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Biomedical subjects

S O Ogren

Publications and source records attributed to S O Ogren.

At least 145 records · Page 8Linked to original sources
PubMed1985

Specific in vitro and in vivo binding of 3H-raclopride. A potent substituted benzamide drug with high affinity for dopamine D-2 receptors in the rat brain.

The substituted benzamide drug raclopride, [((-)-(S)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl) methyl)-6-methoxy-salicylamide tartrate; FLA 870(-); A40664] was shown to be a potent and selective antagonist of dopamine D-2 receptors by its high affinity for striatal 3H-spiperone binding sites and low potency to block dopamine stimulated adenylate cyclase in vitro. In vitro studies showed that 3H-raclopride binds with a high affinity (KD = 1.2 nM) and a low proportion of non-specific binding to rat striatal homogenates. The binding of 3H-raclopride is saturable (Bmax = 23.5 pmoles/g wet wt) and reversible (dissociation half-time = 30 min) with a regional distribution of the specifically bound drug showing the following rank-order: striatum greater than nucleus accumbens greater than olfactory tubercle greater than septum greater than hypothalamus greater than hippocampus greater than frontal cortex. After in vivo administration, 3H-raclopride accumulates preferentially in dopamine rich brain areas with approximately 10 times higher levels in the striatum than in the cerebellum, when examined 30 min after injection. The in vivo binding of 3H-raclopride was saturable, reversible and showed a low component of non-specific binding. More than 90% of the drug reached the brain in a non-metabolized form as judged by thin-layer chromatography. Pharmacological analysis of 3H-raclopride binding showed that it could be displaced by dopamine agonists and antagonists but not by serotoninergic or noradrenergic drugs. Taken together, the results suggest that 3H-raclopride labels dopamine D-2 receptors with high specificity in the rat brain both in vitro and in vivo, and thus, that it should be a useful tool in studies of central dopamine D-2 receptors.

Adenylyl Cyclases↗
PubMed1985

Anticholinergic potency of psychoactive drugs in human and rat cerebral cortex and striatum.

The affinity of selected antipsychotic and antidepressant drugs for the muscarinic receptor was studied in membranes from both human and rat striatum and cerebral cortex. While there are regional differences in the anticholinergic potency of the drugs, there is good agreement between the obtained inhibition constants from the corresponding human and rat striatum (r: 0.98) and from human and rat cerebral cortex (r: 0.96). There is also good agreement between the obtained Ki values within one species: human cerebral cortex versus human striatum (r: 0.99) and for rat cerebral cortex and rat striatum (r: 0.87). Thus, the previously published quantitative estimates of the antimuscarinic activity of psychoactive drugs which were derived from studies on membranes from rat brain give an accurate estimate of the antimuscarinic activity in human brain. The drugs tested in this study include chlorpromazine acetophenazine, haloperidol, sulpiride, remoxipride (FLA-731 (-), a substituted benzamide), amitriptyline and two serotonin uptake blockers: norzimelidine and alaproclate.

Aged↗
PubMed1985

The putative serotonin receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin antagonizes the antinociceptive effect of morphine.

The effect of the selective 5-hydroxytryptamine (5-HT-1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on nociception and morphine analgesia was tested with the tail-flick method in mice. 8-OH-DPAT (0.06-1.0 mg/kg) had no apparent effect on the general behavior of the animals and did not change their reactivity to stimulation with noxious radiant heat. The compound did, however, dose-dependently attenuate the antinociception induced by administration of morphine hydrochloride (5.0 and 10.0 mg/kg). Thus, stimulation of a subpopulation of serotonin receptors may counteract the antinociceptive effect of morphine in the tail-flick test.

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

Separation of the associative and non-associative effects of brain serotonin released by p-chloroamphetamine: dissociable serotoninergic involvement in avoidance learning, pain and motor function.

p-Chloramphetamine (PCA, 0.63-5 mg/kg IP) injected 30-60 min before testing produced a dose-related impairment of avoidance acquisition, prolonged reaction time in the hot-plate test and increased locomotor activity. Pretreatment with the selective serotonin (5-HT) uptake inhibitor zimeldine (10 mg/kg IP) blocked these behavioral effects. Degeneration of brain 5-HT neurons by a high neurotoxic dose of PCA (2 X 10 mg/kg IP) or inhibition of tryptophan hydroxylase by p-chlorophenylalanine (300 mg/kg IP) also blocked the behavioral effects of PCA. There was a complete blockade of the PCA-induced avoidance deficit following pretreatment with metergoline, a central 5-HT receptor blocking agent. On the other hand, metergoline failed to block the hot-plate analgesia and the increased locomotion caused by PCA. Depletion of brain NA and DA by the tyrosine hydroxylase inhibitor H44/68 did not counteract the PCA effect on avoidance or hot-plate performance, but reduced the locomotor stimulating effect. The selective NA neurotoxin DSP4 (50 mg/kg IP) or the opiate antagonist naloxone (1 mg/kg) failed to affect the PCA-induced modulations of the behaviours studied. In addition, PCA administration in doses that caused avoidance deficits, did not result in motor impairment as assessed by the tread mill test. The above results support the hypothesis that the PCA-induced impairment of active avoidance acquisition does not involve changes in nociception or altered locomotor activity. It is concluded that behavioural processes related to serotonergic neurotransmission can be independently modified, suggesting differences in the underlying 5-HT mechanisms.

Amphetamines↗
PubMed1985

Serotonergic potentiation of muscarinic agonist evoked tremor and salivation in rat and mouse.

The dose-effect of oxotremorine upon the onset, duration and magnitude of tremor and salivation was studied in both mice and rats. The threshold doses of oxotremorine (SC) for eliciting tremor were above 50 micrograms/kg in mice and above 150 micrograms/kg in rats and the threshold doses for eliciting salivation were above 75 micrograms/kg in mice and above 200 micrograms/kg in rats. Alaproclate, a nontricyclic 5-HT uptake inhibitor, when injected 30 min prior to the administration of the cholinergic agonist, produced a dose-dependent enhancement of tremor and salivation in both rats and mice. Alaproclate itself did not produce these effects in the absence of a muscarinic cholinergic stimulant such as oxotremorine, arecoline or the acetylcholine esterase inhibitor physostigmine. Both salivation and tremor could be fully blocked by atropine at any dose of the cholinergic stimulant and of alaproclate used. The potentiating effects of alaproclate on salivation and tremor could also be blocked by two serotonin receptor antagonists, metitepine and danitracen, but not by metergoline or cinanserin. Other compounds which inhibit the uptake of 5-HT such as fluoxetine, citalopram, norzimeldine, zimeldine and the non-tricyclic antidepressant, iprindol, did not enhance the cholinergic agonist induced tremor or salivation under the same conditions as did alaproclate. It is suggested that alaproclate exerts the potentiating effect at a hitherto undefined serotonergic receptor site.

Alanine↗
PubMed1985

Involvement of spinal serotonergic pathways in nociception but not in avoidance learning.

The effects of selective lesions of the descending serotonergic (5-HT) pathways on analgesia and avoidance deficit induced by the 5-HT releasing compound p-chloroamphetamine (PCA, 2.5 mg/kg) were investigated in male rats. Intrathecal injection of 5,6-DHT (20 micrograms/rat) reduced the uptake of labelled 5-HT into spinal synaptosomes by approximately 85% but did not significantly affect the uptake of noradrenaline. The lesions produced a significant hyperalgesia and strongly attenuated the analgesic effect of PCA in the hot-plate test. In the flinch-jump test 5,6-DHT lesioned rats receiving PCA did not differ from the saline control group. Spinal lesioning did not, however, affect one-way active avoidance performance and did not prevent the marked impairment of avoidance performance induced by PCA. Thus, the avoidance deficit caused by PCA is independent of the descending serotonergic pathways and of the analgesia induced by PCA. These results support the view of a differential involvement of the ascending and descending serotonergic projections in behavioural processes controlled by aversive stimuli.

5,6-Dihydroxytryptamine↗
PubMed1985

Evidence for selective serotonergic receptor involvement in p-chloroamphetamine-induced antinociception.

Administration of the serotonin (5-HT) releasing compound p-chloroamphetamine (PCA; 2.5 mg/kg) induced potent analgesia in rats tested with the hot plate method. The analgesia was prevented by pretreatment with either of the 5-HT uptake inhibitors alaproclate (20 mg/kg) or fluoxetine (10 mg/kg). Taking into account that the noradrenergic uptake inhibitor desipramine in previous experiments failed to interfere with the effect of PCA, these results demonstrate that PCA selectively acts on 5-HT terminals. The analgesia was attenuated by administration of the 5-HT antagonists methiothepin (0.125-0.5 mg/kg) and danitracen (0.25-2.5 mg/kg) but not by a series of other 5-HT receptor antagonists or antagonists acting on noradrenergic, dopaminergic, GABAergic, histaminergic or muscarinic receptors. It is concluded that the analgesic effect of PCA is mediated via stimulation of a type of 5-HT receptors possibly belonging to the 5-HT-1 class. Further studies are, however, needed in order to firmly establish the relationship to any particular sub-type of 5-HT receptor as characterized in in vitro binding studies.

Amphetamines↗
PubMed1985

In vivo and in vitro studies on the potentiation of muscarinic receptor stimulation by alaproclate, a selective 5-HT uptake blocker.

Alaproclate (10-60 mg/kg) injected i.p. into male mice potentiated and prolonged the oxotremorine and physostigmine-induced tremor in a dose-dependent manner. Atropine completely blocked the tremor caused by oxotremorine or physostigmine both in the presence and absence of alaproclate. Pretreatment with the 5-HT receptor antagonist metitepine completely blocked the enhancement of oxotremorine-induced tremor caused by alaproclate. Biochemical studies indicated that the above effects cannot be explained by assuming that alaproclate a) acts as a cholinergic agonist, b) inhibits the acetylcholine esterase, c) interferes with choline uptake or acetylcholine synthesis, or d) directly potentiates the release of acetylcholine. In ligand binding studies alaproclate was found to be a weak competitive inhibitor of muscarinic antagonist binding to membranes from the rat cerebral cortex, rat striatum, human cerebral cortex and human striatum. (Ki approximately 28-40 microM in all four tissues). The present results suggest that alaproclate may potentiate muscarinic responses by a mechanism involving serotonergic receptor mechanisms rather than by a direct interaction with the muscarinic cholinergic receptors.

Alanine↗
PubMed1985

Central serotonin neurones in avoidance learning: interactions with noradrenaline and dopamine neurones.

The effects of p-chloroamphetamine (PCA), a serotonin (5-HT) releaser, on acquisition and retention were examined in male Sprague-Dawley rats using a one-way active avoidance task. PCA was found to impair avoidance acquisition and retention in a time dependent fashion which followed closely the temporal effects of the drug on 5-HT release in the brain. Thus, the avoidance deficit is related to the rate of change and not to the steady-state levels of 5-HT. The 5-HT releasing effect was most pronounced in the forebrain with less effect in the spinal cord. PCA caused time dependent, regional variations in catecholamine content, which was not related to avoidance performance. The avoidance and retention impairment induced by PCA was blocked by the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) but not by depletion of catecholamines with alpha-methyl-p-tyrosine (H44/68) or by the noradrenergic-selective neurotoxin DSP4. Analysis of the time dependent effects of PCA on monoamine content in saline or PCPA-treated rats indicated that the temporal effects of PCA on avoidance performance is not due to a direct or indirect action on catecholamine neurones. The present experiments support the view that the ascending serotonergic pathways play a significant role in aversive learning in the rat.

Afferent Pathways↗
PubMed1985

Potential neuroleptic agents. 3. Chemistry and antidopaminergic properties of substituted 6-methoxysalicylamides.

A series of substituted 6-methoxysalicylamides were synthesized from their corresponding 2,6-dimethoxybenzamides by demethylation of one methoxy group with boron tribromide. Substituted 6-methoxysalicylamides having a lipophilic aromatic substituent in the 3-position para with respect to the methoxy group, e.g. a bromo or an iodo atom or an ethyl or a propyl group, and having an (S)-N-(1-alkyl-2-pyrrolidinyl)methyl moiety as the side chain were found to be potent blockers of [3H]spiperone binding in vitro and potent inhibitors of the apomorphine syndrome in the rat. Similar to remoxipride but in contrast to haloperidol, some of the substituted salicylamides show a 10-20-fold separation between the dose that inhibits hyperactivity and that which inhibits stereotypy. It was concluded that, besides the requirement of a lipophilic substituent in the position para to the methoxy group for antidopamine activity in vivo, the formation of a coplanar six-membered pseudoring involving the amide moiety and the methoxy group is a structural requirement for activity in vitro.

Animals↗
PubMed1985

The importance of brain serotonergic receptor mechanisms for the action of antidepressant drugs.

The present studies have shown that chronic antidepressant treatment with different types of antidepressant drugs results in adaptive changes in postsynaptic 5-HT receptor mechanisms which appear to result in 5-HT sub- or supersensitivity development depending upon the 5-HT nerve terminal system analyzed. The results underline the heterogeneity of the central 5-HT neuron systems in their responses to chronic antidepressant treatment. In addition, a number of antidepressant drugs have potent, direct actions on 5-HT2 receptors, which may be of clinical relevance.

Animals↗
PubMed1985

[Selective antidopaminergic properties of remoxiprid, a new potential antipsychotic agent].

The pharmacology of S-(-)-3-bromo-2, 6-dimethoxy-N-(1-ethyl-2-pyrrolidinylone-ethyl)-benzamide (remoxipride), a new neuroleptic compound belonging to the benzamide group, has been thoroughly investigated using a number of different techniques. The compound blocks apomorphine-induced stereotypies and hyperactivity, indicating potent antidopaminergic activity. However, in contrast to many other antidopaminergic compounds, remoxipride induces only weak and atypical catalepsy, which indicates that remoxipride might exert less antidopaminergic side effects than other neuroleptic drugs. In vivo receptor binding studies using 3H-spiperone show that remoxipride preferentially blocks dopamine receptors only are blocked to 60% even at very high doses. In vitro receptor binding studies show that remoxipride is devoid of affinity for receptors other than the dopamine D2 receptors except at higher concentrations. These results indicate that remoxipride should be a clinically effective neuroleptic compound exerting less extrapyramidal side effects than the neuroleptics currently used.

Animals↗
PubMed1985

Evidence for a role of brain serotonergic neurotransmission in avoidance learning.

This thesis has analyzed the role of brain serotonergic (5-HT) neurotransmission in avoidance learning in the male rat using neurochemical, pharmacological and behavioural approaches. The acute and long-term effects of p-chloroamphetamine (PCA) on one-way and two-way active avoidance (AA) acquisition and retention and passive avoidance (PA) retention and on central monoamine concentrations were examined in the male rat. The effects of PCA were compared with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA). To characterize the effects of PCA the following neurotoxins were used: 5,6- and 5,7-dihydroxytryptamine (5,6- and 5,7-DHT) and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). The concentrations of biogenic monoamines and their metabolites in discrete brain regions were determined by high pressure liquid chromatography with or without electrochemical detection. The effects on 5-HT receptors in vitro and in vivo were measured by ligand binding studies (using 3H-5-HT and 3H-ketanserin as radioligands) and with behavioural techniques, respectively. Administration of the 5-HT releasing compound PCA prior to training (pre-training) produced a dose- and time-related impairment of one-way AA acquisition and retention and PA retention. A series of studies indicated that the avoidance learning deficits caused by PCA are produced by release of 5-HT, resulting in stimulation of postsynaptic 5-HT receptors. For instance, the avoidance deficit was blocked by pretreatment with the 5-HT uptake inhibitors alaproclate and zimeldine, which inhibit the 5-HT release induced by PCA. The avoidance deficits could not be related to changes (direct or indirect) in NA and DA transmission. Lesion experiments in combination with biochemical analyses provided evidence that the avoidance deficit caused by PCA involves 5-HT terminals of the forebrain, while the descending 5-HT projections seem to play a minor role. The AA acquisition deficit induced by PCA appears to be mediated via stimulation of 5-HT2 receptors, whereas the PA retention is mediated via 5-HT1 receptors. Analysis of the PCA-induced AA deficit indicated that it is mediated by non-associative factors. Thus, the performance of the PCA-treated rats was susceptible to interference from extratask contextual stimuli. Pre-training administration of PCA was found to produce a time-dependent loss in memory retention (PA retention) in animals which had acquired the response. This finding indicates that serotonin also has a role in associative learning processes e.g. in the way information is processed in the rat brain following acquisition.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

The ergolene derivative MPME induces in the rat a behavioural syndrome associated with activation of dopamine D-1 receptors belonging to the dotted type of forebrain dopamine nerve terminals.

The ergolene derivative MPME (PTR 17402; (5R,8R)-8-(4-p-methoxyphenyl)-1-piperazynylmethyl-6- methylergolene], a dopamine (DA) receptor agonist acting mainly at DA D-1 receptors linked to dotted types of forebrain DA nerve terminals, induces a characteristic behavioural syndrome consisting of increased locomotion, head-bobbing and sniffing activity without oral stereotypies or increased rearing. Haloperidol and cis-flupenthixol, nonselective DA receptor antagonists, but not selective D-2 receptor antagonists such as remoxipride and sulpiride, could significantly counteract the locomotion and head-bobbing behaviour induced by MPME. In contrast, the sniffing behaviour induced by MPME was only marginally affected by haloperidol and cis-flupenthixol pretreatment. These results suggest that activation of D-1 receptors in the forebrain mainly linked to the dotted types of DA nerve terminals in the striatum, and in the limbic forebrain, can result in behavioural effects which differ from those caused by stimulation of D-2 receptors located mainly within the diffuse types of DA nerve terminal systems.

Animals↗
PubMed1984

Remoxipride, a new potential antipsychotic compound with selective antidopaminergic actions in the rat brain.

The novel substituted benzamide, remoxipride, preferentially blocked apomorphine-induced hyperactivity with weak effects on stereotypies. The potency of remoxipride was about 50 times higher than that of sulpiride. Remoxipride caused a weak, atypical form of catalepsy and showed a high separation between the ED50 for blockade of apomorphine-induced hyperactivity and the ED50 for induction of catalepsy (ratio 24). Remoxipride was shown to be a selective dopamine D2 receptor antagonist since it displaced [3H]spiperone (IC50 = 1570 nM) but not [3H]flupentixol (IC50 greater than 100 000 nM) in rat striatum, and did not inhibit striatal DA-sensitive adenylate cyclase in vitro (IC50 greater than 100 000 nM). Remoxipride is a potent antagonist of D2 receptors showing a dose-dependent blockade of [3H]spiperone and [3H]n-propylnorapomorphine in vivo binding with a potency equal to that of chlorpromazine. In contrast to haloperidol, remoxipride caused a preferential blockade of in vivo [3H]spierone binding in the mesolimbic DA rich areas and the substantia nigra with much less effect in the striatum. In addition, remoxipride produced a preferential increase of DA utilization following synthesis inhibition in the olfactory tubercle. Only minor changes in NA and 5-HT metabolism were observed while HVA and DOPAC levels were markedly elevated. Taken together, these results indicate that remoxipride is a potent, selective D2 receptor blocking agent with a preferential action in mesolimbic and extrastriatal dopamine-containing neurons.

Adenylyl Cyclases↗
PubMed1984

The 'presynaptic' blocking potency of sulpiride and haloperidol in the rat is age-dependent.

A low dose of pergolide (0.01 mg/kg) caused a marked inhibition of locomotor activity in male rats. Sulpiride significantly blocked the locomotor inhibition in young (6 weeks of age) rats already in low (2.5 mumol/kg) doses, while in adult (15 weeks of age) rats a blockade was achieved first with high 'postsynaptic' doses (50 mumol/kg). Haloperidol slightly blocked the effect of pergolide in both young and adult rats. However, the blocking action of haloperidol was only found in a narrow pharmacological 'window' (0.05 mumol/kg). This study illustrates the importance of considering age-related variations when using behavioural models of 'presynaptic' dopaminergic agonistic activity. It is suggested that 'presynaptic' dopaminergic events are modulated by hormonal changes during growth.

Age Factors↗