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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.

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-HT1Aautoreceptors in the raphe nuclei. The present in vivoelectrophysiological 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-HT1Areceptor 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 CA3pyramidal neurons. This effect of venlafaxine was markedly potentiated by a pretreatment with (-)pindolol (15 mg/kg, i.p.) but not by the selective β-adrenoceptor antagonist metoprolol (15 mg/kg, i.p.). That this effect of venlafaxine was mediated by an activation of postsynaptic 5-HT1Areceptors was suggested by its complete reversal by the 5-HT1Aantagonist WAY 100635 (100 μg/kg, i.v.). A short-term treatment with VLX (20 mg/kg/day ×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 ×2 days). Taken together, these results indicate that (-)pindolol potentiated the activation of postsynaptic 5-HT1Areceptors resulting from 5-HT reuptake inhibition probably by blocking the somatodendritic 5-HT1Aautoreceptor, 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.

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-HT1Areceptor activation hyperpolarizes and inhibits the firing activity of CA3pyramidal neurons in the dorsal hippocampus, the degree of disinhibition produced by the selective 5-HT1Areceptor 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 μg/kg, IV) did not modify the firing activity of dorsal hippocampus CA3pyramidal 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 μg/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 μg/kg, increased significantly the firing rate of CA3pyramidal 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 CA3pyramidal 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.

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.Neuropsychopharmacology (1999) 21 91S–98S.10.1016/S0893-133X(99)00036-6

In the rat dorsal hippocampus and dorsal raphe nucleus, the microiontophoretic application of ergotamine and 5-HT suppressed the firing activity of CA3pyramidal neurons and 5-HT neurons, an effect antagonized by selective 5-HT1Areceptor antagonists. Co-application of ergotamine prevented the inhibitory action of 5-HT on the firing activity of CA3pyramidal neurons but not of 5-HT neurons, indicating that ergotamine acted as a partial 5-HT1Areceptor agonist in the dorsal hippocampus and as a full agonist at 5-HT1Aautoreceptors. 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/1Dreceptor antagonist GR 127935 or the α2-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/1Breceptor/β-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-HT1Areceptor agonist and as an agonist of terminal 5-HT autoreceptor of a yet undefined subtype. In humans, ergotamine also displayed some 5-HT1Areceptor activity but, probably because of lack of receptor selectivity, it did not present the same profile as other 5-HT1Areceptor agonists.

It has been reported that the 5-HT1Aautoreceptor 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-HT1Aagonist 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-HT1Areceptors. 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-HT1Areceptors may induce a rapid and robust antidepressant response.

In microdialysis studies, somatodendritic 5-HT1Areceptors in the dorsal raphe nucleus (DRN) were activated by the local infusion of 50 μM 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-HT1Areceptors were blocked by (−)pindolol. To determine whether (−)pindolol also blocked postsynaptic 5-HT1Areceptors in hippocampus, 5-HT and the prototypical 5-HT1Aagonist 8-OH-DPAT were applied by microiontophoresis onto CA3pyramidal 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-HT1Aautoreceptors 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-HT1Areceptors, such as those located on hippocampal CA3pyramidal neurons. These results provide a neurobiological basis for the reported potentiation of certain antidepressant drugs by pindolol in major depression.

The effects of the selective 5-HT1Areceptor agonist flesinoxan on neuroendocrine function, temperature, and behavior were assessed in male healthy volunteers using a double-blind, placebo-controlled crossover design. Flexinoxan (7 and 14 μg/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-HT1Aantagonist pindolol (30 mg, PO), the nonselective 5-HT1 2antagonist 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-HT1Areceptor function in humans.

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-HT1Aagonist 8-OH-DPAT (30 μg/kg) and the 5-HT1agonist TFMPP (0.5 mg/kg) reduced the 5-hydroxyindole signal by 23% and 18%, respectively. Pretreatment with the 5-HT1Aantagonist (+)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-HT1Dreceptor, 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-HT1agonist 5-carboxy-amiditryptamine (5-CT) and the 5-HT1B1Dagonist 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-HT1Bagonist 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-HT1Bsubtype. The inhibitory effect of 5-CT was blocked by the 5-HT12antagonist methiothepin (1 μM), the 5-HT1Aantagonist S-UH-301 (1 μM), and the 5-HT1B1Dantagonist GR 127935 (1 μM). That of 8-OH-DPAT was blocked by S-UH-301 (1 μM) but not by GR 127935 (1 μM), and that of sumatriptan was blocked by GR 127935 (1 μM) but not by S-UH-301 (1 μM). These results show that, together with 5-HT1Aautoreceptors, 5-HT1Dreceptors negatively modulate the somatodendritic release of 5-HT.