Effects of mazindol on rat brain synaptosomal monoamine uptake

The effects of the anorectic drug mazindol on the uptake of [³H]NA and (³H]5HT by rat hypothalamic synaptosomes and the uptake of [³H]DA by rat striatal synaptosomes were investigated. In in vitro studies drugs were added to the incubation medium. In ex vivo experiments drugs were injected i.p. at various times prior to death and synaptosomal [³H] monoamine uptake subsequently determined. Two other anorectics (d-amphetamine and dl-fenfluramine) and two inhibitors of monoamine uptake (chlorimipramine and desipramine) were included for comparative purposes. Mazindol was a potent inhibitor of [³H]NA and [³H]DA uptake in vitro being approx. 0.5 times as potent as desipramine and d-amphetamine respectively. The abilities of mazindol, fenfluramine and desipramine to block the in vitro uptake of [³H]5HT were comparable and all three drugs were appreciably less potent than chlorimipramine. Following 1hr pretreatment, d-amphetamine was the most potent of the five drugs at inhibiting synaptosomal [³H]NA and [³H]DA uptake. Mazindol was approx. 2.5 times more potent than desipramine at blocking [³H]NA uptake. In contrast to the other drugs, pretreatment with large doses of mazindol had essentially no effect on hypothalamic synaptosomal [³H]5HT uptake. Results of ex vivo studies thus confirm in vivo findings that mazindol is a selective inhibitor of rat brain catecholamine uptake.     

(Z)-Dimethylamino-l-(4-bromophenyl)-l-(3-pyridyl) propene (H 102/09), a New Selective Inhibitor of the Neuronal 5-Hydroxytryptamine Uptake

Abstract The inhibition of the uptake of ³H–(–)–noradrenaline (NA), ³H–dopamine and ¹⁴C–5–hydroxytryptamine (5–HT) in mouse brain slices by (Z)–3–dimethylamino–l–(4–bromophenyl)–l–(3–pyridyl)propene (H 102/09), desipramine and chlorimipramine and their releasing effect on the ³H–amines previously accumulated in the slices were examined. The interactions with reserpine produced hypothermia and sedation and the 5–hydroxytryptophan (5–HTP) syndrome in mice were also studied. Due to the poor inhibitory activity on the NA uptake H 102/09 was a more selective inhibitor of the 5–HT uptake than was chlorimipramine, particularly after administration in vivo, where it was as potent as chlorimipramine (ED50 = 19 μmol/kg intraperitoneally). In vitro chlorimipramine was 6 to 12 times more active than H 102/09. Desipramine was a very selective inhibitor of the NA uptake in vitro and in vivo. The compounds were generally more potent in inhibiting the uptake than in releasing the amines. However, in striatal slices the inhibition of DA uptake could be due to the releasing effect since the difference in potencies were small. The effect of desipramine on 5–HT uptake and that of H 102/09 on NA uptake could also involve a release component. The 5–HTP syndrome was potentiated by H 102/09 and chlorimipramine but not by desipramine. The reserpine hypothermia but not the sedation was potently antagonized and reversed by desipramine and by chlorimipramine at high doses but not by H 102/09, suggesting that NA but not 5–HT is involved in the hypothermic action of reserpine.     

Interactions between reserpine and various compounds on the accumulation of [14C] 5-hydroxytryptamine and [3H]noradrenaline in homogenates from rat hypothalamus.

The effect of reserpine, 5 mg/kg i.p., on the potencies of various compounds in inhibiting the accumulation of [¹⁴C] 15-hydroxytryptamine (5-HT) and [³H] (?)-noradrenaline (NA) in synaptosome-rich homogenates from rat hypothalamus was examined. It was found that some compounds, e.g. tryptamine, α-methyltryptamine, (+)-amphetamine and 4-chloroamphetamine, were considerably more potent in inhibiting the 5-HT accumulation in the reserpinized preparation than in the control preparation, whereas other compounds, e.g. chlorimipramine, zimelidine, norzimelidine, fluoxetine, alaproclate and desipramine, had the same activities in the two preparations. The inhibitory potencies of the same compounds on the [³H] NA accumulation was, on the other hand, not influenced by reserpine. The results indicate that tryptamines and amphetamines inhibit the 5-HT accumulation by releasing 5-HT rather than inhibiting its uptake. The same conclusion cannot be drawn for the inhibitors of the NA accumulation.     

Antagonism of fenfluramine-induced hyperthermia in rats by some, but not all, selective inhibitors of 5-hydroxytryptamine uptake

The injection of fenfluramine (7.5 mg kg-1,i.p.) to rats housed at 27-28 degrees C was associated with an elevation of core body temperature which peaked at approximately 1 h post-injection. One h pretreatment with citalopram (20 mg kg-1, i.p.), chlorimipramine (10 mg kg-1, i.p.), femoxetine (10 mg kg-1, i.p.) and fluoxetine (20 mg kg-1, i.p.) resulted in an attenuated response to fenfluramine. In contrast, Org 6582 (20 mg kg-1) and zimelidine (20 mg kg-1) were devoid of an effect on fenfluramine-induced hyperthermia. The response to fenfluramine was was also blocked by i.p. injections of metergoline (0.2 mg kg-1), methysergide (5 mg kg-1) and mianserin (0.5 mg kg-1). Rectal temperature was unaltered by both the 5-hydroxytryptamine (5-HT) uptake inhibitors and the 5-HT receptor antagonists. The IC50 values (nM) for in vitro inhibition of [3H]-5-HT uptake into rat hypothalamic synaptosomes were for citalopram 2.4, chlorimipramine 8.8, femoxetine 14, fluoxetine 16, Org 6582 75 and zimelidine 250. The injection of all six compounds (20 mg kg-1, i.p.) 1 h before death was associated with an inhibition of [3H]-5-HT uptake into rat hypothalamic synaptosomes which ranged from 47.2% for chlorimipramine to 83.3% for citalopram. Rat hypothalamic 5-HT levels were decreased by approximately 50% 3 h after the injection of fenfluramine (15 mg kg-1, i.p.). This effect was blocked by a 1 h pretreatment with fluoxetine, Org 6582 and zimelidine (all 20 mg kg-1, i.p.). Ki values for displacement of specifically bound [3H]-5-HT (1 nM) to rat hypothalamic membranes were for metergoline 26 nM, methysergide 1.1 microM, mianserin 3.6 microM, chlorimipramine 9.2 microM and fluoxetine 32.7 microM. Values for citalopram, femoxetine, Org 6582 and zimelidine were in excess of 65.4 microM.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of a specific 5-HT uptake inhibitor,citalopram (Lu 10-171), on 3H-5-HT uptake in rat brain synaptosomes in vitro

The uptake of ³H-5-HT in synaptosomes from rat brains was investigated. Addition of DA or NA had only a slight or no effect on the uptake. When the uptake into NA and DA neurons was inhibited by the addition of high concentrations of NA and DA, the uptake of ³H-5-HT was unchanged. This was also found after destruction of NA and DA neurons by 6-hydroxydopamine treatment. Furthermore, the uptake of ³H-5-HT was almost equal in different brain parts containing NA and DA in very different amounts. These observations show that the uptake measured with ³H-5-HT is specific for 5-HT neurons.The present study revealed that citalopram and chlorimipramine inhibited uptake competitively, and in this respect the two drugs were equipotent. Compared with a series of tricyclic thymoleptics, the two drugs were the most potent inhibitors of 5-HT uptake, about 20 to 35 times more active than imipramine and amitriptyline. The metabolites of citalopram were also rather potent. The results obtained in the present study correlate closely with those obtained using inhibition of ¹⁴C-5-HT uptake in blood platelets, or using the inhibition of H 75/12-induced 5-HT depletion in rat brain.When rats were treated orally with citalopram or chlorimipramine, the inhibition of ³H-5-HT uptake in synaptosomes derived from these rats was two times greater after citalopram than after chlorimipramine.     

Comparison of the effects of 6-chloro-2-aminotetralin and of Org 6582, a related chloroamphetamine analog,on brain serotonin metabolism in rats

Org 6582 and 6-chloro-2-aminotetralin can be viewed as p-chloroamphetamine analogs having rigid conformation. Because p-chloroamphetamine exerts multiple actions on brain serotonin neurons, we compared the effect of these rigid analogs on certain parameters of brain serotonin metabolism in rats to determine the extent of dissociation of these multiple actions. 6-Chloro-2-aminotetralin resembled p-chloroamphetamine in lowering brain levels of tryptophan hydroxylase, serotonin and 5-hydroxyindoleacetic acid (5-HIAA) in rat brain, though its effects were less than those of p-chloroam-phetamine and were short-lasting in contrast to the permanent neurotoxic effects of p-chloroamphetamine. Org 6582 did not lower tryptophan hydroxylase or serotonin levels in rat brain; its lowering of 5-HIAA levels can be attributed to its inhibition of serotonin re-uptake. In vitro, Org 6582 was a slightly stronger inhibitor of serotonin uptake than was 6-chloro-2-aminotetralin but a distinctly weaker inhibitor of monoamine oxidase. Inhibition of uptake into serotonin neurons in vivo was evaluated by measuring the ability of 6-chloro-2-aminotetralin and of Org 6582 to antagonize the neurotoxic effects (lowering of serotonin levels or lowering of serotonin uptake) produced by p-chloroamphetamine. In these experiments, Org 6582 but not 6-chloro-2-aminotetralin was a potent inhibitor of uptake into serotonin neurons in vivo, in agreement with the findings of Goodlet et al. [I. Goodlet, S. E. Mireylees and M. F. Sugrue, Br.J. Pharmac.56, 367P (1976)] and of Sugrue et al. [M. F. Sugrue, I. Goodlet and S. E. Mireylees, Eur.J. Pharmac.40, 121 (1976)] on Org 6582.     

Importance of duration of drug action in the antagonism of p-chloroamphetamine depletion of brain serotonin-comparison of fluoxetine and chlorimipramine

Fluoxetine inhibited both the rapid depletion of brain serotonin by p-chloroamphetamine (PCA) and the ultimate irreversible effects of PCA on brain serotonin neurons in rats; the differences between fluoxetine and chlorimipramine as PCA antagonists appeared to be related to the duration of uptake inhibition by these agents. Fluoxetine given along with PCA in a single dose prevented serotonin depletion at all times after PCA. Chlorimipramine antagonized serotonin depletion initially, but at later times there was little or no protection against PCA effects. The dose-dependence of the antagonism of PCA by fluoxetine did not vary greatly with the time of serotonin measurement after PCA. but with chlorimipramine the effectiveness of a given dose depended markedly on that time interval. Lengthening the pretreatment interval prior to PCA injection from 0 to 16 hr diminished the effectiveness of chlorimipramine but not fluoxetine as antagonists of serotonin depletion. The differences between fluoxetine and chlorimipramine may arise primarily because these compounds are metabolized by N-demethylation. The demethylated metabolite of fluoxetine was as potent and specific as fluoxetine itself as a serotonin uptake inhibitor both in vitro and in vivo, whereas the demethylated metabolite of chlorimipramine was less active than chlorimipramine as a serotonin uptake inhibitor and more active as a norepinephrine uptake inhibitor. Chlorimipramine was a more effective PCA antagonist when injected into mice in repeated doses or when injected into rats along with an inhibitor of liver microsomal enzymes. Thus, comparison of uptake inhibitors as antagonists of PCA is strongly influenced by the pharmacokinetics of the drugs involved.     

Effect on radiolabelled-monoamine uptake in vitro of plasma taken from healthy volunteers administered the antidepressant sibutramine HCl

Sibutramine HCl, a monoamine reuptake inhibitor type of antidepressant, was administered to healthy male volunteers as either a single dose (12.5 or 50 mg) or repeated treatment (5–20 mg once daily or 15 mg twice daily). Plasma, obtained at regular intervals during and after sibutramine HCl or placebo treatment, was assayed in vitro for its ability to inhibit the uptake of [³H]-noradrenaline (NA) by rat cortical synaptosomes, [³H]-5-hydroxytryptamine (5HT) by human platelets and [¹⁴C]-dopamine (DA) by rat striatal synaptosomes. After both single and repeated sibutramine HCl administration, the rank order of uptake inhibition was [³H]-NA>[³H]-5HT>[¹⁴C]-DA. The level of monoamine uptake inhibition increased on daily administration to a plateau 4–6 days after initiation of treatment, for example, approximately 60% and 40% inhibition of [³H]-NA and [³H]-5HT, respectively, following 15 mg sibutramine HCl twice daily. The pattern of monoamine uptake inhibition following sibutramine HCl administration to man is similar to that observed in sibutramine HCl-treated rats, and probably at least partly reflects inhibition of uptake by drug metabolites in both species. The inhibition of monoamine uptake following sibutramine HCl administration to man is consistent with an antidepressant effect.     

Specific inhibitory action of a novel antidepressant paroxetine on 5-HT uptake

Effect of a novel antidepressant, paroxetine, on the uptake of serotonin (5-HT), noradrenaline (NA) and dopamine (DA) as well as on various neuro-receptors were investigated in comparison with those of the tricyclic antidepressants amitriptyline, chlorimipramine and imipramine. Paroxetine showed a potent 5-HT uptake inhibitory action, giving the NA/5-HT ratio of 886 in comparison with the ratios of 1.7, 15 and 1.5 for amitriptyline, chlorimipramine and imipramine, respectively. On the other hand, paroxetine showed almost no inhibitory action on the binding of the [3H]-labeled ligands examined in this study [( 3H]quinuclidinyl benzilate, [3H]5-HT, [3H]ketanserine, [3H]pyrilamine, [3H]dihydroalprenolol, [3H]prazosin, [3H]clonidine and [3H]spiroperidol). In contrast, the tricyclic antidepressants showed inhibitory action on a number of bindings and also revealed comparatively high affinities especially for muscarine, histamine-1 and alpha 1-adrenaline receptors responsible for the side effects. From the above findings, it can be concluded that paroxetine has only a weak affinity for various neuro-receptors and inhibits specifically 5-HT uptake.     

Uptake and release of 5-hydroxytryptamine by enteric 5-hydroxytryptaminergic neurones: effects of fluoxetine (Lilly 110140) and chlorimipramine.

The effect of fluoxetine on uptake of 5-hydroxytryptamine (5-HT) by enteric 5-hydroxytryptaminergic neurones has been analyzed in order to compare further these neurones with 5-HT neurones of the CNS. In addition, the effects of fluoxetine and chlorimipramine on efflux of [3H]-5-HT from the myenteric plexus were also evaluated. Fluoxetine was found to be a competitive inhibitor of 5-HT uptake by the myenteric plexus and was a more potent inhibitor of 5-HT uptake than was chlorimipramine. However, chlorimipramine enhanced the efflux of [3H]-5-HT more than could be explained by inhibition of 5-HT uptake and, therefore, appears to have the additional action of releasing the amine. These observations, similar to those of others studying central neurones, support the view that enteric 5-HT neurones resemble those of the CNS and are a useful model for the evaluation of drugs.     

In vivo [3H]spiperone binding to the rat hippocampal formation: Involvement of dopamine receptors

The existence of DA receptors in the rat hippocampus was demonstrated with an in vivo [³H]spiperone radio-receptor assay. Kinetic studies revealed that maximum binding of [³H]spiperone in hippocampus was much smaller than in striatum and frontal cortex but much higher than in cerebellum. In inhibition studies of [³H]spiperone binding, all neuroleptics tested were active in hippocampus as well as in striatum. In contrast, 5HT antagonists were definetely less potent in these two brain regions than in frontal cortex. Finally, even when 5HT receptors were blocked, dipropyl-ATN and haloperidol remained fully effective in hippocampus, striatum, but also in frontal cortex although to a lesser degree. From these results it was concluded that [³H]spiperone binds mainly to DA receptors in hippocampus as well as in striamtum, whereas both 5HT and DA receptors are present in frontal cortex.     

The serotonin autoreceptor: Antagonism by quipazine

The purpose of this study was to attempt to reproduce previous findings regarding the antagonist specificity of the 5 HT autoreceptor and to find additional antagonists of this receptor. Crude synaptosomal preparations of the rat hypothalamus were loaded with [³H]5HT, placed on glass microfiber filters and superfused with modified Krebs-Henseleit buffer at 37°C. The release of [³H]5HT was stimulated by raising the buffer K⁺ concentration and was Ca²⁺-dependent. In the presence of 100 nM fluoxetine (a selective 5HT uptake inhibitor), exogenous 5HT inhibited the K⁺-induced release of [³H]5HT but did not affect basal [³H]5HT release. The K⁺-induced [³H]5HT release was maximally inhibited by 30 nM 5HT to a level of 66.4 ± 4.0% of control. The concentration of 5HT required to inhibit half-maximally K⁺-induced [³H]5HT release was approx. 7nM. Methiothepin and quipazine were found to block the inhibition of K⁺-induced [³H]5HT release by exogenous 5HT (30 nM). The IC₅₀S for blockade of the effects of 5HT were approx. 3.8 and 670 nM for methiothepin and quipazine, respectively. Several other putative 5HT antagonists, the dopamine receptor antagonist, spiperone and the alpha receptor antagonist, phentolamine, were without effect. Thus, the 5HT autoreceptor appears to have a unique specificity for certain 5HT antagonists. In addition, blockade of 5HT autoreceptors may be one mechanism by which quipazine produces behavioral effects characteristic of a 5HT receptor agonist.     

The noradrenaline receptor coupled adenylate cyclase system in brain

Summary The present studies were undertaken to ascertain whether or not an alteration in the availability of serotonin (5 HT) can modify central noradrenergic function at the level of the noradrenaline (NA) receptor coupled adenylate cyclase system in brain. The chronic but not acute administration of the 5HT uptake inhibitors amitriptyline and chlorimipramine reduced the sensitivity of the cyclic AMP generating system to NA in the limbic forebrain. This subsensitivity was linked to a decrease in the B _max value of -adrenergic binding sites without appreciable changes in the K _d values, as assessed by specific ³H-dihydroalprenolol binding. The specific 5HT uptake inhibitor fluoxetine did not change either the responsiveness of the cyclic AMP generating system to NA or the density of -adrenergic receptor sites. Raphé lesions which selectively reduced the level of 5HT also did not cause any changes in the neurohormonal responsiveness or the density of -adrenergic receptor sites. In contrast, medial forebrain bundle lesions which reduced the levels of both 5HT and catecholamines (NA and dopamine) in the forebrain, increased the responsiveness of the cyclic AMP generating system to NA. It can thus be concluded that a selective change in the availability of 5HT per se does not modify noradrenergic receptor function at the level of the NA receptor coupled adenylate cyclase system. The subsensitivity of the noradrenergic receptor system developed following amitriptyline and chlorimipramine may in all likelihood be due to the in vivo conversion to the secondary amines, nortriptyline and desmethylchlorimipramine respectively. These secondary amine metabolites are potent inhibitors of the NA reuptake and consequently could be responsible for the demonstrated in vivo down-regulation of central adrenergic receptor function (homospecific down-regulation).     

EFFECTS OF RESERPINE ON THE CONTENT AND UPTAKE OF DOPAMINE AND NORADRENALINE IN RABBIT ARTERIES

1. Change with time of the content and uptake of dopamine (DA) and noradrenaline (NA) in the renal, superior mesenteric and femoral arteries and abdominal aorta of rabbit after reserpine administration was examined. Endogenous DA and NA were measured by high performance liquid chromatography coupled with electrochemical detector. 2. A single dose of reserpine (3 mg/kg, i.p.) maximally depleted the endogenous DA and NA contents in the four blood vessels 24 h after the administration; the ratios of reductions were 70–90% and approximately 90% of the normal levels, respectively. The DA contents in all four vessels recovered to the normal level within 4 days after reserpine. However, NA content did not recover to the normal levels within 30 days after reserpine except in the mesenteric artery. 3. The activity of dopamine β-hydroxylase (DBH) significantly increased in all four blood vessels 1 h after reserpine. Although the DBH activity returned to the normal level after 3 days in the mesenteric artery, it returned within 24 h in the other three vessels. 4. [³H]-Dopamine and [³H]-NA uptake were almost completely depressed 1 h after reserpine. The [³H]-NA uptake in four vessels recovered to the normal level 2–14 days after reserpine, and [³H]-DA uptake recovered after 30–45 days. Thus, the endogenous DA content in blood vessels was completely restored although DA uptake and NA content were still affected. 5. These results suggested that the recovery of stored DA after reserpine was faster than that of stored NA and the recovery of DA uptake after reserpine was slower than NA uptake. This indicates a possibility that a part of DA pool may be different from NA pool in adrenergic nerve terminals in the blood vessels.     

Disposition and pharmacological effects of m-Chlorophenylpiperazine in rats

1-(m-Chlorophenyl)piperazine (CPP) was a potent inhibitor of [³H]-serotonin binding to membrane receptors from rat brain in vitro, its K_i being 138 nM. It had less effect on [³H]-lysergic acid diethylamide binding (K_i = 300 nM), the relative K_i, values indicating CPP to be a serotonin receptor agonist. A dose-related decrease in 5-hydroxyindoleacetic acid (5-HIAA) concentration in rat brain in vivo, was caused by CPP, with no effect on serotonin concentration, and CPP reduced the rate of 5-HIAA accumulation after probenecid. Also, CPP caused a dose-related increase in corticosterone concentration in rat serum, as did'fluoxetine (an inhibitor of serotonin uptake). Milk-drinking was suppressed by CPP in non-fasted rats, whereas fluoxetine had no effect; the effect of CPP was doserelated and was antagonized by metergoline. These results are consistent with the idea that CPP acts principally as a direct serotonin agonist rather than as a serotonin uptake inhibitor in vivo. The half-life of CPP in brain was just over 1 hr in control rats and about 3hr in rats pretreated with iprindole, an inhibitor of aromatic ring hydroxylation. In iprindole-treated rats, the dose-response curve for lowering the concentration of 5-HIAA CPP at 4hr was shifted to the left, and the duration of 5-HIAA concentration lowering by a 10 mg/kg dose of CPP was prolonged. 1-(p-Chlorophenyl)piperazine had a longer half-life in rat brain than did CPP and caused almost as much serotonin receptor stimulation in vivo as did CPP due to the higher drug levels, despite its lower affinity for serotonin receptors in vitro. In iprindole-treated rats, CPP was more potent than in control rats in elevating serum corticosterone and prolactin. 1-(m-Chlorophenyl)piperazine is a known metabolite of the antidepressant drug trazodone and may contribute to or account for some of the in vivo effects of trazodone.     

Different effects of serotonin (5-HT) uptake blockers in caudate nucleus and hippocampus of the rabbit: Role of monoamine oxidase in dopaminergic terminals

Slices of rabbit hippocampus or caudate nucleus were incubated with [³H]-5-HT (0.1 µM, 60 min) or with [³H]-DA. In hippocampal tissue, the 5-HT uptake blockers chlorimipramine, fluvoxamine, and 6-nitroquipazine (0.1, 1, 10 µM) reduced the percentage content of [³H]-5-HT in a concentration dependent manner. The degree of inhibition of [³H]-5-HT content produced by the 5-HT uptake inhibitors was not affected by the MAO inhibitors pargyline or amezinium (which by themselves enhanced [³H] loading) or the catecholamine uptake inhibitor nomifensine (which by itself did not affect [³H] loading). In caudate nucleus tissue, however, the [³H]-5-HT accumulation was reduced only at the highest concentration of the 5-HT uptake blockers (10 µM). In the additional presence of the MAO inhibitors or nomifensine (which by themselves increased or diminished, respectively, the [³H] labelling) the 5-HT uptake inhibitors became more potent in reducing the percentage [³H]-5-HT accumulation of caudate nucleus slices. These results indicate (1) that a false labelling of [³H]-5-HT into dopaminergic terminals in the caudate nucleus can be prevented by nomifensine, (2) that the 5-HT uptake blockers seem to accumulate within the dopaminergic terminals, where they may display a MAO inhibitory property. The 5-HT uptake blockers were ineffective on the percentage tritium accumulation of caudate nucleus slices incubated with [³H]-DA, regardless of the presence of pargyline or nomifensine. Tritiated DA and deaminated [³H]-metabolites were separated in the superfusate of [³H]-DA-release experiments in caudate nucleus tissue. In the presence of 6-nitroquipazine the percentage efflux of unmetabolized [³H]-DA was significantly enhanced in a concentration and time dependent manner. In comparison to 6-nitroquipazine, fluvoxamine was less potent in that respect. 6-Nitroquipazine inhibited the electrically evoked [³H]-DA and [³H]-ACh release from caudate nucleus slices in a concentration dependent manner. The effects on [³H]-DA release were abolished in the presence of pargyline. The inhibition of [³H]-ACh release was significantly diminished by the D₂-receptor antagonist domperidone. In conclusion, some 5-HT-related drugs may diminish the release of ACh from caudate nucleus slices via an enhanced dopaminergic transmission due to inhibition of MAO within the dopaminergic terminals.     

Neurochemical characterization of a new potent and selective serotonin uptake inhibitor: Lu 10-171

The neurochemical characteristics of a new bicyclic phthalane derivative — Lu 10-171 [1-(3-(dimethylamino)propyl)-1-(p-fluorophenyl)-5-phthalan-carbonitrile; citalopram] — have been investigated. Lu 10-171 and its metabolites were compared with tricyclic thymoleptics in several tests for serotonin (5-HT), noradrenaline (NA), and dopamine (DA) uptake inhibition in vitro and in vivo. Lu 10-171 is a very potent and completely selective inhibitor of the 5-HT reuptake mechanism, being 2–10 times as active as chlorimipramine. The metabolites of Lu 10-171 show weak 5-HT uptake inhibiting properties. Lu 10-171 and its metabolites are devoid of NA uptake inhibiting properties and in this respect they clearly differ from the tricyclic anti-depressants, which possess effects both on 5-HT and NA uptake. The inhibition of 5-HT uptake in vitro is competitive and not connected with an increased efflux of 5-HT. Lu 10-171 and its metabolites only inhibit DA uptake in extremely high concentrations and in this respect they are even weaker than chlorimipramine and other tricyclic thymoleptics. Like the tri-cyclic thymoleptics, Lu 10-171 is without effect on MAO and does not change the endogenous levels of brain monoamines. Due to the selective action on 5-HT uptake, Lu 10-171 seems to be a valuable tool in studying the role of central 5-HT neurone systems in experimental neuropharmacology as well as in the ethiology of depressive illness.     

Inhibition of serotonin uptake by optical isomers of fluoxetine

The optical isomers of fluoxetine, a selective inhibitor of serotonin (5-hydroxytryptamine, 5HT) uptake, have been compared pharmacologically. As inhibitors of ³H-5HT uptake in cortical synaptosomes and of ³H-fluoxetine binding in cortical membranes, the (+)-isomer of fluoxetine was slightly more potent than the (?)-isomer. The potencies to inhibit ³H-5HT uptake ex vivo in synaptosomal preparations of cerebral cortex and brain stem were about the same, except that the (?)-isomer had a much shorter duration of action than the (+)-isomer in rats.     

On the role of 5-hydroxytryptamine in drug-induced antinociception.

1. The effects of four specific inhibitors of 5-hydroxytryptamine (K-HT) uptake on morphine-, methadone- or pethidine-induced antinociception was studied in rats. Antinociception was assessed by means of hot plate (55 degrees C) reaction times. The effect of the compounds on the uptake of [3H]-5-HT into rat whole brain synaptosomes was also investigated. 2. Pretreatment with Org 6582, citalopram, zimelidine or femoxetine at doses devoid of antinociceptive activity potentiated morphine- but not methadone- or pethidine-induced antinociception. 3. A temporal correlation existed between the ability of Org 6582 to potentiate morphine-induced antinociception and to block synaptosomal [3H]-5-HT uptake. 4. 5-HT plays a critical role in the antinociceptive effect of morphine but not of methadone or pethidine.     

Phencyclidine-induced release of [3H]dopamine from chopped striatal tissue

Phencyclidine was examined for its ability to release [³H]dopamine ([³H]DA) from prelabelled chopped rat striatal tissue. A dynamic perfusion system was used in order to minimize the effects of drugs on uptake mechanisms. Cocaine and S-(+)-amphetamine were used to distinguish uptake inhibition from a neurotransmitter releasing action. Phencyclidine, starting at 3 μM, caused a dose-dependent increase in efflux of [³H]DA from chopped striatal tissue. In this same preparation, cocaine, a known neuronal uptake inhibitor of dopamine, was unable to release [³H]DA except in the largest dose of 100 μM. S-(+)Amphetamine, a known releaser of neuronal dopamine, was found to be about ten times more potent than phencyclidine in causing a dose-dependent release of [³H]DA. The results of the above experiments are discussed in relation to the ability of phencyclidine to decrease the synaptosomal accumulation of [³H]DA. It is concluded that some of the psychoactive effects of phencyclidine may be due to the ability of phencyclidine to elicit a release of dopamine from dopaminergic