Llorenç Díaz-Mataix

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.

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.

In vivo actions of aripiprazole on serotonergic and dopaminergic systems in rodent brain

RationaleAripiprazole is an atypical antipsychotic drug with high in vitro affinity for 5-HT1A, 5-HT2A and dopamine (DA) D2 receptors. However, its in vivo actions in the brain are still poorly characterized.ObjectiveThe aim was to study the in vivo actions of aripiprazole in the rat and mouse brain.MethodsBrain microdialysis and single-unit extracellular recordings were performed.ResultsThe systemic administration of aripiprazole reduced 5-HT output in the medial prefrontal cortex (mPFC) and dorsal raphe nucleus of the rat. Aripiprazole also reduced extracellular 5-HT in the mPFC of wild-type (WT) but not of 5-HT1A (−/−) knockout (KO) mice. Aripiprazole reversed the elevation in extracellular 5-HT output produced by the local application of the 5-HT2A/2C receptor agonist DOI in mPFC. Aripiprazole also increased the DA output in mPFC of WT but not of 5-HT1A KO mice, as observed for atypical antipsychotic drugs, in contrast to haloperidol. Contrary to haloperidol, which increases the firing rate of DA neurons in the ventral tegmental area (VTA), aripiprazole induced a very moderate reduction in dopaminergic activity. Haloperidol fully reversed the inhibition in dopaminergic firing rate induced by apomorphine, whereas aripiprazole evoked a partial reversal that was significantly different from that evoked by haloperidol and from the spontaneous reversal of dopaminergic activity in rats treated with apomorphine.ConclusionsThese results indicate that aripiprazole modulates the in vivo 5-HT and DA release in mPFC through the activation of 5-HT1A receptors. Moreover, aripiprazole behaves as a partial agonist at DA D2 autoreceptors in vivo, an action which clearly distinguishes it from haloperidol.

The hallucinogen DOI reduces low-frequency oscillations in rat prefrontal cortex: reversal by antipsychotic drugs.

BACKGROUND Perceptual and psychic alterations and thought disorder are fundamental elements of schizophrenia symptoms, a pathology associated with an abnormal macro- and microcircuitry of several brain areas including the prefrontal cortex (PFC). Alterations in information processing in PFC may partly underlie schizophrenia symptoms. METHODS The 5-HT(2A/2C) agonist DOI and antipsychotic drugs were administered to anesthetized rats. Single unit and local field potential (LFP) extracellular recordings were made in medial PFC (mPFC). Electrolytic lesions were performed in the thalamic nuclei. RESULTS DOI markedly disrupts cellular and network activity in rat PFC. DOI altered pyramidal discharge in mPFC (39% excited, 27% inhibited, 34% unaffected; n = 51). In all instances, DOI concurrently reduced low-frequency oscillations (.3-4 Hz; power spectrum: .25 +/- .02 and .14 +/- .01 microV(2) in basal conditions and after 50-300 microg/kg intravenous (i.v.) DOI, respectively; n = 51). Moreover, DOI disrupted the temporal association between the active phase of LFP and pyramidal discharge. Both effects were reversed by M100907 (5-HT(2A) receptor antagonist) and were not attenuated by thalamic lesions, supporting an intracortical origin of the effects of DOI. The reduction in low-frequency oscillations induced by DOI was significantly reversed by the antipsychotic drugs haloperidol (.1-.2 mg/kg i.v.) and clozapine (1 mg/kg i.v.). CONCLUSIONS DOI disorganizes network activity in PFC, reducing low-frequency oscillations and desynchronizing pyramidal discharge from active phases of LFP. These effects may underlie DOIs psychotomimetic action. The reversal by clozapine and haloperidol indicates that antipsychotic drugs may reduce psychotic symptoms by normalizing an altered PFC function.

Dopamine release induced by atypical antipsychotics in prefrontal cortex requires 5-HT1A receptors but not 5-HT2A receptors

Atypical antipsychotic drugs (APDs) increase dopamine (DA) release in prefrontal cortex (PFC), an effect probably mediated by the direct or indirect activation of the 5-HT(1A) receptor (5-HT(1A)R). Given the very low in-vitro affinity of most APDs for 5-HT(1A)Rs and the large co-expression of 5-HT(1A)Rs and 5-HT(2A) receptors (5-HT(2A)Rs) in the PFC, this effect might result from the imbalance of 5-HT(1A)R and 5-HT(2A)R activation after blockade of these receptors by APDs, for which they show high affinity. Here we tested this hypothesis by examining the dependence of the APD-induced DA release in medial PFC (mPFC) on each receptor by using in-vivo microdialysis in wild-type (WT) and 5-HT(1A)R and 5-HT(2A)R knockout (KO) mice. Local APDs (clozapine, olanzapine, risperidone) administered by reverse dialysis induced a dose-dependent increase in mPFC DA output equally in WT and 5-HT(2A)R KO mice whereas the DA increase was absent in 5-HT(1A)R KO mice. To examine the relative contribution of both receptors to the clozapine-induced DA release in rat mPFC, we silenced G-protein-coupled receptors (GPCRs) in vivo with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) while 5-HT(1A)Rs or 5-HT(2A)/2CRs in the mPFC were selectively protected with the respective antagonists WAY-100635 or ritanserin. The inactivation of GPCRs while preserving ∼70% of 5-HT(2A)/(2C)Rs prevented the clozapine-induced DA rise in mPFC. In contrast, clozapine increased DA in mPFC of EEDQ-treated rats whose 5-HT(1A)Rs were protected (∼50% of control rats). These results indicate that (1) 5-HT(1A)Rs are necessary for the APDs-induced elevation in cortical DA transmission, and (2) this effect does not require 5-HT(2A)R blockade by APDs.

In vivo modulation of 5-hydroxytryptamine release in mouse prefrontal cortex by local 5-HT2A receptors: effect of antipsychotic drugs

In the rat, postsynaptic 5‐hydroxytryptamine2A receptors medial prefrontal cortex control the activity of the serotonergic system through changes in the activity of pyramidal neurons projecting to the dorsal raphe nucleus. Here we extend these observations to mouse brain. The prefrontal cortex expresses abundant 5‐ hydroxytryptamine2A receptors, as assessed by immunohistochemistry, Western blots and in situ hybridization procedures. The application of the 5‐hydroxytryptamine2A/2C agonist DOI (100 µm) by reverse dialysis in the medial prefrontal cortex doubled the local release of 5‐hydroxytryptamine. This effect was reversed by coperfusion of tetrodotoxin, and by the selective 5‐hydroxytryptamine2A receptor antagonist M100907, but not by the 5‐hydroxytryptamine2C antagonist SB‐242084. The effect of DOI was also reversed by prazosin (α1‐adrenoceptor antagonist), BAY × 3702 (5‐hydroxytryptamine1A receptor agonist), NBQX (α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐4‐propionate/kainic acid antagonist) and 1S,3S‐ACPD (mGluR II/III agonist), but not by dizocilpine (N‐methyl‐d‐aspartate antagonist). α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐4‐propionate mimicked the 5‐hydroxytryptamine elevation produced by DOI, an effect also reversed by BAY × 3702. Likewise, the coperfusion of classical (chlorpromazine, haloperidol) and atypical antipsychotic drugs (clozapine, olanzapine) fully reversed the 5‐hydroxytryptamine elevation induced by DOI. These observations suggest that DOI increases 5‐hydroxytryptamine release in the mouse medial prefrontal cortex through the activation of local 5‐hydroxytryptamine2A receptors by an impulse‐dependent mechanism that involves/requires the activation of local α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐4‐propionate receptors. This effect is reversed by ligands of receptors present in the medial prefrontal cortex, possibly in pyramidal neurons, which are involved in the action of antipsychotic drugs. In particular, the reversal by classical antipsychotics may involve blockade of α1‐adrenoceptors, whereas that of atypical antipsychotics may involve 5‐hydroxytryptamine2A receptors and α1‐adrenoceptors.

Activation of pyramidal cells in rat medial prefrontal cortex projecting to ventral tegmental area by a 5-HT1A receptor agonist.

5-HT(1A) receptor agonists increase the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) and DA release in medial prefrontal cortex (mPFC). The mPFC is enriched in 5-HT(1A) receptors and projects to the VTA, where mesocortical dopaminergic neurons originate. We examined whether 5-HT(1A) receptor activation can modulate the activity of mPFC pyramidal neurons projecting to VTA. These were identified by antidromic stimulation from the VTA and were recorded extracellularly in anesthetized rats. The selective 5-HT(1A) agonist BAY x 3,702 (10-80 microg/kg i.v.) increased the firing rate in 14/19 neurons (283 +/- 79%) and reduced the activity of 5/19 neurons (22 +/- 11%), resulting in an overall 2.2-fold increase of the firing rate. Both effects were blocked by the selective 5-HT(1A) antagonist WAY-100635. These results suggest that the increase in dopaminergic activity produced by 5-HT(1A) receptor activation can be driven by an increase in the activity of projection neurons in mPFC.

Modulation of Serotonergic Function in Rat Brain by VN2222, a Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

VN2222 (1-(benzo[b]thiophen-3-yl)-3-[4-(2-methoxiphenyl piperazin-1-yl]propan-1-ol) is a potential antidepressant with high affinity for the serotonin transporter and 5-HT1A receptors. Locally applied, VN2222 enhanced the extracellular 5-hydroxytryptamine (5-HT) concentration (5-HText) in rat striatum to 780% of baseline whereas its systemic administration (1–10 mg/kg s.c.) reduced 5-HText. In the presence of citalopram, 8-OH-DPAT or VN2222 applied in medial prefrontal cortex reduced 5-HText. Fluoxetine, VN2222, and 8-OH-DPAT suppressed the firing rate of dorsal raphe 5-HT neurons (ED50: 790, 14.9, and 0.8 μg/kg i.v., respectively). These effects were antagonized by WAY 100635. Administration of VN2222 for 2 weeks desensitized 5-HT1A receptors as assessed by microdialysis and single-unit recordings (ED50 values for 8-OH-DPAT were 0.45 and 2.34 μg/kg i.v. for controls and rats treated with 6 mg/kg day VN2222). These results show that VN2222 is a mixed 5-HT reuptake inhibitor/5-HT1A agonist that markedly desensitizes 5-HT1A autoreceptors. These properties suggest that it may be a clinically effective dual action antidepressant drug.