically intact animals, whereas monoamine-depleted mice rotated exclusively contralaterally. When AP-5 was given to monoamine-depleted mice treated with the D-2 agonist quinpirole the animals rotated ipsilaterally, whereas monoamine-depleted mice treated with the D-1 agonist SKF 38393 still rotated contralaterally after AP-5 treatment. These data show that glutamatergic neurons projecting to the nucleus accumbens can affect behavior in different directions depending on the degree of dopamine D-2 receptor stimulation.

2-Amino-5-phosphonovalerate↗
PubMed1994

Bony atrophy after mega total hip replacement for bone tumors. 11 cases followed for 3-15 years.

We followed 11 patients 3-15 years after a cemented mega total hip replacement for a proximal femoral bone tumor. 7/8 survivors had good function and only occasional pain. 1 hip had been revised because of deep infection and in 1 case the cup had been exchanged because of aseptic loosening. 2 patients had been operated on because of local recurrence of the tumor. At follow-up, 1 patient had radiographic signs of loosening of the stem after 7 years. There was in 8 cases a pronounced athropy of the femoral cortical bone, not correlated to loosening of the stem.

Adult↗
PubMed1993

Orally active central dopamine and serotonin receptor ligands: 5-, 6-, 7-, and 8-[[trifluoromethyl)sulfonyl]oxy]-2-(di-n-propylamino)tetralins and the formation of active metabolites in vivo.

The racemic triflate derivatives 5-8 of the 5-, 6-, 7-, and 8-hydroxylated 2-(di-n-propylamino)-teralins 1-4 were shown to possess similar pharmacological profiles to their phenolic counterparts in in vitro binding and in vivo biochemical and behavioral assays in rats. Consequently, subcutaneous administration of the 5-, 6-, and 7-triflates displayed essentially dopaminergic agonist properties, while the 8-triflate was shown to be a selective 5-HT1A receptor agonist. With respect to their agonist activities, the triflates were less potent than their phenolic analogs. The absolute oral bioavailability of compound 8 (8-triflate) was 4-5 times greater than the corresponding hydroxylated compound. Interestingly, in the in vivo biochemical assay compound 8 was found to be more potent after oral than after subcutaneous administration, indicating formation of one or more active metabolites. Following a study of the metabolism of compound 8 in rat hepatocytes, the monopropyl analog 9 was identified as the major metabolite and was surprisingly found to be more potent than compound 8. Oral administration of compound 5 (5-triflate) resulted in behavioral and biochemical effects indicative of mixed DA/5-HT1A agonist properties not seen after subcutaneous administration. These results may also be indicative of the formation of active metabolites.

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

Substituted 3-phenylpiperidines: new centrally acting dopamine autoreceptor antagonists.

The (+)-and (-)-enantiomer of compounds 4 and 5 were synthesized and tested for central dopamine (DA) receptor stimulating activity, using biochemical and behavioral tests in rats. Based on the available data the (-)-enantiomers of 4 and 5 are characterized as centrally acting DA autoreceptor antagonists with oral activity. They display a similar pharmacological profile as the prototype DA autoreceptor antagonists (+)-1 and (+)-2 and show a certain preference for the D3 DA receptor antagonist binding site.

Animals↗