Alteració dels Circuits Talamocorticals en el Model NMDA d'Esquizofrènia. Reversió per Antipsicòtics

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Disrupció de les oscil·lacions corticals de baixa freqüència per fenciclidina: un model vàlid per al cribatge de nous fàrmacs antipsicòtics

Trabajo presentado al I Congrés Internacional de Biologia de Catalunya: Global questions on advanced biology, celebrado en Barcelona del 9 al 12 de julio de 2012.Els antagonistes no competitius del receptor NMDA com la fenciclidina (PCP) són àmpliament utilitzats com a model farmacològic d’esquizofrènia. Dades prèvies del nostre laboratori mostren que la PCP disminueix les oscil·lacions corticals de baixa freqüència (OCBF, <4 Hz) en l'escorça prefrontal medial de rates i ratolins anestesiats1,2. Aquesta alteració és revertida pels antipsicòtics (APS) haloperidol i clozapina. L'objectiu d'aquest treball és 1) examinar la possible participació de la transmissió glutamatèrgica i/o gabaèrgica en l'efecte de la PCP 2) validar aquest model per al cribatge de fàrmacs APS e identificació de dianes terapèutiques. Els fàrmacs avaluats són: 1) els agents glutamatèrgics NBQX i LY379268, 2) l’agent gabaèrgic muscimol, 3) APS atípics amb afinitat preferencial pels receptors 5-HT2A (olanzapina, ziprasidona, risperidona i quetiapina), 4) els APS clàssics amb alta afinitat pels receptors D2 (clorpromazina i perfenazina) i 5) controls negatius (l’ansiolític diazepam i l'antidepressiu citalopram). Els APS, l’LY379268 reverteixen significativament la disrupció de les OCBF causada per la PCP. Per altra banda, l’antidepressiu citalopram no reverteix aquests efectes i el diazepam i el muscimol ho fan de forma parcial. Finalment, l’NBQX no reverteix l’efecte de la PCP sobre les esmentades oscil·lacions. Els presents resultats suggereixen que una activació de la transmissió glutamatèrgica excessiva està implicada en els efectes de la PCP tenint en compte els efectes de LY379268 i el muscimol. Per altra banda, els APS de famílies diferents comparteixen la capacitat de restablir aquestes oscil·lacions malgrat les diferents dianes receptorials. En definitiva, aquest estudi recolza la utilització del model de supressió de les OCBF per la PCP per a l’avaluació de fàrmacs APS potencials.Peer reviewe

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-HT2A 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.Supported by the Innovative Medicines Initiative Joint Undertaking (IMI) under Grant Agreement No. 115008 (NEWMEDS). IMI is a public–private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations. Support from the following grants is also acknowledged: SAF 2012-35183 (Ministry of Economy and Competitiveness and European Regional Development Fund), PI09/1245 and PI12/00156 (PN de I+D+I 2008-2011, ISCIII-Subdireccion General de Evaluación y Fomento de la Investigación cofinanced by the European Regional Development Fund. ‘Una manera de hacer Europa’) and Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM (P82, 11INT3). Support from the Generalitat de Catalunya (SGR20093) is also acknowledged. P.C. is supported by the Researcher Stabilization Program of the Health Department of the Generalitat de Catalunya. M.R. is recipient of an IDIBAPS fellowship.Peer reviewe

Phencyclidine activates thalamocortical networks by inhibiting GABAergic neurons in the reticular nucleus of the thalamus

Póster presentado en el 26th ECNP (European College of Neuropsychopharmacology) Congress, celebrado del 5 al 9 de octubre de 2013, en Barcelona (España)Abstract publicado en: European Neuropsychopharmacology 23(Suppl. 2): S423-424 (2013). ISSN: 0924-977X. e-ISSN: 1873-7862. DOI: 10.1016/S0924-977X(13)70670-9Peer Reviewe

Activation of thalamocortical networks by the N-methyl-D-aspartate receptor antagonist phencyclidine: reversal by clozapine

[Background]: Noncompetitive N-methyl-D-aspartate receptor antagonists are widely used as pharmacological models of schizophrenia. Their neurobiological actions are still poorly understood, although the prefrontal cortex (PFC) appears as a key target area.[Methods]: We examined the effect of phencyclidine (PCP) on neuronal activity of the mediodorsal (MD) and centromedial (CM) thalamic nuclei, reciprocally connected with the PFC, using extracellular recordings (n = 50 neurons from 35 Wistar rats) and c-fos expression.[Results]: Phencyclidine (.25 mg/kg intravenous [IV]) markedly disorganized the activity of MD/CM neurons, increasing (424%) and decreasing (41%) the activity of 57% and 20% of the recorded neurons, respectively (23% remained unaffected). Phencyclidine reduced delta oscillations (.15–4 Hz) as assessed by recording local field potentials. The subsequent clozapine administration (1 mg/kg IV) reversed PCP effects on neuronal discharge and delta oscillations. Double in situ hybridization experiments revealed that PCP (10 mg/kg intraperitoneal [IP]) markedly increased c-fos expression in glutamatergic neurons of several cortical areas (prefrontal, somatosensory, retrosplenial, entorhinal) and in thalamic nuclei, including MD/CM. Phencyclidine also increased c-fos expression in the amygdala; yet, it had a small effect in the hippocampus. Phencyclidine did not increase c-fos expression in gamma-aminobutyric acidergic cells except in hippocampus, amygdala, somatosensory, and retrosplenial cortices. Clozapine (5 mg/kg IP) had no effect by itself but significantly prevented PCP-induced c-fos expression.[Conclusions]: Phencyclidine likely exerts its psychotomimetic action by increasing excitatory neurotransmission in thalamo-cortico-thalamic networks involving, among others, PFC, retrosplenial, and somatosensory cortices. The antipsychotic action of clozapine includes, among other actions, an attenuation of the neuronal hyperactivity in thalamocortical networks.The work leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking under Grant Agreement N° 115008 (NEWMEDS). The Innovative Medicines Initiative Joint Undertaking is a public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations. Support from Grants SAF 2007-62378 and FIS PI09/1245 is also acknowledged. PC is supported by the Researcher Stabilization Program of the Health Department of the Generalitat de Catalunya. NS is supported by Centro de Investigación Biomédica en Red de Salud Mental. ET is the recipient of a predoctoral fellowship from the Ministerio de Ciencia e Innovación de España.Peer reviewe

Disruption of low frequency oscillations by phencyclidine: mechanisms involved in antipsychotic reversal

Póster presentado en el 26th ECNP (European College of Neuropsychopharmacology) Congress, celebrado del 5 al 9 de octubre de 2013, en Barcelona (España)Abstract publicado en: European Neuropsychopharmacology 23(Suppl. 2): S454 (2013). ISSN: 0924-977X. e-ISSN: 1873-7862. DOI: 10.1016/S0924-977X(13)70718-1Peer Reviewe

Phencyclidine-induced disruption of oscillatory activity in prefrontal cortex: Effects of antipsychotic drugs and receptor ligands

The non-competitive NMDA receptor (NMDA-R) antagonist phencyclidine (PCP) markedly disrupts thalamocortical activity, increasing excitatory neuron discharge and reducing low frequency oscillations (LFO, <4Hz) that temporarily group neuronal discharge. These actions are mainly driven by PCP interaction with NMDA-R in GABAergic neurons of the thalamic reticular nucleus and likely underlie PCP psychotomimetic activity. Here we report that classical (haloperidol, chlorpromazine, perphenazine) and atypical (clozapine, olanzapine, quetiapine, risperidone, ziprasidone, aripripazole) antipsychotic drugs - but not the antidepressant citalopram - countered PCP-evoked fall of LFO in the medial prefrontal cortex (mPFC) of anesthetized rats. PCP reduces LFO by breaking the physiological balance between excitatory and inhibitory transmission. Next, we examined the role of different neurotransmitter receptors to reverse PCP actions. D2-R and D1-R blockade may account for classical antipsychotic action since raclopride and SCH-23390 partially reversed PCP effects. Atypical antipsychotic reversal may additionally involve 5-HT1A-R activation (but not 5-HT2A-R blockade) since 8-OH-DPAT and BAYx3702 (but not M100907) fully countered PCP effects. Blockade of histamine H1-R (pyrilamine) and ¿1-adrenoceptors (prazosin) was without effect. However, the enhancement of GABAA-R-mediated neurotransmission (using muscimol, diazepam or valproate) and the reduction of excitatory neurotransmission (using the mGluR2/3 agonist LY379268 and the preferential kainite/AMPA antagonist CNQX - but not the preferential AMPA/kainate antagonist NBQX) partially or totally countered PCP effects. Overall, these results shed new light on the neurobiological mechanisms used by antipsychotic drugs to reverse NMDA-R antagonist actions and suggest that agents restoring the physiological excitatory/inhibitory balance altered by PCP may be new targets in antipsychotic drug development.Supported by the Innovative Medicines Initiative Joint Undertaking (IMI) under Grant agreement no. 115008 (NEWMEDS). IMI is a public/private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations. Support from the following Grants is also acknowledged: SAF 2012-35183 (Ministry of Economy and Competitiveness and European Regional Development Fund), PI09/1245 and PI12/00156 (PN de I+D+I 2008-2011, ISCIII-Subdirección General de Evaluación y Fomento de la Investigación cofinanced by the European Regional Development Fund. ‘Una manera de hacer Europa’) and the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM. Support from the Generalitat de Catalunya (2014 SGR798) is also acknowledged.Peer Reviewe

Preservation of dendritic D2 receptor transmission in substantia nigra dopamine neurons with age

Abstract Substantia nigra pars compacta (SNc) dopamine neurons are required for voluntary movement and reward learning, and advanced age is associated with motor and cognitive decline. In the midbrain, D2-type dopamine receptors located at dendrodendritic synapses between dopamine neurons control cell firing through G protein-activated potassium (GIRK) channels. We previously showed that aging disrupts dopamine neuron pacemaker firing in mice, but only in males. Here we show that the amplitude of D2-receptor inhibitory postsynaptic currents (D2-IPSCs) are moderately reduced in aged male mice. Local application of dopamine revealed a reduction in the amplitude of the D2-receptor currents in old males compared to young, pointing to a postsynaptic mechanism. Further experiments indicated that reduced D2 receptor signaling was not due to a general reduction in GIRK channel currents or degeneration of the dendritic arbor. Kinetic analysis showed no differences in D2-IPSC shape in old versus young mice or between sexes. Potentiation of D2-IPSCs by corticotropin releasing factor (CRF) was also not affected by age, indicating preservation of one mechanism of plasticity. These findings have implications for understanding dopamine transmission in aging, and reduced D2 receptor inhibition could contribute to increased susceptibility of males to SNc dopamine neuron degeneration in Parkinson’s disease

Phencyclidine inhibits the activity of thalamic reticular gamma-aminobutyric acidergic neurons in rat brain

© 2014 Society of Biological Psychiatry. Background The neurobiological basis of action of noncompetitive N-methyl-D-aspartate acid receptor (NMDA-R) antagonists is poorly understood. Electrophysiological studies indicate that phencyclidine (PCP) markedly disrupts neuronal activity with an overall excitatory effect and reduces the power of low-frequency oscillations (LFO; <4 Hz) in thalamocortical networks. Because the reticular nucleus of the thalamus (RtN) provides tonic feed-forward inhibition to the rest of the thalamic nuclei, we examined the effect of PCP on RtN activity, under the working hypothesis that NMDA-R blockade in RtN would disinhibit thalamocortical networks. Methods Drug effects (PCP followed by clozapine) on the activity of RtN (single unit and local field potential recordings) and prefrontal cortex (PFC; electrocorticogram) in anesthetized rats were assessed. Results PCP (.25-.5 mg/kg, intravenous) reduced the discharge rate of 19 of 21 RtN neurons to 37% of baseline (p <.000001) and the power of LFO in RtN and PFC to ~20% of baseline (p <.001). PCP also reduced the coherence between PFC and RtN in the LFO range. A low clozapine dose (1 mg/kg intravenous) significantly countered the effect of PCP on LFO in PFC but not in RtN and further reduced the discharge rate of RtN neurons. However, clozapine administration partly antagonized the fall in coherence and phase-locking values produced by PCP. Conclusions PCP activates thalamocortical circuits in a bottom-up manner by reducing the activity of RtN neurons, which tonically inhibit thalamic relay neurons. However, clozapine reversal of PCP effects is not driven by restoring RtN activity and may involve a cortical action.This work was supported by Innovative Medicines Initiative (IMI) Joint Undertaking Grant115008 (Newmeds). IMI is a public-private partnership between the European Union and European Federation of Pharmaceutical Industries and Associations; by Grant PI12/00156 (PN de I+D+I 2008-2011) from the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación, co-financed by the European Union “A Way to build Europe”; by the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental; and by the Researcher Stabilization Program of the Health Department of the Generalitat de Catalunya (PC)Peer Reviewe

Mecanismo de acción de antipsicóticos: papel de receptores 5-HT1A en corteza prefrontal

Comunicación presentada en el: XVI Congreso Nacional de Psiquiatría, celebrado del 25 al 28 de septiembre de 2012, en Bilbao (España)Peer Reviewe