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The paper presents historical prerequisites for designing antidepressants from a group of selective serotonin neuronal reuptake inhibitors (SSRIs): to determine a lower serotonin concentration in the different tissues of depressed patients; to establish a higher serotonin concentration in the treatment of depressed patients with tricyclic antidepressants, and to formulate the serotonergic theory of depression. It also provides a consecutive account of the history of clinical introduction of individual SSRI representatives, such as fluoxetine, zimelidine, fluvoxamine, indalpine, citalopram, sertraline, paroxetine, and escitalopram. There are data from the history of studying the mechanism of SSRI action: from the theory of the importance of an increase in the concentration of serotonin in the synaptic cleft to the current understanding of complex successive intracellular rearrangements at the level of the postsynaptic neuron. The history of studying the efficacy of SSRIs in treating depression is considered in detail. Emphasis is laid on the reasons for a paradoxical difference in the evaluations of the efficiency of therapy with SSRIs versus other groups of antidepressants at different developmental stages of psychopharmacology. The role of marketing technologies in disseminating the data on the efficacy of this or that group of antidepressants is described. The practical significance of differences in individual SSRI representatives (the potency of serotonin uptake inhibition; the degree of selectivity and activity against the serotonergic system; the likelihood of an unfavorable pharmacokinetic interaction with other drugs; the half-life of elimination; the quickness of achieving a therapeutic dose) is analyzed. Whether it is possible and reasonable to differentially choose different SSRI representatives in the treatment of depressions at the present stage is discussed. The authors state their belief that researches should be continued to specify the place of SSRIs among other groups of current antidepressants for the treatment of depressions.

We studied whether serotonin release in the CNS is inhibited via cannabinoid receptors. In mouse brain cortex slices preincubated with [3H]serotonin and superfused with medium containing indalpine and metitepine, tritium overflow was evoked either electrically (3 Hz) or by introduction of Ca2+ (1.3 mM) into Ca2+-free K+-rich (25 mM) medium containing tetrodotoxin. The effects of cannabinoid receptor ligands on the electrically evoked tritium overflow from mouse brain cortex slices preincubated with [3H]choline and on the binding of [3H]WIN 55,212-2 and [35S]GTPgammaS to mouse brain cortex membranes were examined as well. In superfused mouse cortex membranes preincubated with [3H]serotonin, the electrically evoked tritium overflow was inhibited by the cannabinoid receptor agonist WIN 55,212-2 (maximum effect of 20%, obtained at 1 microM; pEC50=7.11) and this effect was counteracted by the CB1 receptor antagonist SR 141716 (apparent pA2=8.02), which did not affect the evoked tritium overflow by itself. The effect of WIN 55,212-2 was not shared by its enantiomer WIN 55,212-3 but was mimicked by another cannabinoid receptor agonist, CP-55,940. WIN 55,212-2 also inhibited the Ca2+-evoked tritium overflow and this effect was antagonized by SR 141716. Concentrations of histamine, prostaglandin E2 and neuropeptide Y, causing the maximum effect at their respective receptors, inhibited the electrically evoked tritium overflow by 33, 69 and 73%, respectively. WIN 55,212-2 (1 microM) inhibited the electrically evoked tritium overflow from mouse brain cortex slices preincubated with [3H]choline by 49%. [3H]WIN 55,212-2 binding to mouse cortex membranes was inhibited by CP-55,940, SR 141716 and WIN 55,212-2 (pKi=9.30, 8.70 and 8.19, respectively) but not by the auxiliary drugs indalpine, metitepine and tetrodotoxin (pKi

1 The mechanism underlying 5-hydroxytryptamine (5-HT) and/or dopamine release induced by (+)-amphetamine ((+)-Amph), 3,4-methylendioxymethamphetamine (MDMA), p-chloroamphetamine (pCA) and (+)-fenfluramine ((+)-Fen) was investigated in rat brain superfused synaptosomes preloaded with the 3H neurotransmitters. 2 Their rank order of potency for [3H]-5-HT-releasing activity was the same as for inhibition of 5-HT uptake (pCAMDMA(+)-Fen>>(+)-Amph). Similarly, their rank order as [3H]-dopamine releasers and dopamine uptake inhibitors was the same ((+)-Amph>>pCA=MDMA>>(+)-Fen). We also confirmed that the release induced by these compounds was prevented by selective transporter inhibitors (indalpine or nomifensine). 3 [3H]-5-HT and/or [3H]-dopamine release induced by all these compounds was partially (31–80%), but significantly Ca2+-dependent. Lack of extracellular Ca2+ did not alter uptake mechanisms nor did it modify the carrier-dependent dopamine-induced [3H]-dopamine release. (+)-Amph-induced [3H]-dopamine release and pCA- and MDMA-induced [3H]-5-HT release were significantly inhibited by ω-agatoxin-IVA, a specific blocker of P-type voltage-operated Ca2+-channels, similar to the previous results on (+)-Fen-induced [3H]-5-HT release. 4 Methiothepin inhibited the Ca2+-dependent component of (+)-Amph-induced [3H]-dopamine release with high potency (70 nM), as previously found with (+)-Fen-induced [3H]-5-HT release. The inhibitory effect of methiothepin was not due to its effects as a transporter inhibitor or Ca2+-channel blocker and is unlikely to be due to its antagonist properties on 5-HT1/2, dopamine or any other extracellular receptor. 5 These results indicate that the release induced by these compounds is both ‘carrier-mediated’ and Ca2+-dependent (possibly exocytotic-like), with the specific carrier allowing the amphetamines to enter the synaptosome. The Ca2+-dependent release is mediated by Ca2+-influx (mainly through P-type Ca2+-channels), possibly triggered by the drug interacting with an unknown intracellular target, affected by methiothepin, common to both 5-HT and dopamine synaptosomes. British Journal of Pharmacology (1997) 121, 1735–1743; doi:10.1038/sj.bjp.0701325

Preference for immediate reward, taken as an index of impulsiveness, has been suggested to be under the preferential control of central serotonin (5-HT) function. The present study examined the effects of the acute administration of drugs which directly or indirectly alter 5-HT transmission on tolerance to delay of reward in rats subjected to a procedure of discrete-trial choice in an operant chamber. Different groups of rats were trained to choose between two levers giving access to reinforcers differing in both magnitude and delay: one food pellet, delayed by 0 or 5 s, vs. five pellets delivered after a prereinforcer interval fixed at either 15, 30, 45, or 60 s, depending on the experiments. The learning curves indicated that rats were able to adjust their choice strategy precisely according to various factors: the respective duration of the delays before the small and large rewards, the immediacy of the small reward delivery, and the lengthening of the trials by a postreinforcer delay (or intertriai interval). Whatever the experimental parameters and stage of the learning, an acute administration of drugs able to reduce 5-HT neuronal activity (benzodiazepines; 5-HT 1A receptor partial agonists: buspirone and MDL 73005EF) or enhance 5-HT transmission (5-HT reuptake inhibitors: indalpine and zimelidine; 5-HT 1A receptor full agonist: 8-OH-DPAT) failed significantly to alter choice strategy (decreased or increased preference for the large but delayed reward, respectively), as they did in other situations such as a T-maze procedure. Only d -amphetamine (0.5 mg/kg), on one occasion, significantly reduced preference for the larger reward. The choice strategy was also insensitive to acute changes in experimental parameters such as a reduction in delay or increase in the magnitude of the large reinforcement. These results indicate that the present operant paradigm is not sensitive to acute modifications in the internal state of the animals and in the reward contingencies, and therefore is not useful to evaluate tolerance to delay and variations in impulsiveness in rats.

Benzodiazepines are routinely administered in combination with antidepressant drugs. Such combination can induce pharmacodynamic or pharmacokinetic interactions resulting in either a potentiation or a reduction of the effects of one of the drugs. The present study was undertaken to determine the effects of benzodiazepines alone and in combination with two classes of antidepressant drugs: "specific" norepinephrine uptake blockers (desipramine, maprotiline) and specific serotonin uptake blockers (indalpine, fluvoxamine) in the learned helplessness paradigm in rats. The present results show that daily injection of diazepam (0.2-2 mg/kg) and lorazepam (0.06-0.25 mg/kg) did not reverse the helpless behavior. The reversal of helpless behavior induced by indalpine (1 mg/kg/day) or fluvoxamine (4 mg/kg/day) was antagonized dose-dependently by daily coadministration of benzodiazepines. In contrast, the effects of desipramine (24 mg/kg/day) or maprotiline (48 mg/kg/day) were not modified.

Narcolepsy is currently treated with anti-depressants to control REM-related symptoms such as cataplexy and with amphetamine-like stimulants for the management of sleepiness. Both stimulant and antidepressant drugs presynaptically enhance monoaminergic transmission but both classes of compounds lack pharmacological specificity. In order to determine which monoamine is selectively involved in the therapeutic effect of these compounds, we examined the effects of selective monoamine uptake inhibitors and release enhancers on cataplexy using a canine model of the human disorder. A total of 14 compounds acting on the adrenergic (desipramine, nisoxetine, nortriptyline, tomoxetine, viloxazine), serotoninergic (fenfluramine, fluoxetine, indalpine, paroxetine, zimelidine) and dopaminergic (amfonelic acid, amineptine, bupropion, GBR 12909) systems were tested. Some additional compounds interesting clinically but with less pharmacological selectivity, i.e., cocaine, dextroamphetamine, methylphenidate, nomifensine and pemoline, were also included in the study. All compounds affecting noradrenergic transmission completely suppressed canine cataplexy at low doses in all dogs tested, whereas compounds which predominantly modified serotoninergic and dopaminergic transmission were either inactive or partially active at high doses. Our results demonstrate the preferential involvement of adrenergic systems in the control of cataplexy and, presumably, REM sleep atonia. Our findings also demonstrate that canine narcolepsy is a useful tool in assessing the pharmacological specificity of antidepressant drugs.

The dissociations of [3H]imipramine, [3H]paroxetine and [3H]citalopram from the 5-HT (serotonin 5-hydroxytryptamine) transporter were found to be markedly influenced by several drugs, although concentrations in the microM range were needed. Most of these drugs attenuated the dissociation rate, i.e. increased the affinity between the ligand and the binding site. A few increased the dissociation rate however. The binding of drugs to the affinity-modulating site was specific, although of low affinity and probably changing the conformation of the high-affinity binding site, thereby changing the fit between the ligand and the interacting amino acid side-chains. Although the drugs usually affected the dissociation rates of the three ligands in the same manner, there were some which had different effects on [3H]imipramine, [3H]paroxetine and [3H]citalopram. For example, 5-HT markedly attenuated the dissociation of [3H]imipramine, had a moderate effect on [3H]paroxetine and very little effect on [3H]citalopram dissociation. This indicates that the three ligands are bound to different domains on the 5-HT transporter. [3H]Citalopram dissociation from human brain and rat brain were differently affected by several drugs. Indalpine augmented the dissociation rate of the [3H]citalopram 5-HT transport complex in human brain but attenuated it in rat brain, thus revealing a species difference of the 5-HT transporter.

Compounds known to selectively inhibit the neuronal reuptake of serotonin are clinically effective antidepressants. However, in a number of the behavioral models used for detecting and analysing antidepressant action these drugs are inactive. The forced swimming test is not consistently sensitive to these drugs but it has recently been reported that a variation of this procedure, the tail suspension test in mice, is sensitive. The present study showed that five compounds previously shown to be selective serotonin uptake inhibitors--fluoxetine, zimeldine, paroxetine, indalpine, and litoxetine--produced dose-related decreases in immobility in the tail suspension test typical of the effects shown by other antidepressants. In separate experiments, fluoxetine, zimeldine, and indalpine decreased locomotor activity at doses similar to those that decreased immobility. In contrast, paroxetine and litoxetine had no effect on locomotion at the dose ranges active in the tail suspension test. These results confirm the sensitivity of the tail suspension test and indicate that serotonin uptake inhibitors probably decrease immobility and reduce locomotor activity through different mechanisms.

We performed an extensive pharmacological study of the 5-hydroxytryptamine (5-HT) transporter polypeptide cloned from human placenta. Transient expression of this 630 amino acid polypeptide in HeLa cells led to saturable 5-HT uptake activity (Km = 858 nM). This 5-HT uptake was blocked by selective 5-HT inhibitors, such as citalopram, litoxetine, sertraline, and indalpine, with Ki values in the low nanomolar range, and it exhibited a pharmacological profile similar to that found in rat brain. [3H]Citalopram binding to membrane preparations of the transfected cells occurred to a single class of high-affinity binding sites (Kd = 5.3 nM) and was potently inhibited by selective 5-HT uptake inhibitors. The pharmacological profile of [3H]citalopram binding to these transfected cells showed a good correlation with that of [3H]paroxetine binding to the rat cerebral cortical 5-HT transporter (r = 0.79). These data confirm that the full pharmacological characteristics of the 5-HT transport system are conferred by the expression of the 630 amino acid human placental 5-HT transporter polypeptide. [3H]Citalopram should, therefore, provide a useful probe for more insights at a molecular level into this cloned 5-HT transport system.

1. 1. The mode of 5-hydroxytryptamine (5-HT) uptake by the rat isolated atria was studied and compared to noradrenaline (NA) uptake. 2. 2. Rat isolated atria were incubated with 14 C-5-HT (46 μM) or 3 H-NA (0.4 μM). After washing, the radioactivity fixed in atria was counted and the total NA, 5-HT and 5-hydroxyindol-3-acetic acid (5-HIAA) atria contents were measured by HPLC. 3. 3. 14 C-5-HT uptake was reduced in atria from 6-hydroxydopamine (100 mg/kg, i.p., 48 hr before experiments) or reserpine (2.5 mg/kg, i.p., 24 and 48 hr before experiments) pretreated rats. 4. 4. The incubation of atria with 5-HT (50 μM) at the same time as 3 H-NA reduced the 3 H-NA value fixed. 5. 5. Addition of desipramine (1 μM) or hydrocortisone (150 μM) before the incubation of atria with 14 C-5-HT was without any effect on 14 C-5-HT uptake. In contrast, fluvoxamine (1 μM) or indalpine (5 μM) caused a slight inhibition. 6. 6. These data indicate that 5-HT is taken into the NA storage vesicles within the atria sympathetic nerves. This uptake does not use the NA carrier and involves partly the 5-HT carrier. An extraneuronal accumulation was noticed and a part of it is intracellular.

Rat hippocampal synaptosomes preloaded with [3H]serotonin and maintained in a superfusion apparatus were exposed for 3 min to d-fenfluramine or fluoxetine. Both drugs evoked a tritium overflow which was reserpine-sensitive requiring the presence of intact synaptic vesicles. However the two drugs displayed different characteristics: 1) the overflow was immediate with dfenfluramine whereas the releasing activity of fluoxetine showed a delay of about 2 min; 2) d-fenfluramine-induced overflow was already apparent at 0.15 μmol/l whereas the minimal effective concentration of fluoxetine was 2.5 μmol/l. Their concentration-effect curves were differently shaped, the effect of d-fenfluramine being saturable at 5–20 μmol/l (EC50 about 1 gmol/l) while no saturation was observed with fluoxetine up to 10 μmol/l; 3) only 1907o of the tritium overflow evoked by fluoxetine (2.5–10 μmol/l) consisted of true [3H]serotonin, compared with 7001o when 0.5 μmol/l d-fenfluramine was used; 4) the releasing action of 0.5 μmol/l d-fenfluramine was completely Ca++-dependent, while at higher dfenfluramine concentrations the Ca++-independent overflow became more important. The fluoxetine induced overflow was mainly. (70010) Ca++-independent; 5) the releasing acitvity of d-fenfluramine was mainly (80%) blocked by the serotonin uptake blockers indalpine, midalcipram and also fluoxetine whereas fluoxetine-induced overflow was insensitive to inhibition of the serotonin carrier.

1. The effects of 5-hydroxytryptamine (5-HT) uptake inhibitors, agonists and antagonists have been evaluated on mouse marble-burying behaviour, a putative test for anxiolytic agents. The high levels of locomotor activity occurring on first exposure to a circular runway (runway were used as a separate test of non-specific drug effects. 2. Fluvoxamine, zimeldine, indalpine and citalopram dose-dependently inhibited burying without affecting runway activity. 5-Hydroxytryptophan (5-HTP, with carbidopa), 5-methoxy-N,N-dimethyltryptamine, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), buspirione, gepirone and ipsapirone reduced burying only at doses reducing runway activity. RU 24969 increased runway activity at all effective doses. 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 1,-(3-trifluoromethylphenyl) piperazine (TFMPP) and 1-(3-chlorophenyl)-piperazine (mCPP) potently and differentially reduced burying at doses below those affecting runway activity. 3. 5-HT antagonists only reduced burying at high doses which also reduced runway activity. Burying inhibition by DOI was antagonized by ritanserin, ICI 169,369 and cyproheptadine but not by pindolol or a low (0.25 mg kg-1) dose of metergoline. Burying inhibition by mCPP was not altered by any of these agents except that it was potentiated by pindolol 5 mg kg-1. 4. Zimeldine burying inhibition was potentiated by ritanserine, ICI 169,369, ICS 205-930, cyproheptadine and pindolol. Runway activity was not affected by these drug combinations. 5. Zimeldine was administered in drinking water at a dose of 10 mg kg-1 daily for 21 days. Burying inhibition had disappeared by day 14 and did not recur 24 or 48h after withdrawal at which times responses to DOI were at control levels.6. Selective inhibition of marble burying was not found to be a property of 5-HT-related putative and actual anxiolytics such as buspirone, gepirone, ipsapirone, ritanserin and ondansetron. Nevertheless it was a general property of both 5-HT uptake inhibitors and 5-HT releasing agents; this generality suggests that elevated synaptic 5-HT could be responsible for the effects of these latter agents. The action of DOI may be attributable to effects at the 5-HT2 receptor but those of the 5-HT agonist and releasing agent mCPP, and the uptake inhibitor zimeldine, could not be attributed to effects at any one 5-HT receptor subtype. This, together with the potentiating effect of several 5-HT antagonists on the response to zimeldine, raises the possibility of multiple interactions between 5-HT receptor subtypes.

The effects of antidepressant drugs on the m-trifluoromethylphenylpiperazine (TFMPP)-induced inhibition of K+-evoked [3H]acetylcholine (3H-ACh) release were studied in rat or guinea-pig hippocampal synaptosomes. The serotonergic agonist TFMPP dose-dependently inhibited the K+-evoked release of 3H-ACh in rat hippocampus (IC50=53 μM). Chlorimipramine (5–500 nM), a typical tricyclic antidepressant, and minaprine (1–100 nM), an atypical antidepressant drug, partially antagonized the effect of TFMPP on 3H-ACh release in a dose-dependent manner. Other antidepressants (imipramine, citalopram, indalpine, fluoxetine, fluvoxamine, oxaprotiline, mianserine, nomifensine), at concentrations ranging from 10 to 500 nM, produced similar effects. Drugs with no antidepressant effect, such as chlorpromazine, clobazam, and cocaine (50, 100 and 500 nM), were without significant influence on the TFMPP effect. In guinea-pig hippocampal synaptosomes, minaprine (50 nM) also reduced the TFMPP-induced inhibition of 3H-ACh release, whilst clobazam (50 nM) was inactive. These results suggest that antidepressant drugs interact in vitro with heterologous serotonergic presynaptic receptors on cholinergic nerve terminals in rat and guinea-pig hippocampus.

1. Wistar rats of a strain presenting spontaneous petit mal-like seizures were injected intraperitoneally with graded doses of 14 non-monoamine oxidase inhibitor antidepressants and the immediate effects on behavior and the EEG were recorded. 2. Amineptine and nomifensine, the two drugs interacting with dopaminergic neurotransmission, reduced the duration of spontaneous spike-wave discharges (SWD) and were thus potentially antiepileptic. 3. Trazodone increased SWD duration. 4. The antidepressants, imipramine-like (imipramine, chlorimipramine, desipramine, metapramine and amitriptyline) and non-imipraminic (minaprine, maprotiline, viloxazine, mianserin, fluvoxamine and indalpine), and the 3 noted above, had potentially convulsive effects.

Established tricyclic antidepressants either affect transmission of both noradrenaline(NA) and serotonin(5-HT), or NA alone. Many newer antidepressants preferentially potentiate 5-HT transmission by inhibiting 5-HT uptake. Selective 5-HT-uptake inhibitors are those which have a high ratio of 5-HT-uptake inhibition as compared to NA-uptake inhibition, together with slight or no effect on other uptake mechanisms, neurotransmitter receptors, enzymes etc. By measuring inhibition of uptake into synaptosomes the following compounds are classified as selective 5-HT-uptake inhibitors (ratio IC50 NA/IC50 5-HT well above one): Citalopram (4400), indalpine (1000), sertraline (840), CGP 6085/A (630), alaproclate (390), paroxetine (280), fluvoxamine (160), cyanimipramine (69), zimelidine (55), fluoxetine (54), femoxetine (37), trazodone (24), and chlorimipramine (14). A similar rank order of selectivity is found in biochemical in vivo studies and in behavioral studies. Potency and selectivity for 5-HT uptake do not coincide. 5-HT uptake inhibitors show high affinity for the 5-HT-uptake sites labeled by radioactive ligands (e. g. 3H -imipramine, 3H-paroxetine), whereas it has low affinity for the NA-and dopamine (DA)-uptake sites as measured using 3H- desipramine and 3H-GBR 12935, respectively. In contrast to tricyclic antidepressants most of which inhibit receptors for acetylcholine, histamine, NA, 5-HT or DA, most selective 5-HT-uptake inhibitors neither bind to nor inhibit these receptors. 5-HT-uptake inhibitors potentiate the effect of 5-HT and 5-HT agonists thereby giving rise to exaggerated 5-HT responses like tremor, hyperactivity, lordosis and abduction of hind limbs. The potentiation of 5-HT is also seen in the hind limb flexor reflex model in spinal rats, as wet-dog shake and as reciprocal forepaw treading in rats. During chronic administration many antidepressant treatments down-regulate the NA-coupled adenylate cyclase system in brain. This is often linked to a reduction of the density of s-receptors. Many selective 5-HT- uptake inhibitors like citalopram do not cause this down-regulation. Since these drugs show clear antidepressant effect this down-regulation seems not to be a prerequisite for clinical antidepressant activity. The same holds true for the behavioural despair test, where many 5-HT uptake inhibitors are inactive.

Serotonergic systems are thought to be involved in the mechanisms of action of antidepressants in humans. There is little evidence, however, to suggest that serotonin uptake blockers are efficacious in animal models of depression. To further explore the antidepressant activity of these drugs, four compounds from this class (citalopram, fluvoxamine, indalpine or zimelidine) were tested in rats subjected to helplessness training. Rats were first exposed to inescapable shocks and 48 h later, shuttle-box training was initiated to evaluate escape learning. Twice-daily IP injections of citalopram (1 mg/kg), fluvoxamine (4 mg/kg), indalpine (1 and 2 mg/kg) and zimelidine (1 and 2 mg/kg) reduced escape deficits in a manner similar to that produced by the tricyclic antidepressants desipramine and clomipramine. Reversal of escape deficit by serotonin uptake blockers was observed only when the drugs were administered after the shuttle-box sessions. At higher doses, the four serotonin uptake blockers were without effect. These data suggest that serotonin uptake blockers exert antidepressant-like effects in animals but only when they produce a moderate stimulation of serotonin neurotransmission.

The binding of [3H]indalpine (4-[2-(3-indolyl)]ethyl piperidine) to slide-mounted sections of rat brain has been characterized. This 5-hydroxytryptamine (5-HT) uptake blocker binds to sections with high affinity (KD approximately 1 nM). The binding is saturable, and can be displaced by the addition of clomipramine (1 microM). Other drugs inhibiting the uptake of 5-HT also have the capacity to inhibit the binding of [3H]indalpine. A significant correlation (r = 0.86) was found between the capacity of these compounds to inhibit the uptake of 5-HT and their potencies as inhibitors of [3H]indalpine binding. Binding was Na+ - and Cl- -dependent and was inhibited competitively by 5-HT. Furthermore, electrolytic lesions of the dorsal raphe or medial forebrain bundle, which cause a degeneration of 5-HT cell bodies and fibers, respectively, resulted in a 30-40% reduction in the binding of [3H]indalpine. [3H]Indalpine binds to the 5-HT uptake recognition sites in a different manner from imipramine-like compounds.

The functional roles of monaminergic transmitters in depression have been widely studied during the past decade. Data from that research suggest that lower levels of the 5-HT metabolite, 5-HIAA, in the cerebrospinal fluid; 5-HT uptake in human platelets; and platelets [3H]-imipramine binding sites occur in depressed patients. In recent years several potent and selective 5-HT uptake inhibitors have become available for clinical studies. The first shown to have antidepressant effects, zimelidine, was followed by similar compounds such as femoxetine, fluvoxamine, Citalopram, indalpine, fluoxetine, paroxetine, and sertraline. The effectiveness of serotonin inhibitors in treating other disorders, such as obsessive–compulsive disorder, anxiety, and panic disorder, has also been demonstrated. This review reports the data from clinical studies with these agents. The 5-HT uptake inhibitors are devoid of anticholinergic properties and have not produced weight gain or sedative side-effects, but may have another profile of side-effects. Headache, nausea, and vomiting have been reported, however.

The mechanism of the increase in heart rate caused by 5-hydroxytryptamine (5-HT) in the spinal guinea-pig was investigated. Administration of 5-HT (15, 30, 60 and 120 micrograms.kg-1 i.v.) elicited dose dependent increases in heart rate. The responses to 5-HT were not modified by methiothepin (0.5 and 1.5 mg.kg-1), ketanserin (0.5-4.5 mg.kg-1) or MDL 72222 (0.5-4.5 mg.kg-1) but were antagonized by the beta-adrenoceptor antagonists, propranolol (0.1-1 mg.kg-1) or atenolol (0.5-4.5 mg.kg-1). Indalpine, which is known to interfere with the uptake of 5-HT by nerve terminals and blood platelets, significantly reduced the effects of 5-HT at a dose (5 mg.kg-1) that also affected the tachycardia elicited by tyramine. The increase in heart rate caused by tyramine in reserpinized animals was attenuated and, unlike normal animals where the responses to 5-HT remained constant after repeated administration, there was a quickly developing tachyphylaxis to 5-HT. These results show that the increase in heart rate elicited by 5-HT in spinal guinea-pigs is not mediated by any of the currently characterized 5-HT receptors ('5-HT1-like', 5-HT2 and 5-HT3), and that a major part of the tachycardia seems to be mediated by a release of catecholamines by a mechanism similar, though perhaps not identical, to that for tyramine. Another as yet unidentified mechanism could be involved besides though perhaps not identical, to that for tyramine. Another as yet unidentified mechanism could be involved besides this action.

Administration of dl -fenfluramine to male rats caused an initial rise, followed by a sustained decrease in plasma renin activity. Both the increase, which reached a maximum at 30 min and the decrease, which was maximal at 4 hr after administration of fenfluramine, were dose-dependent. Pretreatment with either of the blockers of serotonin uptake, fluoxetine or indalpine blocked the increase in plasma renin activity induced by fenfluramine at 30 min, but did not affect the decrease at 4 hr after injection. Similarly, pretreatment with the inhibitor of the synthesis of serotonin, p-chlorophenylalanine methylester (PCPA) blocked the initial (30 min) but not the delayed (4 hr) effect of fenfluramine on plasma renin activity. The initial stimulation of secretion of renin by a submaximal dose (2 mg/kg, i.p.) of fenfluramine was potentiated by pretreatment with the precursor of serotonin l -tryptophan (100 mg/kg, i.p.). Pretreatment with the blocker of the uptake of norepinephrine, desipramine did not prevent the initial (30 min) effect but completely prevented the delayed (4 hr) effect of fenfluramine on plasma renin activity. These results suggest that the initial effect of fenfluramine is mediated via a serotonergic mechanism while the delayed, but long-lasting suppression of plasma renin activity, is mediated via a noradrenergic mechanism.

Several antidepressant treatments enhance serotonergic neurotransmission. The present electrophysiological studies were undertaken to assess the effect of mianserin and indalpine, two antidepressant drugs with different pharmacological profiles, on serotonergic neurotransmission. In a first series of experiments, the responsiveness of hippocampal pyramidal neurons to microiontophoretic applications of serotonin (5-HT), norepinephrine (NE) and γ-aminobutyric acid (GABA) was assessed following mianserin, imipramine (5 mg/kg/day IP) or saline administration for 14 days. At 48 h after the last dose of mianserin, responsiveness to 5-HT was increased whereas that to NE and GABA was not modified. The degree of sensitization to 5-HT was the same as that produced by imipramine. Acute IV administration of mianserin (up to 10 mg/kg) did not decrease the firing rate of dorsal raphe 5-HT neurons. In a second series of experiments, long-term administration of indalpine (5 mg/kg/day IP for 14 days) did not modify the responsiveness of hippocampal pyramidal neurons to microiontophoretically applied 5-HT, NE and GABA whereas imipramine treatment (5 mg/kg/day IP) increased selectively their sensitivity to 5-HT when compared to indalpine-treated rats. In keeping with its potent reuptake-blocking property, acute IV indalpine produced a marked decrease in the firing rate of dorsal raphe 5-HT neurons (ED50 0.33 mg/kg). The firing rate of dorsal raphe 5-HT neurons was assessed following 2-, 7- and 14-day treatments with indalpine (5 mg/day IP). After 2 days, the firing rate of 5-HT neurons was greatly reduced, after 7 days it had recovered partially and after 14 days it had returned to normal. At this point, the responsiveness of 5-HT neurons to IV LSD, an agonist of the 5-HT autoreceptor, and to microiontophoretically-applied 5-HT was decreased twofold, indicating desensitization of the autoreceptor. In conclusion, it is proposed that long-term treatment with mianserin, as with tricyclic antidepressant drugs and electroconvulsive shocks, increases 5-HT neurotransmission via sensitization of postsynaptic neurons to 5-HT whereas long-term treatment with indalpine, as with zimelidine, results in the same final effect via its presynaptic effect on 5-HT neurons presumably by blocking 5-HT reuptake. These data further support the notion that enhancing 5-HT neurotransmission might have an antidepressant effect.

A ten-compartment analog computer model is presented to determine the precise distribution and excretion of two antidepressant drugs, LM 5008 AND Imipramine. Eight patterns were simulated using experimental data and drug distribution in the two undetermined compartments were obtained by the analog model. Close agreement with existing experimental data lends confidence in the model as a valuable tool for predictions in a variety of therapeutic situations.

The intracerebroventricular (i.c.v.) administration of increasing doses of 6-hydroxydopamine (6OHDA) (12.5-50 micrograms) induces in mice a dose-dependent hypothermic effect. This hypothermic effect is not affected either by serotonin uptake inhibitors (indalpine, clomipramine, trazodone, fluoxetine) or by dopamine uptake inhibitors (GBR 12783, amineptine). On the contrary, the hypothermia is partly antagonized by norepinephrine uptake inhibitors (desipramine, nomifensine, viloxazine, maprotiline, protryptiline), as well as amfonelic acid. The antagonism elicited by desipramine is observed when the drug is administered intraperitoneally (from 5 mg/kg) or intracerebroventricularly (from 5 microgram per mouse). 6-hydroxydopamine-induced hypothermia is antagonized by imipramine after a time lag of 1 hour; this antagonism lasts 6-11 hours after intraperitoneal administration of the drug (20 mg/kg). The hypothermic effect of 6-hydroxydopamine is diminished by a previous 6-hydroxydopamine i.c.v. administration (50 micrograms, 7 days before), except in mice pretreated with desipramine at the time of the first 6-hydroxydopamine injection. The hypothermic effect is completely abolished by two previous 6-hydroxydopamine i.c.v. administrations (50 micrograms, 7 days interval). It is also decreased in mice receiving DSP4 15 days before testing (50 mg/kg, i.p.). Finally, neither haloperidol (0.5 mg/kg i.p.) nor SCH23390 (100 micrograms/kg s.c.) antagonize 6-hydroxydopamine-induced hypothermia. It is concluded that this effect is largely depending on central norepinephrine neurons.

In the present paper we confirm and extend previous studies showing heterogeneous 3H-imipramine (3H-IMI) binding sites. Inhibition curves of various drugs (serotonin, imipramine, desmethyl-imipramine, d-fenfluramine, d-norfenfluramine and indalpine, a potent serotonin uptake inhibitor) obtained using 2 nM 3H-IMI and in presence of 120 mM NaCl, confirmed the presence of at least three 3H-IMI binding sites: two of these (high and low affinities) were serotonin-insensitive while the third one was selectively inhibited by serotonin and indalpine with nanomolar affinities. Moreover, this last component was found to be selectively modulated by chronic imipramine treatment thus suggesting a closer relation to serotonin uptake mechanism. These data indicate that the use of a more selective inhibitors of the serotonin-sensitive component (like indalpine or serotonin itself) to define non specific 3H-IMI, may be of help in understanding its relation with serotonin uptake system.

Effects of an inhibitor of the uptake of noradrenaline (maprotiline, 75 and 150mg) and two inhibitors of the uptake of 5-hydroxytryptamine (zimelidine, 100 and 200 mg; indalpine, 25 and 50 mg) on sleep were studied in healthy man. Maprotiline reduced the duration of rapid eye movement (REM) sleep and increased the duration of stage 2 sleep, and there was evidence of sedation the next day. Zimelidine and indalpine reduced the duration of REM sleep, but also reduced the total sleep time and increased wakefulness and stage 1 (drowsy) sleep. It is suggested that in acute studies, the effects of inhibition of uptake on sleep are likely to arise from presynaptic inhibition of release of transmitter, although other mechanisms cannot be excluded. Suppression of REM sleep is believed to be due to the balance between cholinergic and monoaminergic influences being disturbed rather than a specific effect arising from the modulation of a particular transmitter.

A series of 3-(4-piperidinylalkyl)indoles was synthesized and tested as uptake inhibitors of biogenic amines. Some of these compounds are potent and very selective in blocking the 5-hydroxytryptamine (5-HT) uptake, as evidenced by biochemical data and behavioral tests. A discussion on structure-activity relationships is given. The most interesting member of the series, indalpine, 3-[2-(4-piperidinyl)ethyl]indole (1), was selected for clinical studies.

The effects of indalpine (a selective 5-HT uptake inhibitor) on the threshold of lower limb nociceptive flexion reflexes were studied (double blind) in humans. After 3 days' administration, indalpine was found to exert a significant naloxone-reversible depression (threshold increased) of the nociceptive reflexes (naloxone and saline were tested double blind). In contrast, no change was found during treatment with placebo. The functional and therapeutic implications of these results are discussed.

Indalpine or LM 5008 (4-[2-(3-indolyl)ethyl]piperidine), a selective and potent inhibitor of the uptake of 5-hydroxytryptamine, showed analgesic properties in the hot plate test in mice. It enhanced the analgesic effect of morphine and pethidine. This activity could not be explained by alterations of the pharmacokinetics of morphine since the brain morphine level was not changed by pretreatment with indalpine. This drug also antagonized the development of tolerance to morphine in mice. Morphine was 3–7 times more potent in competing for [3H]-naloxone (−NaCl), [3H]-metenkephalin or [3H]-leu-enkephalin binding when animals were pretreated in vivo with indalpine although indalpine itself had no effect on opiate receptor binding sites. In vitro addition of indalpine or 5-HT did not change the activity of morphine on opiate receptor binding sites. In vivo administration of indalpine sensitized the agonist state of opiate receptor binding sites, as measured by [3H]-naloxone (−NaCl) for example, to enkephalin without changing the antagonist state, as measured by [3H]-naloxone (+NaCl). The effect of indalpine was antagonized by the 5-HT synthesis inhibitor PCPA. Moreover, indalpine antagonized the depletion of opioid peptides induced by cyclophosphamide. All these results could suggest a tryptaminergic regulation of opiate receptors.

Indalpine is a potent inhibitor of 5-Hydroxytryptamine uptake by central neurones (Le Fur et al., 1978) and has been shown in comparative clinical trials to be an effective antidepressant agent (Guelfi et al., 1981; Gerard et al., 1981).

Daily injection of triiodothyronine (T3) for 3 consecutive days dose dependently enhanced 1-5-HTP (4 mg/kg)-induced head twitches in mice. This effect was blocked by 1-penbutolol. Pretreatment with a sub-effective dose of T3 (0.06 mg/kg) markedly enhanced the ability of clenbuterol but not indalpine to potentiate the response to 1-5-HTP. Likewise, the effects of T3 were more pronounced on the desipramine- or maprotiline-induced potentiation of head-twitches than on the action of citalopram or clomipramine. These data suggest that the increased responsiveness to 1-5-HTP caused by T3 involves an indirect (noradrenalin-mediated) rather than a direct effect on serotonergic processes.

1. 1. Daily injection of T3 during three consecutive days dose-dependently enhanced L-5-HTP (4 mg/kg)-induced head-twitches in mice. 2. 2. Pretreatment with a sub-effective dose of T3 (0.06 mg/kg) markedly enhanced the ability of drugs acting mainly on noradrenergic systems (clenbuterol, desipramine, maprotiline and nomifensine) to increase the response to L-5-HTP. 3. 3. In contrast the potentiating effects of T3 were moderate on drugs with mixed action on serotonergic and noradrenergic systems (amitriptyline, clomipramine and imipramine) and minimal on drugs acting mainly on serotonergic systems (citalopram, fluvoxamine and indalpine). 4. 4. These data suggest that the increased responsiveness to L-5-HTP caused by T3 involves an indirect (norepinephrine-mediated) rather than a direct effect on serotonergic processes.

A high-performance liquid chromatographic method using a fluorometric detector was developed for the determination of plasma concentrations of the antidepressant indalpine (I) and its major metabolite 4-[2-(3-indolyl)ethyl]-2-piperidinone (PK). the same procedure was used to measure, in urine, levels of I and of the metabolite, either conjugated or unconjugated. The sensitivity of the assay is 5 ng ml-1 of plasma or urine for both I and PK. Mean recoveries from plasma for PK, I, and the internal standard (quinine sulfate) were 86.4, 86.8, and 88.5 per cent, respectively. Mean recovery from urine for I was 82.5%. This method was used to establish the pharmacokinetic profiles of I and PK following a single oral administration of I (100 mg) in 8 healthy volunteers. Peak plasma concentrations for I and PK were obtained in an average time of 2.1 and 2.6 h (tmax), respectively. The mean absorption t1/2 of I was 0.8 h, the mean Vda 878 l and the mean clearance 58 l h-1. The mean t1/2 for I and PK was 10.4 and 11.9 h, respectively. In a 12 h urine collection 3 per cent of I was excreted unchanged. No conjugated or unconjugated metabolite was found in urine samples. This method was also used to determine plasma levels 10 h post-dose (50 mg t.i.d.) during chronic oral administration in 20 hospitalized patients. Mean plasma concentrations of I and PK post-dose were 116 ng ml-1 and 43 ng ml-1, respectively.

In order to document the role of monoamines in the reduction of paradoxical sleep by antidepressant drugs, we examined the effect of indalpine, a selective inhibitor of serotonin uptake. Indalpine dose dependently decreased paradoxical sleep and delayed its first appearance. Pretreatment with parachlorophenylalanine markedly decreased the effect of indalpine. In contrast, pretreatment with α-methylparatyrosine potentiated the indalpine-induced depression of paradoxical sleep. The results of the study indicate that the increase of extracellular concentration of 5-HT has an inhibitory effect on paradoxical sleep, and this effect is enlarged if catecholaminergic activity is reduced.

The effects of serotonin receptor agonists and antagonists on the electrically (3 Hz) evoked 3H overflow were determined on pig brain cortex slices preincubated with 3H-serotonin and superfused with physiological salt solution containing indalpine (an inhibitor of serotonin uptake) plus phentolamine. The potencies of the serotonin receptor agonists and antagonists were compared with their affinities for 5-HT1A, 5-HT1B, 5-HT1c, and 5-HT1D binding sites in pig or rat tissue membranes; in addition, the potencies of the agonists were compared to their potencies in inhibiting adenylate cyclase activity in membranes of calf substantia nigra. In the superfusion experiments on pig brain cortex slices the following rank orders of potencies were obtained: agonists, serotonin > 5-methoxytryptamine = 5-carboxamidotryptamine >R U 24969 (5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole) > SDZ 21009 (4(3-terbutylamino- 2-hydroxypropoxy)indol- 2-carbonic-acid-isopropylester) ≥ yohimbine ≥ cyanopindolol > 8-OHDPAT (8-hydroxy-2-(di-n-propylamino)tetralin) ≥ CGS 12066 B (7-trifluoromethyl-4(4-methyl-l-piperazinyl)-pyrrolo[1,2-a]quinoxaline); ipsapirone and urapidil were ineffective; antagonists (antagonism determined against 5methoxytryptamine as an agonist), metitepine > metergoline > mianserin. Propranolol, spiperone or mesulergine did not produce a shift of the concentration-response curve for 5-methoxytryptamine. The potencies of the serotonin receptor agonists in pig brain cortex slices were significantly correlated with their affinities for 5-HT1c and 5-HT1D binding sites in membranes of the pig choroid plexus and caudate nucleus, respectively, but not with their affinities for 5-HT1A and 5-HT1B sites in membranes of the cerebral cortex of pig and rat, respectively. The agonist potencies in decreasing 3H overflow were also significantly correlated with their potencies in inhibiting adenylate cylase activity in calf substantia nigra (i.e., a 5-HT1D receptor-mediated effect). In conclusion, the pig brain cortical 5-HT autoreceptor probably belongs to the 5-HT1D subtype. The involvement of 5-HT1c recognition sites was excluded by the low potency of mianserin as an antagonist and, in particular, by the ineffectiveness of the 5-HT1c receptor antagonist mesulergine.

Many of the currently available antidepressant drugs produce unwanted anticholinergic effects which range from minor effects such as blurred vision and dryness of the mouth to urinary retention and exacerbation of glaucoma. Anticholinergic effects may be particularly severe in middle-aged and elderly patients. In addition many of the peripheral symptoms associated with depression may be exacerbated by treatment with those antidepressants which have significant anticholinergic activity.

In the mouse forced-swimming model, dose-dependent reversal of immobility was induced by the alpha-agonist clonidine given IP 30 min before testing. In addition, three preferential inhibitors of 5-HT uptake (citalopram, indalpine and fluvoxamine) had similar activity in the dose range 8–16 mg/kg as did the 5-HT1 agonist 8-OH-DPAT (1–4 mg/kg). Pretreatment with alpha-methyl-para-tyrosine (100 mg/kg) did not prevent clonidine (1 mg/kg) action, suggesting that there was mediation by alpha post-junctional receptors. The effect of clonidine was unaltered by prazosin (2 mg/kg) and reversed by yohimbine (4 mg/kg) and 5-MeODMT (1 mg/kg), whereas it was potentiated by reserpine (2.5 mg/kg), methysergide (2 mg/kg) and ketanserin (8 mg/kg). Moreover, an ineffective dose of clonidine (0.06 mg/kg at 45 min pre-testing) made active subthreshold doses of various antidepressants (given at 30 min pre-testing): imipramine (4 mg/kg), amitriptyline (1 mg/kg), maprotiline (8 mg/kg), citalopram (2 mg/kg), indalpine, fluvoxamine and mianserin (4 mg/kg), viloxazine (2 mg/kg). Similar interactions were found with iprindole and nialamide (32 mg/kg), which were inactive alone up to 64 mg/kg, and 8-OH-DPAT (0.5 mg/kg) but not with major and minor tranquillizers. It is suggested that one effect of antide-pressants might be the triggering of different relationships between alpha-2 and 5-HT mechanisms.

An investigation of the site of interaction of a variety of tricyclic and nontricyclic 5-HT uptake inhibitors with the neuronal sodium-dependent 5-HT transporter was undertaken. The dissociation of [ 3 H]paroxetine binding induced by indalpine (10 ωM), SL 81.0385 (10 ωM), fluoxetine (10 ωM), citalopram (10 ωM), paroxetine (0.15 ωM), imipramine (10 ωM) and 5-HT (50 ωM) produced monophasic dissociation curves and gave t 1 2 values of dissociation similar to that induced by dilution alone. In inhibition studies of [ 3 H] paroxetine binding with citalopram, imipramine and 5-HT, increases in the concentration of [ 3 H]radioligand used led to parallel rightward shifts of the inhibition curves with no diminution of the maximum degree of inhibition ( I max ). “Schild-type” analyses of the data obtained from the inhibition curves with these 3 compounds gave slopes close to unity. In chemical modification studies, treatment of membrane fractions with N -ethylmaleimide led to a pronounded reduction in specific [ 3 H]paroxetine binding. Preincubation of these membranes with SL 81.0385, fluoxetine, imipramine, tryptamine and 5-HT provided significant protection against this NEM-induced inactivation. The above findings are interpreted to provide evidence for a common or at least overlapping binding site for the tricyclic and nontricyclic 5-HT uptake inhibitors with the substrate recognition site of the neuronal sodium-dependent 5-HT transporter.

This study investigated whether benzodiazepines reduce the capacity of animals to wait for food reward. Rats trained in a T-maze were allowed to choose between two magnitudes of reward: immediate, but small (two pellets) vs delayed, but large (eight pellets). The rats learned within ten sessions to select (80–100%) the arm leading to the largest reward. Separate groups of rats were then confined for 15, 30 or 60 s in the arm associated with the largest reward before gaining access to the spacially contiguous goal-box. The choice of the other arm was not followed by a period of waiting. Under these conditions, the frequency with which the small-reward arm was chosen increased linearly as a function of the duration of the waiting period. Diazepam (2–4 mg/kg IP) dose-dependently increased the number of times the small-reward arm was chosen during the sessions for which the waiting period was fixed at 15 or 30 s. Nitrazepam (2 mg/kg IP), chlordiazepoxide (16 mg/kg IP) and clobazam (16 mg/kg IP) had similar effects. The action of diazepam was counteracted by simultaneous administration of flumazepil (Ro 15-1788, 8 mg/kg PO). In the absence of confinement, these benzodiazepines, diazepam (4 mg/kg) excepted, did not modify selection of the large-reward arm. Conversely, the serotonin uptake blockers indalpine (2–4 mg/kg IP) and zimelidine (8–16 mg/kg IP) dose-dependently increased preference for the arm leading to the delayed (25 s) but large reward. These results suggest that benzodiazepines, perhaps by increasing impulsivity, render the animals less prone than controls to tolerate delayed access to reward. It is hypothesized that serotonergic neurons play a crucial role in impulse control and in the benzodiazepines-induced shift towards the immediate reward.

1. Mice when suspended by the tail will alternate between active attempts to escape and immobility. Immobility like that measured in the behavioral despair test is reduced by a wide variety of antidepressant agents. 2. The present paper describes a computerized version of this test (ITEMATIC-TST) which in addition to recording immobility measures the power of the movements. 3. Various tricyclic (amitriptyline, desipramine, imipramine), MAOI (clorgyline, moclobemide, nialamide, pargyline, toloxatone) and atypical antidepressants (bupropion, citalopram, indalpine, mianserin, nomifensine, viloxazine) were tested and compared with psychostimulants (d-amphetamine, caffeine), neuroleptics (chlorpromazine, haloperidol, sulpiride), anxiolytics (clobazam, diazepam) and agents acting on the cholinergic system (atropine, oxotremorine). 4. All antidepressants decreased the duration of immobility and most increased the power of movements. 5. The psychostimulants also decreased immobility but only amphetamine increased the power of movements. 6. Neuroleptics increased immobility without affecting the power of movements, whereas anxiolytics increased immobility but decreased the power of movements. 7. Atropine had a profile similar to antidepressants whereas oxotremorine tended to have opposite effects. 8. The results suggest that the automated test system with its two parameters is not only sensitive to antidepressants but could also be useful for generating activity profiles for different kinds of psychotropic agent.

4-(3-Indolyl-alkyl)piperidine derivatives (LM 5005, LM 5008, LM 5015) strongly inhibited 5-HT accumulation into rat brain synaptosomes and human blood platelets in vitro but were weaker inhibitors of NA and DA uptake. These new compounds inhibited, like clomipramine, the neuronal membrane active transport whereas reserpine blocked the synaptic vesicle storage process of biogenic amines. They had no effect on 5-HT release from human blood platelets. The duration of 5-HT uptake inhibition in vivo by LM 5015 was equal to that observed with clomipramine (about 3 hr) and longer for LM 5008 and LM 5005. The piperidine derivatives did not inhibit 5-HT uptake into synaptosomes from specific regions of rat brain in the same manner. Unlike the trieyclic antidepressants, LM 5005 and LM 5008 did not block the in vivo uptake of NA into rat heart and LM 5015 was a weak inhibitor. These results suggest that 4-(3-indolyl-alkyl)piperidine derivatives represent a new class of potent and selective inhibitors of 5-HT uptake into rat brain synaptosomes and human blood platelets.

The idea of protein receptors plays an important role in biochemistry. The concept of ‘structural complementarity’ between an exogenous or endogenous molecule and the protein binding site(s) is now well established. This requirement will be designated by ‘structural specificity’. We will develop here a complementary point of view, based on the existence of ‘thermodynamic specificity’. It may be explained by considering the example of noradrenaline (NA), serotonin (5-HT) and four antidepressant drugs (midalcipran, citalopram, indalpine, and imipramine), blockers of the uptake of the above endogenous neuromediators.