Maurizio Riga

Clozapine Reverses Phencyclidine-Induced Desynchronization of Prefrontal Cortex through a 5-HT 1A Receptor-Dependent Mechanism

The non-competitive NMDA receptor (NMDA-R) antagonist phencyclidine (PCP)—used as a pharmacological model of schizophrenia—disrupts prefrontal cortex (PFC) activity. PCP markedly increased the discharge rate of pyramidal neurons and reduced slow cortical oscillations (SCO; 0.15–4 Hz) in rat PFC. Both effects were reversed by classical (haloperidol) and atypical (clozapine) antipsychotic drugs. Here we extended these observations to mice brain and examined the potential involvement of 5-HT2A and 5-HT1A receptors (5-HT2AR and 5-HT1AR, respectively) in the reversal by clozapine of PCP actions. Clozapine shows high in vitro affinity for 5-HT2AR and behaves as partial agonist in vivo at 5-HT1AR. We used wild-type (WT) mice and 5-HT1AR and 5-HT2AR knockout mice of the same background (C57BL/6) (KO-1A and KO-2A, respectively). Local field potentials (LFPs) were recorded in the PFC of WT, KO-1A, and KO-2A mice. PCP (10 mg/kg, intraperitoneally) reduced SCO equally in WT, KO-2A, and KO-1A mice (58±4%, 42±7%, and 63±7% of pre-drug values, n=23, 13, 11, respectively; p<0.0003). Clozapine (0.5 mg/kg, intraperitoneally) significantly reversed PCP effect in WT and KO-2A mice, but not in KO-1A mice nor in WT mice pretreated with the selective 5-HT1AR antagonist WAY-100635.The PCP-induced disorganization of PFC activity does not appear to depend on serotonergic function. However, the lack of effect of clozapine in KO-1A mice and the prevention by WAY-100635 indicates that its therapeutic action involves 5-HT1AR activation without the need to block 5-HT2AR, as observed with clozapine-induced cortical dopamine release.

P.2.e.003 Role of 5-HT3 receptors in the mechanism of action of the investigational antidepressant vortioxetine

Poster presentado en el 26th ECNP (European College of Neuropsychopharmacology) Congress, celebrado del 5 al 9 de octubre de 2013, en Barcelona (Espana)

Disruption of thalamocortical activity in schizophrenia models: relevance to antipsychotic drug action

Non-competitive NMDA receptor antagonists are widely used as pharmacological models of schizophrenia due to their ability to evoke the symptoms of the illness. Likewise, serotonergic hallucinogens, acting on 5-HT(2A) receptors, induce perceptual and behavioural alterations possibly related to psychotic symptoms. The neurobiological basis of these alterations is not fully elucidated. Data obtained in recent years revealed that the NMDA receptor antagonist phencyclidine (PCP) and the serotonergic hallucinogen 1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane; DOI) produce a series of common actions in rodent prefrontal cortex (PFC) that may underlie psychotomimetic effects. Hence, both agents markedly disrupt PFC function by altering pyramidal neuron discharge (with an overall increase) and reducing the power of low frequency cortical oscillations (LFCO; < 4 Hz). In parallel, PCP increased c-fos expression in excitatory neurons of various cortical areas, the thalamus and other subcortical structures, such as the amygdala. Electrophysiological studies revealed that PCP altered similarly the function of the centromedial and mediodorsal nuclei of the thalamus, reciprocally connected with PFC, suggesting that its psychotomimetic properties are mediated by an alteration of thalamocortical activity (the effect of DOI was not examined in the thalamus). Interestingly, the observed effects were prevented or reversed by the antipsychotic drugs clozapine and haloperidol, supporting that the disruption of PFC activity is intimately related to the psychotomimetic activity of these agents. Overall, the present experimental model can be successfully used to elucidate the neurobiological basis of schizophrenia symptoms and to examine the potential antipsychotic activity of new drugs in development.

Defining the brain circuits involved in psychiatric disorders: IMI-NEWMEDS.

Despite the vast amount of research on schizophrenia and depression in the past two decades, there have been few innovative drugs to treat these disorders. Precompetitive research collaborations between companies and academic groups can help tackle this innovation deficit, as illustrated by the achievements of the IMI-NEWMEDS consortium.

Subchronic vortioxetine treatment -but not escitalopram- enhances pyramidal neuron activity in the rat prefrontal cortex

&NA; Vortioxetine (VOR) is a multimodal antidepressant drug. VOR is a 5‐HT3‐R, 5‐HT7‐R and 5‐HT1D‐R antagonist, 5‐HT1B‐R partial agonist, 5‐HT1A‐R agonist, and serotonin transporter (SERT) inhibitor. VOR shows pro‐cognitive activity in animal models and beneficial effects on cognitive dysfunction in major depressive patients. Here we compared the effects of 14‐day treatments with VOR and escitalopram (ESC, selective serotonin reuptake inhibitor) on neuronal activity in the medial prefrontal cortex (mPFC). Ten groups of rats (5 standard, 5 depleted of 5‐HT with p‐chlorophenylalanine ‐pCPA‐, used as model of cognitive impairment) were fed with control food or with two doses of VOR‐containing food. Four groups were implanted with minipumps delivering vehicle or ESC 10 mg/kg·day s.c. The two VOR doses enable occupation by VOR of SERT+5‐HT3‐R and all targets, respectively, and correspond to SERT occupancies in patients treated with 5 and 20 VOR mg/day, respectively. Putative pyramidal neurons (n = 985) were recorded extracellularly in the mPFC of anesthetized rats. Sub‐chronic VOR administration (but not ESC) significantly increased neuronal discharge in standard and 5‐HT‐depleted conditions, with a greater effect of the low VOR dose in standard rats. VOR increased neuronal discharge in infralimbic (IL) and prelimbic (PrL) cortices. Hence, oral VOR doses evoking SERT occupancies similar to those in treated patients increase mPFC neuronal discharge. The effect in 5‐HT‐depleted rats cannot be explained by an antagonist action of VOR at 5‐HT3‐R and suggests a non‐canonical interaction of VOR with 5‐HT3‐R. These effects may underlie the superior pro‐cognitive efficacy of VOR compared with SSRIs in animal models. HighlightsUnlike escitalopram, subchronic vortioxetine enhances PFC neuronal activity in rats.This effect occurs at clinically‐relevant oral doses of vortioxetine.Vortioxetine increases neuronal discharge in prelimbic and infralimbic cortices.Effects in 5‐HT‐depleted rats suggest a non‐canonical interaction with 5‐HT3‐R.These effects may underlie pro‐cognitive and antidepressant actions of vortioxetine.

The serotonergic hallucinogen 5-methoxy-N,N-dimethyltryptamine disrupts cortical activity in a regionally-selective manner via 5-HT1A and 5-HT2A receptors

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen, acting as a non-selective serotonin 5-HT(1A)/5-HT(2A)-R agonist. Psychotomimetic agents such as the non-competitive NMDA-R antagonist phencyclidine and serotonergic hallucinogens (DOI and 5-MeO-DMT) disrupt cortical synchrony in the low frequency range (<4 Hz) in rat prefrontal cortex (PFC), an effect reversed by antipsychotic drugs. Here we extend these observations by examining the effect of 5-MeO-DMT on low frequency cortical oscillations (LFCO, <4 Hz) in PFC, visual (V1), somatosensory (S1) and auditory (Au1) cortices, as well as the dependence of these effects on 5-HT(1A)-R and 5-HT(2A)-R, using wild type (WT) and 5-HT(2A)-R knockout (KO2A) anesthetized mice. 5-MeO-DMT reduced LFCO in the PFC of WT and KO2A mice. The effect in KO2A mice was fully prevented by the 5-HT(1A)-R antagonist WAY-100635. Systemic and local 5-MeO-DMT reduced 5-HT release in PFC mainly via 5-HT(1A)-R. Moreover, 5-MeO-DMT reduced LFCO in S1, Au1 and V1 of WT mice and only in V1 of KO2A mice, suggesting the involvement of 5-HT(1A)-R activation in the 5-MeO-DMT-induced disruption of V1 activity. In addition, antipsychotic drugs reversed 5-MeO-DMT effects in WT mice. The present results suggest that the hallucinogen action of 5-MeO-DMT is mediated by simultaneous alterations of the activity of sensory (S1, Au1, V1) and associative (PFC) cortical areas, also supporting a role of 5-HT(1A)-R stimulation in V1 and PFC, in addition to the well-known action on 5-HT(2A)-R. Moreover, the reversal by antipsychotic drugs of 5-MeO-DMT effects adds to previous literature supporting the usefulness of the present model in antipsychotic drug development.

The serotonin hallucinogen 5-MeO-DMT alters cortico-thalamic activity in freely moving mice: Regionally-selective involvement of 5-HT 1A and 5-HT 2A receptors

&NA; 5‐MeO‐DMT is a natural hallucinogen acting as serotonin 5‐HT1A/5‐HT2A receptor agonist. Its ability to evoke hallucinations could be used to study the neurobiology of psychotic symptoms and to identify new treatment targets. Moreover, recent studies revealed the therapeutic potential of serotonin hallucinogens in treating mood and anxiety disorders. Our previous results in anesthetized animals show that 5‐MeO‐DMT alters cortical activity via 5‐HT1A and 5‐HT2A receptors. Here, we examined 5‐MeO‐DMT effects on oscillatory activity in prefrontal (PFC) and visual (V1) cortices, and in mediodorsal thalamus (MD) of freely‐moving wild‐type (WT) and 5‐HT2A‐R knockout (KO2A) mice. We performed local field potential multi‐recordings evaluating the power at different frequency bands and coherence between areas. We also examined the prevention of 5‐MeO‐DMT effects by the 5‐HT1A‐R antagonist WAY‐100635. 5‐MeO‐DMT affected oscillatory activity more in cortical than in thalamic areas. More marked effects were observed in delta power in V1 of KO2A mice. 5‐MeO‐DMT increased beta band coherence between all examined areas. In KO2A mice, WAY100635 prevented most of 5‐MeO‐DMT effects on oscillatory activity. The present results indicate that hallucinatory activity of 5‐MeO‐DMT is likely mediated by simultaneous alteration of prefrontal and visual activities. The prevention of these effects by WAY‐100635 in KO2A mice supports the potential usefulness of 5‐HT1A receptor antagonists to treat visual hallucinations. 5‐MeO‐DMT effects on PFC theta activity and cortico‐thalamic coherence may be related to its antidepressant activity. This article is part of the Special Issue entitled ‘Psychedelics: New Doors, Altered Perceptions’. Hightlights5‐MeO‐DMT alters cortico‐thalamic activity more in mPFC and V1 than MD thalamus.5‐MeO‐DMT augments beta band coherence between cortico‐thalamic areas.5‐HT1A‐R antagonism avoids 5‐MeO‐DMT actions in KO2A mice.Increase in PFC theta band by 5‐MeO‐DMT may be related to its antidepressant effect.

The serotonergic hallucinogen 5-MeO-DMT disrupts cortical activity in rodents

Trabajo presentado en el 29th ECNP Congress, celebrado en Viena, Austria, del 17 al 20 de septiembre de 2016

P.2.017 The hallucinogen 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) disrupts cortical function: reversal by antipsychotic drugs

Poster presentado en el 2013 ECNP Workshop on Neuropsychopharmacology for Young Scientists in Euope, celebrado del 7 al 10 de marzo de 2013 en Nice (Francia)