Tricyclic antidepressants: long-term treatment increases responsivity of rat forebrain neurons to serotonin.

Long-term treatment of rats with clinically effective tricyclic antidepressant drugs induced a selective increase in the inhibitory response of forebrain neurons to serotonin applied by microiontophoresis. Long-term administration of some related drugs which lack antidepressant efficacy failed to induce such a change. The enhanced response to serotonin induced by the clinically active tricyclic drugs took 1 to 2 weeks to develop, a time course which correlates with the delayed onset of therapeutic effects in humans.

Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists.

At clinically relevant doses, selective serotonin (5-HT) reuptake inhibitors (SSRIs) and MAO inhibitors (MAOIs) increase the extracellular concentration of 5-HT in the midbrain raphé nuclei, thereby activating inhibitory somatodendritic 5-HT1A autoreceptors. Consequently, the firing activity of 5-HT neurons is reduced and the enhancement of extracellular 5-HT concentration in forebrain is dampened. Overriding this feedback by using antagonists of 5-HT1A autoreceptors permits SSRIs to produce a marked increase of extracellular 5-HT in the forebrain. Hence, combined treatment with an SSRI and a 5-HT1A antagonist increases the extracellular concentration of 5-HT more so than the former drug alone. The treatment of patients with major depression using an SSRI and pindolol, a 5-HT1A/ beta-adrenoceptor antagonist, markedly reduced the latency of the antidepressant response in previously untreated patients and induced a rapid improvement in treatment-resistant patients.

Current advances and trends in the treatment of depression.

The pathophysiology of major affective illness is poorly understood. However, several lines of preclinical and clinical evidence indicate that an enhancement of 5-HT-mediated neurotransmission might underlie the therapeutic effect of most antidepressant treatments. This net effect would, however, be obtained via different mechanisms. A better understanding of the neurobiological basis for the delayed onset of action of antidepressant treatments has led to the elaboration of strategies that could accelerate the antidepressant response. These strategies are discussed in this article by Pierre Blier and Claude de Montigny.

Cholecystokinin tetrapeptide induces panic-like attacks in healthy volunteers. Preliminary findings.

A total of 31 intravenous injections of the tetrapeptide cholecystokinin (30-33) were carried out in ten healthy subjects. In seven subjects, cholecystokinin-4 provoked a short-lasting (one to four minutes) panic-like attack (an intense unexplainable fear) at doses between 20 and 100 micrograms. In the other three subjects, doses of 80 to 100 micrograms induced severe anxiety, but no panic-like attack. All subjects experienced severe gastrointestinal symptoms. Pretreatment with lorazepam, but not with meprobamate or naloxone, prevented the psychic effects of cholecystokinin-4 in subjects who had experienced a panic-like attack with the same dose of this peptide. Following the peptide injection, levels of plasma free catecholamines, lactate, and glucose were unchanged, whereas levels of plasma cortisol and prolactin were increased. The intravenous injection of the sulfated cholecystokinin octapeptide (26-33) in two subjects (doses of 35 and 40 micrograms, respectively) produced severe gastrointestinal symptoms, but failed to induce any anxiety or panic-like attacks. These preliminary findings suggest that cholecystokinin-4 may have a panic-inducing effect. It remains to be established if this peptide exerts this effect via a direct activation of central cholecystokinin receptors.

Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression. Correlations with the neurobiologic actions of tricyclic antidepressant drugs and lithium ion on the serotonin system.

Preliminary reports suggested that the addition of lithium carbonate to the regimen of patients treated with, but not responding to, a tricyclic antidepressant (TCA) drug can induce a rapid alleviation of depression. We examined the effect of lithium carbonate addition in 39 patients with unipolar depression whose conditions were not improved by at least three weeks' TCA drug administration. In 30 of 42 observations, lithium carbonate brought about a greater than 50% improvement within 48 hours. In a second study, the effects of lithium carbonate addition were compared in five amitriptyline hydrochloride-pretreated and five placebo-pretreated patients who showed no improvement after a three-week treatment. All five patients receiving amitriptyline showed a greater than 50% improvement 48 hours after lithium carbonate addition, whereas only one patient in the placebo group showed a marked response. In a third study the effect of lithium carbonate withdrawal was studied in nine TCA-resistant patients who had shown a marked improvement 48 hours after lithium addition. Only five of these patients had a relapse five days after lithium discontinuation. Since animal studies have shown that TCA drugs sensitize forebrain neurons to serotonin and that lithium enhances the activity of serotonin-containing neurons, we propose that the antidepressant effect of lithium addition in TCA-resistant patients might be mediated by enhancing serotonin neurotransmission.

Possible serotonergic mechanisms underlying the antidepressant and anti-obsessive-compulsive disorder responses.

Considerable evidence is now available to support the pivotal role of the serotonin (5-HT) system is exerting the antidepressant response in humans. Different type of antidepressant treatments enhance 5-HT neurotransmission via different pre- or postsynaptic mechanisms. The time course for the occurrence of these adaptive changes in the brain of laboratory animals is consistent with the delayed onset of the antidepressant response in humans. The drugs effective in obsessive-compulsive disorder (OCD) also enhance 5-HT neurotransmission in brain regions involved in mediating OCD symptoms but with a more prolonged delay, consistently with the larger time necessary to obtain therapeutic effect in OCD than in depression. The elucidation of these mechanisms of action lead to the development of new pharmacologic strategies to potentiate the therapeutic effect of the drugs currently available and the identification of novel targets to accelerate and further improve treatment response in depression and OCD.

Modulation of the firing activity of rat serotonin and noradrenaline neurons by (+/-)pindolol.

BACKGROUND: (+/-)Pindolol is a beta-adrenergic/5-HT1A receptor antagonist used in combination with certain antidepressant drugs to accelerate the onset of the antidepressive response. METHODS: The aim of the present study was to assess, using an in vivo electrophysiologic paradigm, the effect of (+/-)pindolol on the spontaneous firing activity of rat dorsal raphe serotonin (5-HT) and locus coeruleus noradrenaline (NA) neurons. RESULTS: (+/-)Pindolol did not modify the firing activity of dorsal raphe 5-HT neurons at low doses (10 and 200 micrograms/kg, i.v.), but it prevented the suppressant effect of the 5-HT autoreceptor agonist lysergic acid diethylamide (LSD, 10 micrograms/kg, i.v.) but not that of the 5-HT1A receptor 8-hydroxy-N,N-dipropyl-aminotetralin (8-OHDPAT, 5 micrograms/kg, i.v.). At a higher dose (500 micrograms/kg, i.v.), (+/-)pindolol decreased 5-HT neuronal firing and this effect was reversed by the selective 5-HT1A receptor antagonist WAY 100635 (100 micrograms/kg, i.v.), suggesting that it could act as a partial 5-HT1A autoreceptor agonist. In the locus coeruleus, the high dose of (+/-)pindolol decreased the firing activity of NA neurons and this effect was reversed by the 5-HT2A receptor antagonist MDL 100907 (200 micrograms/kg, i.v.). Finally, both a lesion of NA neurons and the administration of MDL 100907 prevented the suppressant effect of (+/-)pindolol on the firing of 5-HT neurons. CONCLUSIONS: It is suggested that, at low doses, (+/-)pindolol acts as a somatodendritic 5-HT1A autoreceptor antagonist whereas at a higher dose, it decreases the tonic excitatory input from NA neurons to 5-HT neurons.

Rapid response to the addition of lithium in iprindole-resistant unipolar depression: a pilot study.

The authors administered lithium carbonate, 900 mg/day, in an open study to seven patients with a major unipolar depression refractory to 3-week treatment with iprindole, 90 mg/day, a tricyclic antidepressant devoid of any action on monoaminergic reuptake. All patients showed clinically significant improvement within 48 hours. Since iprindole induces in the animal a sensitization of forebrain neurons to serotonin (5-HT), as do other tricyclic antidepressants, and lithium enhances the activity of 5-HT neurons, the authors propose that an enhanced release of 5-HT on sensitized target neurons might underlie the rapid antidepressant effect in tricyclic-refractory depression when lithium is added to the treatment regimen.

Serotonin and drug-induced therapeutic responses in major depression, obsessive-compulsive and panic disorders.

The therapeutic effectiveness of antidepressant drugs in major depression was discovered by pure serendipity. It took over 20 years before the neurobiological modifications that could mediate the antidepressive response were put into evidence. Indeed, whereas the immediate biochemical effects of these drugs had been well documented, their antidepressant action generally does not become apparent before 2 to 3 weeks of treatment. The different classes of antidepressant treatments were subsequently shown to enhance serotonin neurotransmission albeit via different pre- and postsynaptic mechanisms. Clinical trials based on this hypothesis led to the development of treatment strategies producing greater efficacy and more rapid onset of antidepressant action; that, is lithium addition and pindolol combination, respectively. It is expected that the better understanding recently obtained of the mechanism of action of certain antidepressant drugs in obsessive-compulsive and panic disorders will also lead to more effective treatment strategies for those disorders.

Selective activation of postsynaptic 5-HT1A receptors induces rapid antidepressant response.

It has been reported that the 5-HT1A autoreceptor antagonist pindolol can accelerate the antidepressant response to the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine, presumably by preventing the initial decrease in firing activity of 5-HT neurons produced by the SSRI. The present study was aimed at further exploring this treatment strategy in three groups of 10 patients with unipolar major depression allocated sequentially to three treatment arms for 28 days. The administration of the selective 5-HT1A agonist buspirone (20 mg/day for 1 week and 30 mg/day thereafter) with pindolol (2.5 mg TID) was used to activate selectively postsynaptic 5-HT1A receptors. This combination produced a greater than 50% reduction of depressive symptoms in the first week in 8 of 10 patients and the response was sustained for the remainder of the trial. In contrast, the combination of tricyclic antidepressant drugs devoid of effect on the 5-HT reuptake process (desipramine or trimipramine, 75 mg/day for 1 week and 150 mg/day thereafter) with pindolol resulted in only one of ten patients achieving a 50% improvement after 28 days. The combination of the SSRI fluvoxamine (50 mg/day for 1 week and 100 mg/day thereafter) with pindolol produced a marked antidepressant effect but did not act as rapidly as the buspirone plus pindolol combination with none, four, and eight patients achieving a 50% amelioration after 7, 14, and 21 days of treatment, respectively. These results provide further evidence that pindolol may accelerate the antidepressant effect of drugs that alter the function of the 5-HT neurons and that the selective activation of postsynaptic 5-HT1A receptors may induce a rapid and robust antidepressant response.

Electrophysiologic evidence for desensitization of alpha 2-adrenoceptors on serotonin terminals following long-term treatment with drugs increasing norepinephrine synaptic concentration.

Previous results from our laboratory have indicated that small intravenous doses of the alpha 2-adrenergic agonist clonidine increase serotonin (5-HT) neurotransmission by attenuating the release of endogenous norepinephrine (NE), as a result of the activation of alpha 2-adrenergic autoreceptor on NE neurons, and that high doses of clonidine decrease 5-HT neurotransmission by directly activating alpha 2-adrenergic heteroreceptors on 5-HT terminals. The aim of the present study was to assess whether antidepressant treatments that increase the synaptic concentration of NE or 5-HT alter the ability of clonidine to modulate 5-HT neurotransmission through these two alpha 2-adrenoceptors. Rats were treated for 3 weeks with 0.75 mg/kg per day of befloxatone (a reversible inhibitor of monoamine oxidase A), 10 mg/kg per day of nisoxetine (a selective NE reuptake inhibitor), 10 mg/kg per day of paroxetine (a selective 5-HT reuptake inhibitor) or saline using subcutaneous osmotic minipumps (removed 48 hours before the experiment). No significant change in the effect of the small dose of clonidine (10 micrograms/kg, i.v.) was found following the befloxatone, the nisoxetine, or the paroxetine treatments. The reduction of 5-HT neurotransmission by the high dose of clonidine (400 micrograms/kg, i.v.) was no longer present in rats treated with nisoxetine or befloxatone, but was unaltered in those treated with paroxetine. Furthermore, in rats pretreated with the NE neurotoxin 6-hydroxydopamine, a long-term treatment with befloxatone failed to alter the reducing effect of the high dose of clonidine but abolished the reducing effect of the low dose of clonidine. These results suggest that antidepressant drugs that increase NE synaptic concentration induce a desensitization of alpha 2-heteroreceptor on 5-HT terminals.

Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments. An in vivo electrophysiologic study in the rat.

The neurobiologic mechanisms whereby the long-term administration of different antidepressant treatments enhance the efficacy of 5-HT synaptic transmission was investigated using an electrophysiologic paradigm in chloral hydrate anesthetized rats. Repeated electroconvulsive shocks (ECS; administered every other day for 14 days) as well as the sustained 21-day administration of the tricyclic antidepressant imipramine (10 mg/kg/day) and of the selective 5-hydroxytryptamine (5-HT) reuptake blocker paroxetine (5 mg/kg/day), increased the suppressant effect of the electrical stimulation of the afferent 5-HT pathway on the firing activity of CA3 hippocampus pyramidal neurons. The long-term treatments with imipramine and ECS, but not with paroxetine, increased the responsiveness of postsynaptic CA3 hippocampus pyramidal neurons to the microiontophoretic application of 5-HT and to that of the selective 5-HT1A receptor ligand 8-OH-DPAT. In contrast, the long-term treatment with paroxetine, but not with imipramine or ECS, attenuated the negative feedback exerted by terminal 5-HT autoreceptors on 5-HT release. This was indicated by two series of experiments. First, the capacity of the acute intravenous injection of the terminal 5-HT autoreceptor antagonist methiothepin to increase the efficacy of the stimulation was abolished in paroxetine-treated rats. Second, the decreased suppressant effect on pyramidal neuron firing activity usually obtained by increasing the frequency of the stimulation from 1 to 5 Hz (shown to be due to an increase in terminal 5-HT autoreceptor activation at the higher frequency) was also reduced in paroxetine-treated rats. The present data confirm and extend those of previous electrophysiologic studies showing that an enhanced 5-HT synaptic transmission is a common end result of long-term administration of various types of antidepressant treatments. Furthermore, they suggest that the mechanisms underlying this enhanced synaptic transmission differ according to the type of treatment administered. Tricyclic antidepressants and ECS enhance 5-HT synaptic transmission by increasing the sensitivity of postsynaptic 5-HT1A receptors, whereas selective 5-HT reuptake blockers produce this effect by reducing the function of terminal 5-HT autoreceptors, thereby increasing the amount of 5-HT released per stimulation-triggered action potential.

5-HT1D receptors regulate 5-HT release in the rat raphe nuclei. In vivo voltammetry and in vitro superfusion studies.

The aim of the present study was to characterize the pharmacological profile of 5-hydroxytryptamine (5-HT) receptors modulating 5-HT release in the mesencephalic raphe region. In a first series of experiments, differential normal pulse voltammetry and nafion-coated electrodes were used to measure extracellular 5-HT in the dorsal raphe of anesthesized rats. The intravenous administration of the selective 5-HT1A agonist 8-OH-DPAT (30 micrograms/kg) and the 5-HT1 agonist TFMPP (0.5 mg/kg) reduced the 5-hydroxyindole signal by 23% and 18%, respectively. Pretreatment with the 5-HT1A antagonist (+)WAY100135 (0.5 mg/kg IV) 30 minutes before the injection of the agonists, blocked the effect of 8-OH-DPAT but not that of TFMPP. The effect of TFMPP was blocked by (+/-)mianserin, a drug with high affinity for the rat 5-HT1D receptor, suggesting a role of this receptor subtype in the modulation of 5-HT release at the cell body level of 5-HT neurons. This was confirmed by in vitro superfusion experiments using mesencephalic raphe slices. The prototypical 5-HT1 agonist 5-carboxy-amiditryptamine (5-CT) and the 5-HT1B/1D agonist sumatriptan (1-1,000 nM) induced a concentration-dependent inhibition of the electrically evoked release of [3H]5-HT from preloaded raphe slices. 8-OH-DPAT (100 nM) produced an inhibitory effect similar to that of sumatriptan (100 nM). The selective 5-HT1B agonist CP 93129 (10-10,000 nM), had no effect in raphe slices, but it dose dependently inhibited [3H]5-HT release from hippocampal slices where autoreceptors are of the 5-HT1B subtype. The inhibitory effect of 5-CT was blocked by the 5-HT1/2 antagonist methiothepin (1 microM), the 5-HT1A antagonist S-UH-301 (1 microM), and the 5-HT1B/1D antagonist GR 127935 (1 microM). That of 8-OH-DPAT was blocked by S-UH-301 (1 microM) but not by GR 127935 (1 microM), and that of sumatriptan was blocked by GR 127935 (1 microM) but not by S-UH-301 (1 microM). These results show that, together with 5-HT1A autoreceptors, 5-HT1D receptors negatively modulate the somatodendritic release of 5-HT.

Effect of ergotamine on serotonin-mediated responses in the rodent and human brain.

In the rat dorsal hippocampus and dorsal raphe nucleus, the microiontophoretic application of ergotamine and 5-HT suppressed the firing activity of CA3 pyramidal neurons and 5-HT neurons, an effect antagonized by selective 5-HT1A receptor antagonists. Co-application of ergotamine prevented the inhibitory action of 5-HT on the firing activity of CA3 pyramidal neurons but not of 5-HT neurons, indicating that ergotamine acted as a partial 5-HT1A receptor agonist in the dorsal hippocampus and as a full agonist at 5-HT1A autoreceptors. Ergotamine decreased, in a concentration-dependent manner, the electrically evoked release of [3H]5-HT in preloaded rat and guinea pig hypothalamus slices; this effect was prevented by the nonselective 5-HT receptor antagonist methiothepin but not by the selective 5-HT1B/1D receptor antagonist GR 127935 or the alpha 2-adrenoceptor antagonist idazoxan. Although body temperature in humans remained unchanged following inhaled ergotamine, in the rat, subcutaneously injected ergotamine produced a hypothermia that was prevented by a pretreatment with the 5-HT1A/1B receptor/beta-adrenoceptor antagonist pindolol. Finally in humans, ergotamine did not alter prolactin or adrenocorticotropic hormone levels, but increased growth hormone level, which was prevented by pindolol. Cortisol level was increased in humans by ergotamine, but this enhancement was unaltered by pindolol. In conclusion, the present results suggest that ergotamine acted in the rat brain as a 5-HT1A receptor agonist and as an agonist of terminal 5-HT autoreceptor of a yet undefined subtype. In humans, ergotamine also displayed some 5-HT1A receptor activity but, probably because of lack of receptor selectivity, it did not present the same profile as other 5-HT1A receptor agonists.

Effect of pindolol on the function of pre- and postsynaptic 5-HT1A receptors: in vivo microdialysis and electrophysiological studies in the rat brain.

In microdialysis studies, somatodendritic 5-HT1A receptors in the dorsal raphe nucleus (DRN) were activated by the local infusion of 50 microM citalopram, a selective 5-HT reuptake inhibitor (SSRI). This reduced extracellular 5-HT by about 50% in dorsal striatum, an area receiving 5-HT afferents exclusively from the DRN. (-)Pindolol dose-dependently attenuated this citalopram-induced reduction of striatal extracellular 5-HT. Consistent with its 5-HT reuptake blocking properties, single doses of the SSRI paroxetine (1 and 3 mg/kg IP) and citalopram (1 mg/kg IP) significantly elevated extracellular 5-HT in the dorsal striatum. Pretreatment with (-)pindolol (15 mg/kg IP) potentiated the effect of 3 mg/kg paroxetine and 1 mg/kg citalopram on striatal extracellular 5-HT. A 2-day treatment with 10 mg/kg/day (SC) of paroxetine reduced by 60% the spontaneous activity of 5-HT neurons of the DRN. However, 5-HT neurons displayed normal activity in rats treated with paroxetine and (-)pindolol for 2 days. The inhibitory effect of LSD on 5-HT neuronal firing activity was also markedly attenuated in (-)pindolol-treated rats, indicating that somatodendritic 5-HT1A receptors were blocked by (-)pindolol. To determine whether (-)pindolol also blocked postsynaptic 5-HT1A receptors in hippocampus, 5-HT and the prototypical 5-HT1A agonist 8-OH-DPAT were applied by microiontophoresis onto CA3 pyramidal neurons following the same treatment. (-)Pindolol did not modify the responsiveness of these neurons to 5-HT and 8-OH-DPAT. Taken together, these results indicate that (-)pindolol can potentiate the effects of an SSRI on extracellular 5-HT concentration by preventing the activation of somatodendritic 5-HT1A autoreceptors resulting from the blockade of the 5-HT transporter in the raphe. This presumably leads to enhanced 5-HT neurotransmission because (-)pindolol would not alter the responsiveness of certain postsynaptic 5-HT1A receptors, such as those located on hippocampal CA3 pyramidal neurons. These results provide a neurobiological basis for the reported potentiation of certain antidepressant drugs by pindolol in major depression.

Potentiation by (-)Pindolol of the activation of postsynaptic 5-HT(1A) receptors induced by venlafaxine.

The increase of extracellular 5-HT in brain terminal regions produced by the acute administration of 5-HT reuptake inhibitors (SSRI's) is hampered by the activation of somatodendritic 5-HT(1A) autoreceptors in the raphe nuclei. The present in vivo electrophysiological studies were undertaken, in the rat, to assess the effects of the coadministration of venlafaxine, a dual 5-HT/NE reuptake inhibitor, and (-)pindolol on pre- and postsynaptic 5-HT(1A) receptor function. The acute administration of venlafaxine and of the SSRI paroxetine (5 mg/kg, i.v.) induced a suppression of the firing activity of dorsal hippocampus CA(3) pyramidal neurons. This effect of venlafaxine was markedly potentiated by a pretreatment with (-)pindolol (15 mg/kg, i.p.) but not by the selective beta-adrenoceptor antagonist metoprolol (15 mg/kg, i.p.). That this effect of venlafaxine was mediated by an activation of postsynaptic 5-HT(1A) receptors was suggested by its complete reversal by the 5-HT(1A) antagonist WAY 100635 (100 microg/kg, i.v.). A short-term treatment with VLX (20 mg/kg/day x 2 days) resulted in a ca. 90% suppression of the firing activity of 5-HT neurons in the dorsal raphe nucleus. This was prevented by the coadministration of (-)pindolol (15 mg/kg/day x 2 days). Taken together, these results indicate that (-)pindolol potentiated the activation of postsynaptic 5-HT(1A) receptors resulting from 5-HT reuptake inhibition probably by blocking the somatodendritic 5-HT(1A) autoreceptor, but not its postsynaptic congener. These results support and extend previous findings providing a biological substratum for the efficacy of pindolol as an accelerating strategy in major depression.

Increased tonic activation of rat forebrain 5-HT(1A) receptors by lithium addition to antidepressant treatments.

The present study was undertaken to determine whether lithium addition to long-term treatment with different classes of antidepressant drugs could induce a greater effect on the serotonin (5-HT) system than the drugs given alone. Because 5-HT(1A) receptor activation hyperpolarizes and inhibits the firing activity of CA(3) pyramidal neurons in the dorsal hippocampus, the degree of disinhibition produced by the selective 5-HT(1A) receptor antagonist WAY 100635 was determined using in vivo extracellular recordings. In controls, as well as in rats receiving a lithium diet for 3 days, the administration of WAY 100635 (25-100 microg/kg, IV) did not modify the firing activity of dorsal hippocampus CA(3) pyramidal neurons. When the tricyclic antidepressant imipramine (10 mg/kg/day, SC), the monoamine oxidase inhibitor tranylcypromine (2.5 mg/kg/day, SC) and the selective 5-HT reuptake inhibitor paroxetine (10 mg/kg/day, SC) were administered alone for 21 days, a dose of 50 microg/kg of WAY 100635 was needed to increase significantly the firing activity of these neurons. On the other hand, WAY 100635, at a dose of only 25 microg/kg, increased significantly the firing rate of CA(3) pyramidal neurons in rats receiving both a long-term antidepressant treatment and a short-term lithium diet. It is concluded that the addition of lithium to antidepressant treatments produced a greater disinhibition of dorsal hippocampus CA(3) pyramidal neurons than any treatments given alone. The present results support the notion that the addition of lithium to antidepressants may produce a therapeutic response in treatment-resistant depression by enhancing 5-HT neurotransmission.

Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects.

Duloxetine is a dual inhibitor of norepinephrine (NE) and serotonin (5-HT) uptake. Initial trials conducted in depressed patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy as an antidepressant. The aim of this study was to assess the effects of duloxetine on the 5-HT and NE reuptake processes in healthy human volunteers. Twenty-seven healthy young males without a history of psychiatric disorder were randomly assigned to four groups, each group receiving one of the following daily drug regimens: placebo, clomipramine (a potent 5-HT/NE reuptake blocker) 100 mg/day, duloxetine 20 mg/day, or duloxetine 60 mg/day. In order to assess the NE reuptake process, the pressor response to intravenous tyramine (4 and 6 mg) was measured. Determination of the whole blood 5-HT content was used to evaluate the 5-HT reuptake blockade. These measurements were performed at baseline and repeated after 7 and 14 days of drug intake. Both duloxetine, at doses of 20 to 60 mg/day, and clomipramine significantly interfered with the 5-HT reuptake process, as demonstrated by marked decreases in blood 5-HT concentrations. However, the same doses of duloxetine, unlike clomipramine, failed to impede the usual increase in blood pressure that follows a tyramine intravenous infusion, indicating that clomipramine but not duloxetine blocked NE reuptake. At doses tested in a population of healthy volunteers, duloxetine acted as a selective 5-HT reuptake inhibitor, having no clear effect on the NE reuptake process. Nevertheless, given that the highest dose of duloxetine increased supine systolic blood pressure, it is possible that it represents the threshold regimen for NE reuptake inhibition.

Serotonin1A receptor activation by flesinoxan in humans. Body temperature and neuroendocrine responses.

The effects of the selective 5-HT1A receptor agonist flesinoxan on neuroendocrine function, temperature, and behavior were assessed in male healthy volunteers using a double-blind, placebo-controlled crossover design. Flesinoxan (7 and 14 micrograms/kg), administered intravenously in 11 healthy volunteers, elicited a dose-related decrease in body temperature and increases in growth hormone, adrenocorticotropic hormone (ACTH), cortisol, and prolactin plasma levels. In a second independent study, 12 healthy volunteers were pretreated sequentially, at one-week intervals, with either the 5-HT1A antagonist pindolol (30 mg, PO), the nonselective 5-HT1/2 antagonist methysergide (4 mg, PO), or placebo, prior to being administered flesinoxan (1 mg, IV). The growth hormone response to flesinoxan was blocked by pindolol but not by methysergide, whereas the prolactin response was blocked by methysergide but not by pindolol. The ACTH and cortisol responses to flesinoxan were potentiated by methysergide. The flesinoxan-induced hypothermia was attenuated by both methysergide and pindolol, although the latter effects did not reach statistical significance. The present results suggest that the growth hormone response and the hypothermic response to the intravenous infusion of flesinoxan may serve as a valid index of 5-HT1A receptor function in humans.

Effects of quipazine on pre- and postsynaptic serotonin receptors: single cell studies in the rat CNS.

Many behavioural and biochemical studies have pointed to an agonistic activity of quipazine on serotonin (5-HT) receptors. In the present electrophysiological study, the effect of quipazine on pre- and postsynaptic 5-HT receptors in the rat was studied. Quipazine, administered intravenously, depressed the firing rate of 5-HT-containing dorsal raphe neurones (ED50 = 0.82 mg/kg). Microiontophoretic applications of quipazine on 5-HT-containing neurones in the dorsal raphe and on neurones of two forebrain regions receiving a 5-HT input (the ventral lateral geniculate nucleus and the dorsal hippocampus) consistently depressed neuronal firing rate as did 5-HT and D-lysergic acid diethylamide (LSD). Quipazine was more potent on 5-HT neurones than on the ventral lateral geniculate nucleus and hippocampal neurones: the post/presynaptic efficacy ratio for quipazine was similar to that of LSD. Following a selective denervation of 5-HT neurones with intraventricular injection of 5,7-di-hydroxy-tryptamine in desipramine-pretreated rats, the responsiveness of neurones in the ventral lateral geniculate nucleus to quipazine, applied microiontophoretically, was increased as was that to 5-HT and to LSD. These results provide direct evidence for the agonistic activity of quipazine on both pre- and postsynaptic 5-HT receptors.