Luz Romero

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.

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 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-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.

Preferential Potentiation of the Effects of Serotonin Uptake Inhibitors by 5‐HT1A Receptor Antagonists in the Dorsal Raphe Pathway: Role of Somatodendritic Autoreceptors

Abstract: 5‐HT1A autoreceptor antagonists enhance the effects of antidepressants by preventing a negative feedback of serotonin (5‐HT) at somatodendritic level. The maximal elevations of extracellular concentration of 5‐HT (5‐HText) induced by the 5‐HT uptake inhibitor paroxetine in forebrain were potentiated by the 5‐HT1A antagonist WAY‐100635 (1 mg/kg s.c.) in a regionally dependent manner (striatum > frontal cortex > dorsal hippocampus). Paroxetine (3 mg/kg s.c.) decreased forebrain 5‐HText during local blockade of uptake. This reduction was greater in striatum and frontal cortex than in dorsal hippocampus and was counteracted by the local and systemic administration of WAY‐100635. The perfusion of 50 µmol/L citalopram in the dorsal or median raphe nucleus reduced 5‐HText in frontal cortex or dorsal hippocampus to 40 and 65% of baseline, respectively. The reduction of cortical 5‐HText induced by perfusion of citalopram in midbrain raphe was fully reversed by WAY‐100635 (1 mg/kg s.c.). Together, these data suggest that dorsal raphe neurons projecting to striatum and frontal cortex are more sensitive to self‐inhibition mediated by 5‐HT1A autoreceptors than median raphe neurons projecting to the hippocampus. Therefore, potentiation by 5‐HT1A antagonists occurs preferentially in forebrain areas innervated by serotonergic neurons of the dorsal raphe nucleus.

The 5-HT1A antagonist WAY-100635 selectively potentiates the presynaptic effects of serotonergic antidepressants in rat brain.

The increases in extracellular serotonin (5-hydroxytryptamine; 5-HT) produced by some antidepressent drugs in forebrain are attenuated by the activation of somatodendritic 5-HT1A autoreceptors by the excess 5-HT induced by these agents in the midbrain raphe. Using microdialysis, we have examined the effects of the selective 5-HT1A antagonist WAY-100635 in rats pretreated with the selective 5-HT reuptake inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, the tricyclic antidepressants clomipramine and desipramine and the monoamine oxidase inhibitor phenelzine. WAY-100635 markedly potentiated the increases in 5-HT produced by the SSRIs, clomipramine and phenelzine but it did not alter that produced by desipramine. These results indicate that the effects of serotonergic antidepressant drugs (but not those of desipramine, which mainly blocks noradrenaline reuptake) can be potentiated by 5-HT1A autoreceptor blockade.

Desensitization of 5-HT1A Autoreceptors by a Low Chronic Fluoxetine Dose Effect of the Concurrent Administration of WAY-100635☆

Using microdialysis, receptor autoradiography and in situ hybridization, we examined the effects of fluoxetine alone or with WAY-100635 on: (a) extracellular 5-HT in frontal cortex; and (b) density and sensitivity of 5-HT1A autoreceptors in rat brain. WAY-100635 (0.3 mg/kg, s.c.) doubled the increase in extracellular 5-HT produced by fluoxetine (3 mg/kg, i.p.) in frontal cortex. Two-week minipump treatments with these daily doses significantly raised extracellular 5-HT to 275 ± 33% (fluoxetine) and 245 ± 10% (fluoxetine plus WAY-100635) of controls. Fluoxetine 3 mg/kg·day desensitized dorsal raphe 5-HT1A autoreceptors, an effect prevented by the concurrent WAY-100635 administration. However, WAY-100635 (alone or with fluoxetine) did not change 5-HT1A autoreceptor sensitivity. The density of 5-HT1A receptors and its encoding mRNA, was unaffected by these treatments. These results suggest that prolonged blockade of 5-HT1A receptors in vivo prevents the autoreceptor desensitization induced by fluoxetine but does not result in receptor sensitization.

Reduction of in vivo striatal 5-hydroxytryptamine release by 8-OH-DPAT after inactivation of Gi/Go proteins in dorsal raphe nucleus

5-HT1A receptor agonists reduce firing-dependent terminal 5-HT synthesis and release by activating somatodendritic 5-HT1A receptors. We have examined the effects of 8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT, 0.1 mg/kg s.c.) on in vivo striatal 5-HT release in conscious rats with somatodendritic 5-HT1A receptors inactivated by the application of pertussis toxin in the dorsal raphe nucleus. The uncoupling of 5-HT1A receptors from hyperpolarizing potassium channels was demonstrated by the inability of the intra-raphe application of citalopram to reduce striatal release (control animals had a 47% reduction, an effect prevented by previous treatment with the 5-HT1A antagonist (-)-tertatolol). Yet 8-OH-DPAT (0.1 mg/kg s.c.) decreased striatal 5-HT release by 66% (peak effect) in pertussis toxin-treated rats, a value comparable to that found in naive animals (74%). This raises the possibility that other 8-OH-DPAT-sensitive serotonergic receptors different from 5-HT1A autoreceptors may be involved in the control of terminal 5-HT release.

Sigma 1 receptor: a new therapeutic target for pain.

Sigma 1 receptor (σ₁ receptor) is a unique ligand-regulated molecular chaperone located mainly in the endoplasmic reticulum and the plasma membrane. σ₁ receptor is activated under stress or pathological conditions and interacts with several neurotransmitter receptors and ion channels to modulate their function. The effects reported preclinically with σ₁ receptor ligands are consistent with a role for σ₁ receptor in central sensitization and pain hypersensitivity and suggest a potential therapeutic use of σ₁ receptor antagonists for the management of neuropathic pain as monotherapy. Moreover, data support their use in opioid adjuvant therapy: combination of σ₁ receptor antagonists and opioids results in potentiation of opioid analgesia, without significant increases in opioid-related unwanted effects. Results from clinical trials using selective σ₁ receptor antagonists in several pain conditions are eagerly awaited to ascertain the potential of σ₁ receptor modulation in pain therapy.

Basal and stimulated extracellular serotonin concentration in the brain of rats with altered serotonin uptake.

We examined the relationship between the density of serotonergic (5‐hydroxytryptamine [5‐HT]) uptake sites and extracellular 5‐HT concentration in the rat brain using microdialysis with two different models, lesions with 5,7‐dihydroxytryptamine (50 μg in the dorsal raphe nucleus (DRN) 15 days before) and sublines of rats genetically selected displaying extreme values of platelet 5‐HT uptake. Compared to controls, lesioned rats had a reduced cortical concentration of 5‐hydroxyindoles (45%), unchanged basal extracellular 5‐HT in the DRN and ventral hippocampus (VHPC), and reduced basal 5‐hydroxyindoleacetic acid (5‐HIAA) concentrations (46%, DRN; 22%, VHPC). Yet the perfusion of 100 mmol/L KCl or 1 μmol/L citalopram elevated dialysate 5‐HT significantly more in the DRN and VHPC of controls. In genetically selected rats, platelet 5‐HT content and uptake were highly correlated (r2 = 0.9145). Baseline dialysate 5‐HT (VHPC) was not different between high and low 5‐HT rats and from normal Wistar rats. However, KCl or citalopram perfusion increased dialysate 5‐HT significantly more in high 5‐HT than in low 5‐HT rats, and the former displayed a greater in vivo tissue 5‐HT recovery. Significant but small differences in the same direction were noted in [3H]citalopram binding in several brain areas, as measured autoradiographically. Thus, basal extracellular 5‐HT (but not 5‐HIAA) concentrations are largely independent on the density of serotonergic innervation and associated changes in uptake sites. However, marked differences emerge during axonal depolarization or reuptake blockade. The significance of these findings for the treatment of mood disorders in patients with neurological disorders is discussed. Synapse 28:313–321, 1998.

Adaptative Changes of the Serotonergic System After Antidepressant Treatments

The search for an adequate treatment of major depression is one of the main challenges of Neuropharmacology. To date, no single drug is effective in all patients treated, probably due to the heterogeneity of the disease and to individual differences in the response to the agents used. Despite provoking pharmacological effects when given at once, all treatments need to be administered for several weeks before amelioration signs begin to emerge. This has led to the notion that —rather than the inhibition of uptake or monoamine oxidase (MAO) activity per se— adaptative changes of aminergic receptors mediate the clinical effects.

Sigma-1 receptor antagonism as opioid adjuvant strategy: enhancement of opioid antinociception without increasing adverse effects.

While opioids are potent analgesics widely used in the management of pain, a number of well-known adverse effects limit their use. The sigma-1 receptor is a ligand-regulated molecular chaperone involved in pain processing, including modulation of opioid antinociception. However, data supporting the potential use of sigma-1 receptor ligands as suitable opioid adjuvants are based on studies that use non selective ligands. Also, safety issues derived from combination therapy are poorly addressed. In this study we used the new selective sigma-1 receptor antagonist S1RA (E-52862) to characterize the effect of selective sigma-1 receptor blockade on opioid-induced efficacy- and safety-related outcomes in mice. S1RA (40 mg/kg) had no effect in the tail-flick test but did enhance the antinociceptive potency of several opioids by a factor between 2 and 3.3. The potentiating effect of S1RA on morphine antinociception did not occur in sigma-1 receptor knockout mice, which supports the selective involvement of the sigma-1 receptor. Interestingly, S1RA co-administration restored morphine antinociception in tolerant mice and reverted the reward effects of morphine in the conditioned place preference paradigm. In addition, enhancement of antinociception was not accompanied by potentiation of other opioid-induced effects, such as the development of morphine analgesic tolerance, physical dependence, inhibition of gastrointestinal transit, or mydriasis. The use of sigma-1 receptor antagonists as opioid adjuvants could represent a promising pharmacological strategy to enhance opioid potency and, most importantly, to increase the safety margin of opioids. S1RA is currently in phase II clinical trials for the treatment of several pain conditions.