Pau Celada

Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity : Role in atypical antipsychotic action

Atypical antipsychotics increase dopamine (DA) release in the medial prefrontal cortex (mPFC), an effect possibly involved in the superior effects of atypical versus classical antipsychotics on cognitive/negative symptoms. We examined the role of 5-HT1A receptors in the mPFC on the modulation of dopaminergic activity and the mesocortical DA release in vivo. The highly selective 5-HT1A agonist BAY x 3702 (BAY; 10-40 μg/kg, i.v.) increased the firing rate and burst firing of DA neurons in the ventral tegmental area (VTA) and DA release in the VTA and mPFC. The increase in DA release in both areas was potentiated by nomifensine coperfusion. The selective 5-HT1A antagonist WAY-100635 reversed the effects of BAY in both areas, and the changes in the VTA were prevented by frontocortical transection. The application of BAY in rat and mouse mPFC by reverse dialysis increased local extracellular DA at a low concentration (3 μm) and reduced it at a higher concentration (30 μm). Both effects disappeared in 5-HT1A knock-out mice. In the presence of bicuculline, BAY reduced DA release at all concentrations. The atypical antipsychotics clozapine, olanzapine, and ziprasidone (but not haloperidol) enhanced DA release in the mPFC of wild-type but not 5-HT1A knock-out mice after systemic and local (clozapine and olanzapine) administration in the mPFC. Likewise, bicuculline coperfusion prevented the elevation of DA release produced by local clozapine or olanzapine application. These results suggest that the activation of mPFC 5-HT1A receptors enhances the activity of VTA DA neurons and mesocortical DA release. This mechanism may be involved in the elevation of extracellular DA produced by atypical antipsychotics.

Origin and functional role of the extracellular serotonin in the midbrain raphe nuclei.

There is considerable interest in the regulation of the extracellular compartment of the transmitter serotonin (5-hydroxytryptamine, 5-HT) in the midbrain raphe nuclei because it can control the activity of ascending serotonergic systems and the release of 5-HT in terminal areas of the forebrain. Several intrinsic and extrinsic factors of 5-HT neurons that regulate 5-HT release in the dorsal (DR) and median (MnR) raphe nucleus are reviewed in this article. Despite its high concentration in the extracellular space of the raphe nuclei, the origin of this pool of the transmitter remains to be determined. Regardless of its origin, is has been shown that the release of 5-HT in the rostral raphe nuclei is partly dependent on impulse flow and Ca(2+) ions. The release in the DR and MnR is critically dependent on the activation of 5-HT autoreceptors in these nuclei. Yet, it appears that 5-HT autoreceptors do not tonically inhibit 5-HT release in the raphe nuclei but rather play a role as sensors that respond to an excess of the endogenous transmitter. Both DR and MnR are equally responsive to the reduction of 5-HT release elicited by the local perfusion of 5-HT(1A) receptor agonists. In contrast, the effects of selective 5-HT(1B) receptor agonists are more pronounced in the MnR than in the DR. However, the cellular localization of 5-HT(1B) receptors in the raphe nuclei remains to be established. Furthermore, endogenous noradrenaline and GABA tonically regulate the extracellular concentration of 5-HT although the degree of tonicity appears to depend upon the sleep/wake cycle and the behavioral state of the animal. Glutamate exerts a phasic facilitatory control over the release of 5-HT in the raphe nuclei through ionotropic glutamate receptors. Overall, it appears that the extracellular concentration of 5-HT in the DR and the MnR is tightly controlled by intrinsic serotonergic mechanisms as well as afferent connections.

How does pindolol improve antidepressant action

Since 1994, the beta-adrenoceptor and 5-HT(1A/1B) receptor ligand pindolol has been used to accelerate or enhance the clinical effects of antidepressant drugs, such as the selective 5-HT reuptake inhibitors (SSRIs), that act primarily on 5-HT-containing neurones. Pindolol was initially thought to act by preventing the inhibition of 5-HT release, elicited by SSRIs and other 5-HT-acting drugs, as a result of its ability to antagonize the action of 5-HT at midbrain raphe 5-HT(1A) autoreceptors that control the activity of ascending 5-HT-mediated pathways. However, the partial agonist properties of pindolol at 5-HT(1A) receptors and beta-adrenoceptors suggest that other explanations for its action are also possible. In this article, recent controversial data on the mechanism of action of pindolol, which are crucial for the development of more rapid and efficient antidepressant therapies, will be discussed.

Serotonin modulation of cortical neurons and networks

The serotonergic pathways originating in the dorsal and median raphe nuclei (DR and MnR, respectively) are critically involved in cortical function. Serotonin (5-HT), acting on postsynaptic and presynaptic receptors, is involved in cognition, mood, impulse control and motor functions by (1) modulating the activity of different neuronal types, and (2) varying the release of other neurotransmitters, such as glutamate, GABA, acetylcholine and dopamine. Also, 5-HT seems to play an important role in cortical development. Of all cortical regions, the frontal lobe is the area most enriched in serotonergic axons and 5-HT receptors. 5-HT and selective receptor agonists modulate the excitability of cortical neurons and their discharge rate through the activation of several receptor subtypes, of which the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT3 subtypes play a major role. Little is known, however, on the role of other excitatory receptors moderately expressed in cortical areas, such as 5-HT2C, 5-HT4, 5-HT6, and 5-HT7. In vitro and in vivo studies suggest that 5-HT1A and 5-HT2A receptors are key players and exert opposite effects on the activity of pyramidal neurons in the medial prefrontal cortex (mPFC). The activation of 5-HT1A receptors in mPFC hyperpolarizes pyramidal neurons whereas that of 5-HT2A receptors results in neuronal depolarization, reduction of the afterhyperpolarization and increase of excitatory postsynaptic currents (EPSCs) and of discharge rate. 5-HT can also stimulate excitatory (5-HT2A and 5-HT3) and inhibitory (5-HT1A) receptors in GABA interneurons to modulate synaptic GABA inputs onto pyramidal neurons. Likewise, the pharmacological manipulation of various 5-HT receptors alters oscillatory activity in PFC, suggesting that 5-HT is also involved in the control of cortical network activity. A better understanding of the actions of 5-HT in PFC may help to develop treatments for mood and cognitive disorders associated with an abnormal function of the frontal lobe.

The activation of 5-HT2A receptors in prefrontal cortex enhances dopaminergic activity

Atypical antipsychotics show preferential 5‐HT2A versus dopamine (DA) D2 receptor affinity. At clinical doses, they fully occupy cortical 5‐HT2 receptors, which suggests a strong relationship with their therapeutic action. Half of the pyramidal neurones in the medial prefrontal cortex (mPFC) express 5‐HT2A receptors. Also, neurones excited through 5‐HT2A receptors project to the ventral tegmental area (VTA). We therefore hypothesized that prefrontal 5‐HT2A receptors can modulate DA transmission through excitatory mPFC–VTA inputs. In this study we used single unit recordings to examine the responses of DA neurones to local (in the mPFC) and systemic administration of the 5‐HT2A/2C agonist 1‐[2,5‐dimethoxy‐4‐iodophenyl‐2‐aminopropane] (DOI). Likewise, using microdialysis, we examined DA release in the mPFC and VTA (single/dual probe) in response to prefrontal and systemic drug administration. The local (in the mPFC) and systemic administration of DOI increased the firing rate and burst firing of DA neurones and DA release in the VTA and mPFC. The increase in VTA DA release was mimicked by the electrical stimulation of the mPFC. The effects of DOI were reversed by M100907 and ritanserin. These results indicate that the activity of VTA DA neurones is under the excitatory control of 5‐HT2A receptors in the mPFC. These observations may help in the understanding of the therapeutic action of atypical antipsychotics.

Serotonin 5-HT1A Receptors as Targets for Agents to Treat Psychiatric Disorders: Rationale and Current Status of Research

Psychiatric disorders represent a large economic burden in modern societies. However, pharmacological treatments are still far from optimal. Drugs used in the treatment of major depressive disorder (MDD) and anxiety disorders (selective serotonin [5-HT] reuptake inhibitors [SSRIs] and serotonin-noradrenaline reuptake inhibitors [SNRIs]) are pharmacological refinements of first-generation tricyclic drugs, discovered by serendipity, and show low efficacy and slowness of onset. Moreover, antipsychotic drugs are partly effective in positive symptoms of schizophrenia, yet they poorly treat negative symptoms and cognitive deficits. The present article reviews the neurobiological basis of 5-HT1A receptor (5-HT1A-R) function and the role of pre- and postsynaptic 5-HT1A-Rs in the treatment of MDD, anxiety and psychotic disorders. The activation of postsynaptic 5-HT1A-Rs in corticolimbic areas appears beneficial for the therapeutic action of antidepressant drugs. However, presynaptic 5-HT1A-Rs play a detrimental role in MDD, since individuals with high density or function of presynaptic 5-HT1A-Rs are more susceptible to mood disorders and suicide, and respond poorly to antidepressant drugs. Moreover, the indirect activation of presynaptic 5-HT1A-Rs by SSRIs/SNRIs reduces 5-HT neuron activity and terminal 5-HT release, thus opposing the elevation of extracellular 5-HT produced by blockade of the serotonin transporter (SERT) in the forebrain. Chronic antidepressant treatment desensitizes presynaptic 5-HT1A-Rs, thus reducing the effectiveness of the 5-HT1A autoreceptor-mediated negative feedback. The prevention of this process by the non-selective partial agonist pindolol accelerates clinical antidepressant effects. Two new antidepressant drugs, vilazodone (marketed in the USA) and vortioxetine (in development) incorporate partial 5-HT1A-R agonist properties with SERT blockade. Several studies with transgenic mice have also established the respective role of pre- and postsynaptic 5-HT1A-Rs in MDD and anxiety. In agreement with pharmacological studies, presynaptic and postsynaptic 5-HT1A-R activation appears necessary for anxiolytic and antidepressant effects, respectively, yet, neurodevelopmental roles for 5-HT1A-Rs are also involved. Likewise, the use of small interference RNA has enabled the showing of robust antidepressant-like effects in mice after selective knock-down of 5-HT1A autoreceptors. Postsynaptic 5-HT1A-Rs in the prefrontal cortex (PFC) also appear important for the superior clinical effects of clozapine and other second-generation (atypical) antipsychotic drugs in the treatment of schizophrenia and related psychotic disorders. Despite showing a moderate in vitro affinity for 5-HT1A-Rs in binding assays, clozapine displays functional agonist properties at this receptor type in vivo. The stimulation of 5-HT1A-Rs in the PFC leads to the distal activation of the mesocortical pathway and to an increased dopamine release in PFC, an effect likely involved in the clinical actions of clozapine in negative symptoms and cognitive deficits in schizophrenia. The anxiolytic/antidepressant properties of 5-HT1A-R agonists in preclinical tests raised expectations enormously. However, these agents have achieved little clinical success, possibly due to their partial agonist character at postsynaptic 5-HT1A-Rs, together with full agonist properties at presynaptic 5-HT1A autoreceptors, as well as their gastrointestinal side effects. The partial 5-HT1A-R agonists buspirone, gepirone, and tandospirone are marketed as anxiolytic drugs, and buspirone is also used as an augmentation strategy in MDD. The development of new 5-HT1A-R agonists with selectivity for postsynaptic 5-HT1A-Rs may open new perspectives in the field.

Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine

NMDA receptor (NMDA-R) antagonists are extensively used as schizophrenia models because of their ability to evoke positive and negative symptoms as well as cognitive deficits similar to those of the illness. Cognitive deficits in schizophrenia are associated with prefrontal cortex (PFC) abnormalities. These deficits are of particular interest because an early improvement in cognitive performance predicts a better long-term clinical outcome. Here, we examined the effect of the noncompetitive NMDA-R antagonist phencyclidine (PCP) on PFC function to understand the cellular and network elements involved in its schizomimetic actions. PCP induces a marked disruption of the activity of the PFC in the rat, increasing and decreasing the activity of 45% and 33% of the pyramidal neurons recorded, respectively (22% of the neurons were unaffected). Concurrently, PCP markedly reduced cortical synchrony in the delta frequency range (0.3–4 Hz) as assessed by recording local field potentials. The subsequent administration of the antipsychotic drugs haloperidol and clozapine reversed PCP effects on pyramidal cell firing and cortical synchronization. PCP increased c-fos expression in PFC pyramidal neurons, an effect prevented by the administration of clozapine. PCP also enhanced c-fos expression in the centromedial and mediodorsal (but not reticular) nuclei of the thalamus, suggesting the participation of enhanced thalamocortical excitatory inputs. These results shed light on the involvement of PFC in the schizomimetic action of NMDA-R antagonists and show that antipsychotic drugs may partly exert their therapeutic effect by normalizing a disrupted PFC activity, an effect that may add to subcortical dopamine receptor blockade.

Strategies for producing faster acting antidepressants

Existing antidepressant treatments exhibit limited efficacy and a slow onset of action. Several neurobiological adaptive mechanisms might delay the clinical effects of antidepressants, whose therapeutic action is primarily triggered by an increase of serotonergic and noradrenergic neurotransmission. Here, we review several potential mechanisms that could be useful to increase the speed of current antidepressant drugs, such as additional blockade of aminergic autoreceptors or antagonism of certain postsynaptic (5-HT2A, 5-HT2C) receptors. The potential use of strategies not based on monoaminergic transmission, such as CRF and NK1 receptor antagonists, or more novel strategies, based on glutamatergic or GABAergic transmission or on intracellular messengers, are also reviewed.

The role of 5‐HT1B receptors in the regulation of serotonin cell firing and release in the rat brain

The release of 5‐HT in terminal areas of the rodent brain is regulated by 5‐HT1B receptors. Here we examined the role of 5‐HT1B receptors in the control of 5‐HT output and firing in the dorsal raphe nucleus (DR), median raphe nucleus (MnR) and forebrain of the rat in vivo. The local perfusion (30–300 µm) of the selective 5‐HT1B receptor agonist CP‐93,129 to freely moving rats decreased 5‐HT release in the DR and more markedly in the MnR. Likewise, 300 µm CP‐93,129 reduced 5‐HT output in substantia nigra pars reticulata, ventral pallidum, lateral habenula and the suprachiasmatic nucleus. The effect of CP‐93,129 was prevented by SB‐224289, but not by WAY‐100635, selective 5‐HT1B and 5‐HT1A receptor antagonists, respectively. SB‐224289 did not alter dialysate 5‐HT in any raphe nuclei. The intravenous administration of the brain‐penetrant selective 5‐HT1B receptor agonist CP‐94,253 (0.5–2.0 mg/kg) to anesthetized rats decreased dialysate 5‐HT in dorsal hippocampus and globus pallidus, increased it in MnR and left it unaltered in the DR and medial prefrontal cortex. SB‐224289, at a dose known to block 5‐HT1B autoreceptor‐mediated effects (5 mg/kg), did not prevent the effect of CP‐94,253 on MnR 5‐HT. The intravenous administration of CP‐94,253 (0.05–1.6 mg/kg) to anesthetized rats increased the firing rate of MnR, but not DR‐5‐HT neurons. The local perfusion of CP‐94,253 in the MnR showed a biphasic effect, with 5‐HT reductions at 0.3–3 µm and increase at 300 µm. These results suggest that 5‐HT cell firing and release in midbrain raphe nuclei (particularly in the MnR) are under control of 5‐HT1B receptors. The activation of 5‐HT1B autoreceptors (possibly located on 5‐HT nerve endings and/or varicosities within DR and MnR) reduces 5‐HT release. The effects of higher concentrations of 5‐HT1B receptor agonists seem more compatible with the activation of 5‐HT1B heteroreceptors on inhibitory neurons.

Monoamine oxidase inhibitors increase preferentially extracellular 5-hydroxytryptamine in the midbrain raphe nuclei. A brain microdialysis study in the awake rat

SummaryWe have examined the local and systemic effects of clorgyline, tranylcypromine and deprenyl on extracellular serotonin (5-HT) and 5-hydroxyindoleacetic acid in the raphe nuclei and in frontal cortex of awake, freely-moving rats using microdialysis. When administered through the dialysis probe, monoamine oxidase (monoamine: oxygen oxidoreductase (deaminating), E.C. 1.4.3.4., MAO) inhibitors increased 5-HT output in a dose-dependent manner in both brain areas. The effects were more pronounced in the raphe nuclei for the three MAO inhibitors at all doses assayed.When the monoamine oxidase inhibitors were given i.p., dialysate 5-HT increased dramatically, after tranylcypromine (15 mg/kg), in raphe nuclei and frontal cortex (area under the curve (AUC) to 4 h post-treatment: 63-fold and 11-fold, respectively) whereas the effects of clorgyline (10 mg/kg) were much less pronounced (+ 47% increase in the AUC for raphe nuclei, P < 0.09; + 18% increase in the AUC for frontal cortex, n.s.). Deprenyl (2.5 mg/kg, i.p.) induced a moderate (+ 22%) increase of dialysate 5-HT from the raphe nuclei but did not cause a change in dialysate 5-HT from the frontal cortex (+ 4%). However, clorgyline, or deprenyl, dramatically increased dialysate 5-HT in animals which had been pre-treated with the above dose of deprenyl, or clorgyline, respectively, showing that the blockade of both forms of MAO results in much larger increases of extracellular 5-HT than does the blockade of either form alone.These results indicate that: (a) deamination by MAO participates actively in the control of the extracellular concentration of 5-HT in those areas of the brain that are rich in serotoninergic nerve terminals as well as in cell bodies, (b) in vivo, brain 5-HT is deaminated preferentially by MAO-A but its full inhibition does not result in an increased release of 5-HT, in spite of a large accumulation of 5-HT in the brain tissue, (c) MAO-B deaminates 5-HT when the A-form is inhibited (in this situation, MAO-B participates actively in the control of a releasable pool of 5-HT), (d) the raphe nuclei appears to be a preferential site of action of MAO inhibitors, administered either locally or systemically. These results may help to understand the model of action of MAO inhibitors as antidepressant drugs.