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S Hjorth

Publications and source records attributed to S Hjorth.

At least 91 records · Page 5Linked to original sources
PubMed1987

Anxiolytic-like action of the 3-PPP enantiomers in the Vogel conflict paradigm.

The effect of the (+)- and (-)-enantiomers of 3-PPP [conventional and atypical dopamine (DA)-receptor active agent, respectively] were investigated in a commonly used animal model of anxiety: the Vogel licking-conflict test. Low doses (less than or equal to 0.5 mg/kg SC) of both 3-PPP enantiomers resulted in anti-conflict (= anxiolytic-like) actions in this test. (-)-3-PPP proved to be almost as potent as apomorphine in releasing the punished responding (minimum effective doses; (-)-3-PPP: 0.016, and apomorphine: 0.006 mg/kg SC), whereas (+)-3-PPP was about 10 times less effective than apomorphine. In the higher dose range (greater than or equal to 1.0 mg/kg), both 3-PPP enantiomers instead induced an apparent "pro"-conflict effect; i.e. decreased responding to a level significantly below baseline, thus resulting in a biphasic dose-response curve. Simple alterations in the animals' motivation to drink, in shock threshold or in motor capabilities did not seem to be major explanatory factors either for the anti- or for the "pro"-conflict effects. With regard to the latter, the possibility is discussed of an interaction between the experimental test situation and non conflict-related effects of the drugs, thus interfering with the punished drinking. The findings are interpreted within the concept that low doses of the 3-PPP enantiomers, in particular (-)-3-PPP, may attenuate anxiety-elicited increases in the neurotransmission in certain meso-cortical/limbic DA pathways, i.e. consistent with the previously shown preferentially "limbic" net antidopaminergic profile of action of (-)-3-PPP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Biphasic effect of L-5-HTP in the Vogel conflict model.

The effect of L-5-HTP (25 400 mg/kg IP) following inhibition of the peripheral aromatic amino acid decarboxylase by means of benserazide (25 mg/kg IP) was investigated in a test modified from Vogel's drinking conflict model. At 50 mg/kg an anti-conflict action was detected, while higher doses (100-400 mg/kg) decreased punished responding. A lower dose (25 mg/kg) had no effect. Non-specific effects--such as alterations in muscle tone, in motivation to drink or in the sensitivity to electrical shock--could not explain the anxiolytic- and anxiogenic-like actions of 50 and 100 mg/kg, respectively. The bi-phasic effect of L-5-HTP is discussed in terms of different subpopulations of central serotoninergic receptors, possibly exerting opposing influences on conflict responding. The study emphasises the importance of 5-HT mechanisms in anxiety, and the possibility of finding novel anxiolytics among drugs selectively affecting central 5-HT neurotransmission.

5-Hydroxytryptophan↗
PubMed1987

Separation of dopaminergic and serotonergic inhibitory mechanisms in the mediation of estrogen-induced lordosis behaviour in the rat.

The administration of the putative 5-hydroxytryptamine1 (5-HT1) agonist 8-hydroxy-2(di-n-propylamino) tetralin (8-OH-DPAT) (0.0625-1.0 mg X kg-1) suppresses lordosis behaviour induced in ovariectomized female rats by daily treatment for 3-5 days with estradiol benzoate (1.25 micrograms/rat). A similar suppressive effect on the lordosis behaviour can be obtained by administration of the dopamine/serotonin agonist, lisuride (0.1-0.4 mg X kg-1), or after the administration of the dopamine (DA) agonists, apomorphine (0.2-0.8 mg X kg-1) or quinpirole (0.75-2.50 mg X kg-1). The suppressive effects on the lordosis behaviour by 8-OH-DPAT cannot be antagonized by the DA receptor antagonist haloperidol (0.2 mg X kg-1) neither with methiotepin (0.5 mg X kg-1), which is assumed to be a non-selective 5-HT receptor blocking agent, nor with pirenperone (0.25 mg X kg-1) which is assumed to be a 5-HT2 receptor blocking agent. However, a partial blockade of the lordosis suppressive effects of 8-OH-DPAT was obtained by treatment with (-)-pindolol, which is thought to be a partial 5-HT1 blocking agent, suggesting that 8-OH-DPAT exerts its suppressive effects on the lordosis behaviour through the 5-HT system. Haloperidol causes a complete blockade of the suppressive effects of apomorphine and quinpirole suggesting that these drugs exert their inhibitory effects on the lordosis behaviour by activating the DA system.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

C1- and C3-methyl-substituted derivatives of 7-hydroxy-2-(di-n-propylamino)tetralin: activities at central dopamine receptors.

C1- and C3-methyl-substituted derivatives of the potent dopamine (DA) receptor agonist 7-hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT) have been synthesized, and their conformational preferences have been studied by use of NMR spectroscopy, X-ray crystallography, and molecular mechanics (MMP2) calculations. The compounds were tested for activity at central DA receptors, by use of biochemical and behavioral tests in rats. (1S,2R)-7-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin [(+)-10] was demonstrated to be sevenfold less potent than (2R)-7-OH-DPAT as a DA receptor agonist. The other new compounds were of lower potency or inactive.

Animals↗
PubMed1987

(+)-cis-8-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin: a potent and highly stereoselective 5-hydroxytryptamine receptor agonist.

C1-Methylated derivatives of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1) were synthesized and tested for central 5-HT and dopamine receptor activity by use of a biochemical test method in rats. cis-8-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin (8) was found to be a 5-HT receptor agonist. The (+)-enantiomer of 8 had a potency equal to that of 1, whereas (-)-8 and the trans isomer (+/-)-9 were inactive.

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

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

Stereoselective inhibition of prolactin secretion by (-)-HW-165, a novel 3-PPP congener; further support for similarities between central DA autoreceptors and pituitary lactotroph DA receptors.

The novel atypical dopamine (DA) receptor agonist HW-165 (trans-7-hydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline), a 'rigid' 3-PPP congener, and its enantiomers were investigated with regard to their actions on prolactin (PRL) release in rats. Racemic HW-165 dose dependently inhibited the elevation of PRL secretion induced by monoamine synthesis disruption (NSD 1015) combined either with abolished DA nerve impulse flow (GBL) or with monoamine depletion (reserpine). Racemic HW-165 was roughly equipotent to 3-PPP but 5-10-fold less potent than apomorphine. The PRL inhibitory action of racemic HW-165 was stereoselectively prevented by the DA antagonist (+)-butaclamol. Since the chiral aspect of lactotroph DA receptor activation by 'atypical' DA receptor agonists has not been covered in previous investigations the effects of the HW-165 enantiomers were now studied. Our findings suggest that the PRL inhibitory properties of racemic HW-165 reside in its (-) enantiomer, (+)-HW-165 being devoid of activity. Taken together, the results reinforce the concept that the pituitary lactotroph DA receptors mediating the inhibition of PRL release are similar, notably also from a stereochemical point of view, to central DA receptor sites with presumed high agonist sensitivity, such as DA autoreceptors.

4-Butyrolactone↗
PubMed1986

Suppression of lordosis behavior by the putative 5-HT receptor agonist 8-OH-DPAT in the rat.

The administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), inhibited the lordosis induced by estradiol benzoate or estradiol benzoate plus progesterone in ovariectomized rats. There was no facilitation of lordosis by 8-OH-DPAT in animals pretreated with a threshold dose of estradiol benzoate. The results are consistent with the view that 8-OH-DPAT is an agonist at 5-HT receptors and provide further support for an inhibition role of central 5-HT in the mediation of lordosis behavior.

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

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↗
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

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

Modifications of sleep parameters in the rat by (+)- and (-)-3-PPP.

The effects of subcutaneous administration of the two enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP), a new dopamine analogue, were studied with regard to their effects on sleep parameters in the rat. The studies with both enantiomers were carried out taking into account their different effects on central dopaminergic receptors. At low doses they act preferentially as autoreceptor agonists; at higher doses the (+)-form is also an agonist while the (-)-form acts as an antagonist at postsynaptic dopamine receptors. The results showed the following: (1) with the high dose of (+)-3-PPP there was no change in REM sleep, but a marked increase in wakefulness; (2) with the high dose of (-)-3-PPP there was a significant increase in REM sleep and in the mean duration of REM episodes; (3) with the low dose of (+)-3-PPP similar results to those described for high-dose (-)-3-PPP were obtained; (4) there was no significant alteration of sleep parameters with the low dose of (-)-3-PPP. The data are discussed in terms of an active role for dopamine in the regulation of REM sleep.

Animals↗
PubMed1985

Hypothermia in the rat induced by the potent serotoninergic agent 8-OH-DPAT.

The potent, centrally acting 5-HT receptor agonist 8-OH-DPAT was shown to induce a clearcut hypothermic response in naive and PCPA-pretreated conscious rats, maintained at 22 degrees C. PCPA pretreatment decreased the threshold dose of 8-OH-DPAT required to cause hypothermia, indicating that a sensitisation of 5-HT-receptor dependent mechanisms was involved. The results are discussed with reference to recent 5-HT receptor subclassification. It is suggested that body temperature measurements in the rat might provide a simple in vivo physiological means of studying central serotoninergic mechanisms, including 5-HT receptor sensitivity modification.

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