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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.

After 1 mg DST, 25 major depressive patients (DSM-III) received at random either a specific inhibitor of noradrenaline reuptake (Maprotiline) or an inhibitor of serotinin reuptake (Indalpine or Citalopram). After at least 3 weeks of treatment, no difference was found in treatment response between suppressors and non suppressors. This study is unable to confirm the usefulness of the DST in selection of treatment according to its central activity on serotonin or noradrenaline-reuptake.

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.

Indalpine, inhibits the re-uptake of 5HT but it is obvious that there is no single agreed hypothesis to explain depression. Whatever the proposed mechanism of action of an antidepressant, the main question for the clinician is “is the drug an effective and safe antidepressant in clinical practice,” and the following trial was carried out to determine Indalpine’s efficacy by comparing it to an established antidepressant. This design was chosen because of the ethical difficulties of placebo controlled out-patient trials but it is scientifically the weaker design because the null hypothesis is then that the two drugs are equally effective and failure to reject this hypothesis may be the result of a poorly designed trial, too small numbers, etc. Thus one does not prove the two drugs to be similar, one simply fails to prove that they differ. Despite such difficulties, however, double blind control trials are essential tools for the assessment of a new antidepressant and many such trials are necessary before the effectiveness of a drug can be said to be established. With placebo effect and observer bias, open trials are unsuitable for assessing such drugs.

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.

Plasma levels of free and conjugated 3,4-dihydroxyphenylethyleneglycol (DOPEG), the main deaminated metabolite of norepinephrine, were assayed in 48 depressed patients before initiating a treatment with either maprotiline, an inhibitor of norepinephrine reuptake, or indalpine, a specific inhibitor of serotonin reuptake. The two groups of depressed patients were comparable. The therapeutic effect was evaluated by using the Hamilton Rating Scale for Depression. No difference in pretreatment plasma free and conjugated DOPEG levels was found between the responders and the nonresponders to maprotiline or indalpine. Neither was there any difference in the pretreatment levels of plasma free DOPEG between the two groups of responders and the two groups of nonresponders to either drug. Finally, there was no difference in the therapeutic response to maprotiline or to indalpine between the patients with high and low plasma DOPEG levels before treatment. These results indicate that there is no relationship between the initial plasma levels of DOPEG in depressed patients and their therapeutic response to a norepinephrine or a serotonin reuptake blocker.

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.

Extracellular levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were monitored by microdialysis in the hippocampal formation previously denervated of its serotonergic input by an intraventricular injection of 5,7-dihydroxytryptamine (5,7-DHT), and in 5,7-DHT denervated hippocampi reinnervated by grafted fetal rat serotonin neurons. Two weeks after 5,7-DHT lesion, baseline 5-HT release was reduced to levels below detection, and KCl- and p-chloro-amphetamine-evoked release was reduced by 90-95%. In the chronically denervated hippocampus (3 months after lesion), baseline 5-HT release had recovered to near-normal levels, but KCl- and p-chloroamphetamine-evoked release remained severely impaired. Addition of the 5-HT re-uptake blocker indalpine to the perfusion medium induced a 5-6-fold increase in serotonin overflow in the normal hippocampus, while the serotonin overflow in the 5,7-DHT denervated hippocampus remained unaffected. The intrahippocampal fetal raphe transplants restored 5-HT release to near-normal levels, not only under baseline conditions but also in the presence of re-uptake blockade. Both KCl- and p-chloroamphetamine-induced release had recovered in the grafted hippocampus and the responses were even greater than those seen in normal animals. In both normal and grafted hippocampus addition of the sodium channel blocker tetrodotoxin reduced 5-HT overflow to the level seen in the denervated hippocampus. The new hippocampal serotonin innervation, established by the grafts, was markedly denser than normal, and the tissue 5-HT and 5-HIAA levels were 3-4-fold higher than normal in the grafted hippocampi. The 5-HIAA level in the perfusate collected from the grafted hippocampi showed a similar increase above normal, whereas 5-HT release was maintained within the normal range, both under baseline conditions and in the presence of re-uptake blockade. The results indicate that the grafted serotonergic raphe neurons are spontaneously active at the synaptic level, despite their ectopic location. The ability of the grafted neurons to maintain 5-HT release within the normal range suggests that local regulatory mechanisms at the terminal level can compensate for abnormalities in the graft-derived innervation density.

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.

SummaryIndalpine 150 mg per day and mianserin 60 mg per day were compared in a double-blind study of 65 depressed out-patients: 52 patients completed the 4-week trial. At the end of four weeks there was no significant difference in antidepressant effect between the two drugs; but in the first two weeks, improvement in the mianserin-treated group was significantly greater than that in the indalpine group. The mianserin-treated group reported more side-effects of sedation (eg. drowsiness, clumsiness, heaviness of limbs etc.) and one patient on indalpine developed a mild leucopenia.

The potential value of pretreatment urinary 3-methoxy, 4-hydroxyphenylethyleneglycol (MHPG) levels to predict the therapeutic response to antidepressants was studied by measuring urinary MHPG output in 42 depressed inpatients treated with a selective inhibitor of serotonin (Indalpine) or noradrenaline (Maprotiline) reuptake. Among the 42 depressed inpatients there were 33 cases of major depressive episode. Patients were treated for at least 3 weeks, firstly with intravenous infusions of maprotiline or indalpine which have been administered at random. No difference in pretreatment urinary MHPG levels was found between the responders to indalpine (1.08 +/- 0.48 micrograms/24 h/mg of creatinine) and the responders to maprotiline (1.15 +/- 0.62 micrograms/24 h/mg of creatinine). However, there was a difference in the pretreatment levels of urinary MHPG between the non-responders to indalpine (0.56 +/- 0.28 microgram/24 h/mg of creatinine) and the non-responders to maprotiline (1.37 +/- 0.68 micrograms/24 h/mg of creatinine). No correlation between this biochemical parameter and HDRS score was found. These results indicate that, in this study, there is no obvious relationship between the pretreatment urinary MHPG levels in depressed patients and their therapeutic response to specific inhibitors of noradrenaline or serotonin reuptake. However, there was a positive trend towards a lower pretreatment MHPG level to be associated with lack of response to indalpine.

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.