Consequences of partial and severe dopaminergic lesion on basal ganglia oscillatory activity and akinesia

Severe chronic dopamine (DA) depletion increases the proportion of neurons in the basal ganglia that fire rhythmic bursts of action potential (LFO units) synchronously with the cortical oscillations. Here we report on how different levels of mesencephalic DA denervation affect substantia nigra pars reticulata (SNpr) neuronal activity in the rat and its relationship to akinesia (stepping test). Chronic nigrostriatal lesion induced with 0 (control group), 4, 6 or 8 microg of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle resulted in a dose-dependent decrease of tyrosine hydroxylase positive (TH+) neurons in the SN and ventral tegmental area (VTA). Although 4 microg of 6-OHDA reduced the number of TH+ neurons in the SN by approximately 60%, both stepping test performance and SNpr neuronal activity remained indistinguishable from control animals. By contrast, animals that received 6 microg of 6-OHDA showed a marked reduction of TH+ cells in the SN ( approximately 75%) and VTA ( approximately 55%), a significant stepping test deficit and an increased proportion of LFO units. These changes were not dramatically enhanced with 8 microg 6-OHDA, a dose that induced an extensive DA lesion (> 95%) in the SN and approximately 70% reduction of DA neurons in the VTA. These results suggest a threshold level of DA denervation for both the appearance of motor deficits and LFO units. Thus, the presence of LFO activity in the SNpr is not related to a complete nigrostriatal DA neuron depletion (ultimate stage parkinsonism); instead, it may reflect a functional disruption of cortico-basal ganglia dynamics associated with clinically relevant stages of the disease.Fil: Tseng, Kuei Y.. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; ArgentinaFil: Kargieman, Lucila. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Gacio, Sebastian. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; ArgentinaFil: Riquelme, Luis Alberto. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; ArgentinaFil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; Argentin

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

Role of prefrontal cortex in pharmacological models of schizophrenia and antipsychotic action

NMDA receptor (NMDA-R) antagonists are extensively used as schizophrenia models due to their ability to evoke positive and negative symptoms as well as cognitive deficits similar to those of the illness. Likewise, 5-HT2A receptor agonists display hallucinogen actions resembling psychotic symptoms. Overall, these drugs are useful models of schizophrenia for the screening of new antipsychotic drugs. However, the cellular and network elements involved in these actions are poorly known. Data obtained by several groups in recent years indicate that the prefrontal cortex (PFC) and anatomically related areas play a major role in these actions. This paper summarizes data obtained by the authors supporting that a) NMDA-R antagonists (phencyclidine –PCP–, dizocilpine –MK–801–) and 5-HT2A agonists (DOI) alter the function of PFC in a similar fashion, and b) antipsychotic drugs exert their therapeutic action, at least in part, by normalizing hyperactivity states in PFC. While the actions of NMDA-R antagonists may involve blockade of these receptors in PFC and subcortical areas, that of antipsychotic drugs, in particular atypical drugs like clozapine, appear to be mediated essentially by a local action in PFC. These results help to better understand the neurobiological basis of the action of pharmacological models of schizophrenia and the mode of action of antipsychotic drugs.Work supported by grants SAF2007-62378, FIS PI070111 and FIS FIS PI060264.Peer reviewe

5-HT<inf>2A</inf> receptors are involved in cognitive but not antidepressant effects of fluoxetine

© 2015 Elsevier B.V. and ECNP. The prefrontal cortex (PFC) plays a crucial role in cognitive and affective functions. It contains a rich serotonergic (serotonin, 5-HT) innervation and a high density of 5-HT receptors. Endogenous 5-HT exerts robust actions on the activity of pyramidal neurons in medial PFC (mPFC) via excitatory 5-HT2A and inhibitory 5-HT1A receptors, suggesting the involvement of 5-HT neurotransmission in cortical functions. However, the underlying mechanisms must be elucidated. Here we examine the role of 5-HT2A receptors in the processing of emotional and cognitive signals evoked by increasing the 5-HT tone after acute blockade of the 5-HT transporter. Fluoxetine (5-20mg/kg i.p.) dose-dependently reduced the immobility time in the tail-suspension test in wild-type (WT) and 5-HT2A knockout (KO2A) mice, with non-significant differences between genotypes. Fluoxetine (10mg/kg i.p.) significantly impaired mice performance in the novel object recognition test 24h post-administration in WT, but not in KO2A mice. The comparable effect of fluoxetine on extracellular 5-HT in the mPFC of both genotypes suggests that presynaptic differences are not accountable. In contrast, single unit recordings of mPFC putative pyramidal neurons showed that fluoxetine (1.8-7.2mg/kg i.v.) significantly increased neuronal discharge in KO2A but not in WT mice. This effect is possibly mediated by an altered excitatory/inhibitory balance in the PFC in KO2A mice. Overall, the present results suggest that 5-HT2A receptors play a detrimental role in long-term memory deficits mediated by an excess 5-HT in PFC.Funding for this study was provided by Grants SAF 2012-35183, the Ministry of Economy and Competitiveness, co-financed by European Regional Development Fund (ERDF) and by the Grants PI12/00156, PI13/01390 and PI10/00290 (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 Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM. AC was supported by a postdoctoral contract from the ISCIII (CD05/00234)Peer Reviewe

NMDA antagonist and antipsychotic actions in cortico-subcortical circuits

Cognitive deficits in schizophrenia are associated with prefrontal cortex (PFC) abnormalities. Schizophrenic patients show a reduced performance in tasks engaging the PFC and a reduction of markers of cellular integrity and function. Non-competitive N-methyl-Daspartate (NMDA) receptor antagonists are widely used as pharmacological models of schizophrenia due to their ability to exacerbate schizophrenia symptoms in patients and to elicit psychotomimetic actions in healthy volunteers. Also, these drugs evoke behavioral alterations in experimental animals that resemble schizophrenia symptoms. The PFC seems to be a key target area for these agents. However, the cellular and network elements involved are poorly known. Cognitive deficits are of particular interest since an early antipsychotic-induced improvement in cognitive performance predicts a better long-term clinical outcome. Here we report that the non-competitive NMDA receptor antagonist phencyclidine (PCP) induces a marked disruption of the activity of PFC. PCP administration increased the activity of a substantial proportion of pyramidal neurons, as evidenced by an increase in discharge rate and inc- fos expression. Examination of the effects of PCP on other brain areas revealed an increasedc- fos expression in a number of cortical and subcortical areas, but notably in thalamic nuclei projecting to the PFC. The administration of classical (haloperidol) and/or atypical (clozapine) antipsychotic drugs reversed PCP effects. These results indicate that PCP induces a marked disruption of the network activity in PFC and that antipsychotic drugs may partly exert their therapeutic effect by normalizing hyperactive cortico-thalamocortical circuits.Work supported by grant SAF2007-62378. Support from CIBERSAM and SENY Fundació is also acknowledged. The Department of Neurochemistry and Neuropharmacology is "Grup de Recerca de Qualitat" (Generalitat de Catalunya (2005- SGR00758).Peer reviewe