Levorphanol: Revisiting an Underutilized Analgesic

Effect of lithium on content and uptake of norepinephrine and 5-hydroxytryptamine in mouse brain synaptosomes and mitochondria

Effects of prolonged administration of milnacipran, a new antidepressant, on receptors and monoamine uptake in the brain of the rat

It is a favoured view today that thymoleptics owe their antidepressant activity to blockade of a mechanism which we like to call the membrane pump (see Carlsson, 1966) by means of which biogenic amines released from nerve endings are taken up again. Blockade of the membrane pump should lead to an increase in the amine concentrations at receptor sites in the brain. Sigg et al. (SiGG, 1959; Sigg, Soffer and Gyermek, 1963) demonstrated the ability of imipramine and related drugs to potentiate noradrenaline and sympathetic nerve stimulation. The first biochemical evidence came from Marshall, Stirling, Tait and Todrick (1960) who demonstrated the blocking action of imipramine on 5-hydroxytryptamine (5-HT) uptake by platelets. Soon afterwards a similar action of imipramine on noradrenaline (NA) uptake by adrenergic nerves was demonstrated (Axelrod, Whitby and Hertting, 1961; Hertting, Axelrod, Kopin and Whitby, 1961). Blockade by imipramine of NA uptake by brain tissue was also demonstrated in vitro (Dengler, Spiegler and Titus, 1961) and in vivo (Glowinski and Axelrod, 1965). For review, see e.g. Sulser and Dingell (1966).

The structure activity relationships of tryptolines and some other beta-carbolines and tryptamines as inhibitors of serotonin (5-HT), dopamine (DA) and noradrenaline (NA) uptake were studied in rat brain synaptosomes. All beta-carbolines inhibited to higher degree the uptake of 5-HT than that of DA or NA(IC50's 5-100 times lower). The most potent tryptoline derivative was 6-hydroxy-tetrahydro-beta-carboline (5-hydroxytryptoline, 6-OH-THBC) with an IC50 of 5.0 x 10(-7) M at a 5-HT concentration of 10(-7) M. 6-Methoxy-tetrahydro-beta-carboline (5-methoxytryptoline) was slightly weaker; the inhibition of 5-HT uptake and DA uptake being competitive. Also tetrahydro-beta-carboline (tryptoline) was more potent than its 1-methylderivative, tetrahydroharmane (methtryptoline) or norharmane (beta-carboline). All of them were, however, weaker inhibitors of 5-HT uptake than the freely rotating indoleamines N-methyl-tryptamine (N-Me-T) or 5-HT itself. N-Me-T and 5-HT were also more potent inhibitors of DA and NA uptake than most of the beta-carbolines, DA uptake, however, was inhibited better by 6-OH-THBC than by 5-HT or N-ME-T. Tetrahydro-beta-carbolines may inhibit 5-HT uptake also in vivo but is unlikely that catecholamine uptake is affected.

Brain cholecystokinin (CCK)- and noradrenergic activities are two neurochemical systems implicated in anxiety and deficits in novelty-related behaviour. In order to clarify a possible interaction between CCK- and noradrenergic neurotransmission in the brain, DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine], a neurotoxin that selectively destroys noradrenaline-containing nerve terminals originating from the locus coeruleus, was administered to rats IP (10 and 50 mg/kg) seven days before decapitation. Noradrenaline uptake was very markedly reduced in the frontal cortex and hippocampus of the DSP-4 treated animals, whereas the decrease in the hypothalamus was smaller but still statistically significant. Dopamine uptake in the corpus striatum, as well as serotonin uptake in the frontal cortex, hippocampus and hypothalamus, were not influenced by DSP-4 treatment. Concomitantly, CCK receptor binding in certain brain regions was markedly affected. Thus, CCK receptor density was significantly higher in the frontal cortex and hippocampus of DSP-4-treated rats. If desipramine (25 mg/kg) was administered before DSP-4 treatment, the DSP-4-induced changes both in noradrenaline uptake and CCK receptor binding were not present, suggesting that both effects were exerted after uptake of the neurotoxin by the nerve terminals. The time-course of the development of changes in CCK-8 binding paralleled with some lag the development of changes in noradrenaline uptake. These findings demonstrate the denervation of noradrenergic input from the locus coeruleus induces certain alterations in the CCKergic neurotransmission. These alterations are similar to those seen in rats with deficits in response to novel stimuli, and may therefore mediate the neophobic responses observed in animals after lesions of noradrenergic innervation of the forebrain.

The uptake of 3 H- l -norepinephrine was examined in isolated perfused rat lungs, and the mechanism of uptake was compared with that previously found for 5-hydroxytryptamine. Most of the norepinephrine taken up by the lungs was rapidly deaminated and O-methylated, and the metabolic products were subsequently returned to the perfusate. The presence of iproniazid and tropolone markedly inhibited this metabolism; because the metabolites were released from the lungs more rapidly than was norepinephrine itself, these inhibitors appeared to increase the rate of uptake of the amine. The uptake of norepinephrine was a saturable, temperature-dependent process with a K m of 1.11 x 10 -6 M and a V max measured during metabolic inhibition of 2.78 x 10 -9 moles/g min -1 . Uptake was inhibited by cocaine, imipramine, ouabain, and potassium-free medium as well as by decreasing the sodium concentration or increasing the potassium concentration of the medium. Although normetanephrine reduced the uptake of norepinephrine, metaraminol had no effect. Autoradiography indicated that norepinephrine was taken up into endothelial and smooth muscle cells, but the mechanism of the uptake appeared to combine features characteristic of both extraneuronal and neuronal uptake. The mechanism of uptake of norepinephrine by the lungs is compatible with a sodium-dependent, carrier-mediated transport, but several differences appear to exist between the transport and the site of uptake of norepinephrine and 5-hydroxytryptamine.

Trimethyltin inhibits uptake of neurotransmitters into mouse forebrain synaptosomes

Influence of orphenadrine HCl and its N-demethylated derivatives on the in vitro uptake of noradrenaline and 5-hydroxytryptamine by rat brain slices

Pharmacological profile of the antidepressant adinazolam, a triazolobenzodiazepine

The neurochemical and behavioural profile of Lu 17‐133, (±)‐trans‐4‐[3‐(3,4‐dichlorophenyl)‐indan‐1‐yl]‐1‐piperazineethanol has been characterized and compared with that of a series of inhibitors of biogenic amine uptake. Lu 17‐133 inhibits the uptake of dopamine and noradrenaline in the nanomolar range, but it has only a weak effect on serotonin uptake. Blockade of receptors for dopamine (D‐1, D‐2), noradrenaline (α1, α2), histamine (H1), acetylcholine (muscarinic), and serotonin (5‐HT2) was absent or seen only at micromolar concentrations. The biochemical profile is close to that of GBR 13.069, GBR 12.921, and Lu 19‐005 (INN name, Indatraline). Lu 17‐133 shows only weak behavioural effects. In high doses, it potentiates apomorphine and 5‐HTP and reverses the effect of tetrabenazine in mice. It has minimal stimulatory property, as it increases very weakly the locomotor activity in mice and does not induce stereotypy (either low‐component or oral stereotypy) in rats. It does not induce ipsilateral circling behaviour in 6‐OHDA‐lesioned rats, although in combination with scopolamine, a full ipsilateral rotation is seen. Lu 17‐133 has no anticataleptic effect and does not generalize to the discriminative stimulus properties induced by d‐amphetamine. Experiments have shown that there is no clear correlation between inhibitory effect on dompamine uptake and in vivo effects in the models detecting dopamine‐stimulating compounds; nor is there any obvious correlation between effects in different in vivo test models. The neurochemical and behavioural characteristics of Lu 17‐133‐inhibition of dopamine‐ and noradrenaline‐uptake in vitro with low stimulatory properties in vivo make it an interesting candidate as a new antidepressant drug.

Characterization of [3H]5-hydroxytryptamine uptake within rat cerebrovascular tree

SL 81.0385 (4‐[(2‐naphthalenyl)methoxy]piperidine) is a potent competitive inhibitor of serotonin uptake into rat hypothalamic synaptosomes and human platelets (IC50 values of 18 and 13 nM, respectively), which exhibits a high selectivity for inhibiting serotonin uptake relative to noradrenaline or dopamine uptake in vitro. SL 81.0385 also exhibits potent serotonin uptake inhibiting properties in vivo as demonstrated by its ability to antagonize the p‐chloroamphetamine‐induced depletion of rat cerebral serotonin levels (ED50 = 2.5 mg/kg i.p.). Similarly, SL 81.0385 is a potent inhibitor of 3H‐imipramine and 3H‐paroxetine binding to the serotonin transporter complex in rat cortical membranes (Ki values of 0.5 and 3.2 nM, respectively), but it exhibits a much lesser affinity for radioligand binding to the noradrenaline, adrenaline, and dopamine transporters. The selectivity of SL 81.0385 for serotonergic systems is also demonstrated by its effects on cerebral monoamine metabolism. Indeed, SL 81.0385 decreases, ex vivo, endogenous 5‐hydroxyindoleacetic acid (5‐HIAA) levels in the rat striatum, and, in vivo, extracellular 5‐HIAA concentrations (as measured by differential pulse voltammetry) in the rat cerebral cortex. In contrast, SL 81.0385 fails to decrease striatal levels of 3,4‐dihydroxyphenylacetic acid and homovanillic acid and hypothalamic levels of total, 3,4‐dihydroxyphenylethyleneglycol. SL 81.0385 is devoid of inhibitory activity toward monoamine oxidase and has no affinity for cerebral muscarinic, H1 histaminergic, α1‐, α2‐, and β‐adrenergic, D2 dopaminergic, and benzodiazepine receptors, and it possesses only weak affinity for 5‐HT2 receptors. The present results indicate that SL 81.0385 is a highly potent and selective inhibitor of serotonin uptake, chemically unrelated to the tricyclics, and it should find application in the treatment of depression, obesity, and alcoholism.

Behavioural effects on dopaminergic transmission of a phenylindane derivative, Lu 19-005 [(+/-)-trans-3-(3,4-dichlorophenyl)-N-methyl-l-indanamine, HCI], with potent inhibitory effect on dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake in rats and the effect on DA, NA and 5-HT activity in mice have been studied and compared with those of other known DA, NA and 5-HT uptake inhibitors with different selectivity ratios. Lu 19-005 induced stereotyped behaviour after parenteral and oral administration with a duration of action of more than 24 h. The stereotyped licking and biting induced by Lu 19-005 was antagonized by reserpine and cis(Z)-flupentixol, but not affected by prazosin, p-chlorophenylalanine and alpha-methyl-p-tyrosine pretreatments. Metergoline slightly facilitated the onset of stereotypy. Lower doses of Lu 19-005 induced ipsilateral circling in unilaterally 6-hydroxy-DA-lesioned rats. Finally, Lu 19-005 antagonized the catalepsy induced by perphenazine. In mice, Lu 19-005 potentiated the apomorphine-induced gnawing, reversed tetrabenazine-induced ptosis and potentiated the behavioural effects of 5-HTP within a similar dose range. The effects of Lu 19-005 were compared with those of other reference compounds. Nomifensine had qualitatively similar effects in rats although of much shorter duration. In mice, nomifensine selectively reversed tetrabenazine-induced ptosis. Weaker effects in all test models were found with bupropion, LR 5182 and GBR 13.069, compounds with inhibitory effect on DA and NA uptake. The DA-, NA- and 5-HT-uptake inhibitor diclofensine, however, had no effect in rats except in the 6-hydroxy-DA-circling test and had low potency in mice. The specific 5-HT- and NA-uptake inhibitors citalopram and talsupram, respectively, were ineffective in all rat models.(ABSTRACT TRUNCATED AT 250 WORDS)

Paroxetine

Dysthymia and depressive disorders: dopamine hypothesis