RESUMEN
The infralimbic (IL) cortex is the rodent equivalent of human ventral anterior cingulate cortex (vACC), which plays a key role in the pathophysiology and treatment of major depressive disorder (MDD). The modulation of glutamatergic neurotransmission in IL [but not in the adjacent prelimbic (PrL) cortex] evokes antidepressant-like or depressive-like behaviors, associated with changes in serotonin (5-HT) function, highlighting the relevance of glutamate/serotonin interactions in IL for emotional control. 5-HT modulates neuronal activity in PrL and cingulate (Cg) cortex but its effects in IL are largely unknown. We therefore compared the in vivo effects of 5-HT on pyramidal neuron activity in IL (n = 61) and PrL (n = 50) of anesthetized rats. IL pyramidal neurons were more responsive to physiological dorsal raphe stimulation (0.9 Hz) than PrL neurons (84% vs. 64%, respectively) and were inhibited to a greater extent (64% vs. 36%, respectively). Orthodromic activations (8% in PrL) were absent in IL, whereas biphasic responses were similar (20%) in both areas. Excitations were mediated by 5-HT2A-R activation, whereas inhibitions involved 3 different components: 5-HT1A-R, 5-HT3-R and GABAA-R, respectively. The remarkable inhibitory action of 5-HT in IL suggests that 5-HT-enhancing drugs may exert their antidepressant action by normalizing a glutamatergic hyperactivity in the vACC of MDD patients.
Asunto(s)
Trastorno Depresivo Mayor , Serotonina , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Corteza Cerebral , Trastorno Depresivo Mayor/tratamiento farmacológico , Humanos , Células Piramidales/fisiología , RatasRESUMEN
Schizophrenia is a severe mental disorder featuring psychotic, depressive, and cognitive alterations. Current antipsychotic drugs preferentially target dopamine D2-R and/or serotonergic 5-HT2A/1A-R. They partly alleviate psychotic symptoms but fail to treat negative symptoms and cognitive deficits. Here we report on the putative antipsychotic activity of (1-[(3-fluorophenyl)sulfonyl]-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline dihydrochloride) (FPPQ), a dual serotonin 5-HT3-R/5-HT6-R antagonist endowed with pro-cognitive properties. FPPQ fully reversed phencyclidine-induced decrease of low-frequency oscillations in the medial prefrontal cortex of anaesthetized rats, a fingerprint of antipsychotic activity. This effect was mimicked by the combined administration of the 5-HT3-R and 5-HT6-R antagonists ondansetron and SB-399â 885, respectively, but not by either drug alone. In freely moving rats, FPPQ countered phencyclidine-induced hyperlocomotion and augmentation of gamma and high-frequency oscillations in medial prefrontal cortex, dorsal hippocampus, and nucleus accumbens. Overall, this supports that simultaneous blockade of 5-HT3R and 5-HT6-R-like that induced by FPPQ-can be a new target in antipsychotic drug development.
Asunto(s)
Antipsicóticos , Encéfalo , Fenciclidina , Quinolinas , Antagonistas de la Serotonina , Animales , Antipsicóticos/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Fenciclidina/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Quinolinas/farmacología , Ratas , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacologíaRESUMEN
BACKGROUND: The hemizygous 22q11.2 microdeletion is a common copy number variant in humans. The deletion confers high risk for neurodevelopmental disorders, including autism and schizophrenia. Up to 41% of deletion carriers experience psychotic symptoms. METHODS: We present a new mouse model (Df(h22q11)/+) of the deletion syndrome (22q11.2DS) and report on, to our knowledge, the most comprehensive study undertaken to date in 22q11.2DS models. The study was conducted in male mice. RESULTS: We found elevated postpubertal N-methyl-D-aspartate (NMDA) receptor antagonist-induced hyperlocomotion, age-independent prepulse inhibition (PPI) deficits and increased acoustic startle response (ASR). The PPI deficit and increased ASR were resistant to antipsychotic treatment. The PPI deficit was not a consequence of impaired hearing measured by auditory brain stem responses. The Df(h22q11)/+ mice also displayed increased amplitude of loudness-dependent auditory evoked potentials. Prefrontal cortex and dorsal striatal elevations of the dopamine metabolite DOPAC and increased dorsal striatal expression of the AMPA receptor subunit GluR1 was found. The Df(h22q11)/+ mice did not deviate from wild-type mice in a wide range of other behavioural and biochemical assays. LIMITATIONS: The 22q11.2 microdeletion has incomplete penetrance in humans, and the severity of disease depends on the complete genetic makeup in concert with environmental factors. In order to obtain more marked phenotypes reflecting the severe conditions related to 22q11.2DS it is suggested to expose the Df(h22q11)/+ mice to environmental stressors that may unmask latent psychopathology. CONCLUSION: The Df(h22q11)/+ model will be a valuable tool for increasing our understanding of the etiology of schizophrenia and other psychiatric disorders associated with the 22q11DS.
Asunto(s)
Envejecimiento/fisiología , Síndrome de DiGeorge/fisiopatología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Filtrado Sensorial/fisiología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Envejecimiento/efectos de los fármacos , Animales , Percepción Auditiva/fisiología , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Potenciales Evocados Auditivos del Tronco Encefálico , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Corteza Prefrontal/metabolismo , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Reflejo de Sobresalto/fisiologíaRESUMEN
5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen component of Ayahuasca, an Amazonian beverage traditionally used for ritual, religious and healing purposes that is being increasingly used for recreational purposes in US and Europe. 5MeO-DMT is of potential interest for schizophrenia research owing to its hallucinogenic properties. Two other psychotomimetic agents, phencyclidine and 2,5-dimethoxy-4-iodo-phenylisopropylamine (DOI), markedly disrupt neuronal activity and reduce the power of low frequency cortical oscillations (<4 Hz, LFCO) in rodent medial prefrontal cortex (mPFC). Here we examined the effect of 5-MeO-DMT on cortical function and its potential reversal by antipsychotic drugs. Moreover, regional brain activity was assessed by blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). 5-MeO-DMT disrupted mPFC activity, increasing and decreasing the discharge of 51 and 35% of the recorded pyramidal neurons, and reducing (-31%) the power of LFCO. The latter effect depended on 5-HT1A and 5-HT2A receptor activation and was reversed by haloperidol, clozapine, risperidone, and the mGlu2/3 agonist LY379268. Likewise, 5-MeO-DMT decreased BOLD responses in visual cortex (V1) and mPFC. The disruption of cortical activity induced by 5-MeO-DMT resembles that produced by phencyclidine and DOI. This, together with the reversal by antipsychotic drugs, suggests that the observed cortical alterations are related to the psychotomimetic action of 5-MeO-DMT. Overall, the present model may help to understand the neurobiological basis of hallucinations and to identify new targets in antipsychotic drug development.
Asunto(s)
Antipsicóticos/farmacología , Banisteriopsis/química , Ondas Encefálicas/efectos de los fármacos , Alucinógenos/farmacología , Metoxidimetiltriptaminas/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Visual/efectos de los fármacos , Aminoácidos/farmacología , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Clozapina/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Neuroimagen Funcional , Alucinógenos/antagonistas & inhibidores , Haloperidol/farmacología , Imagen por Resonancia Magnética , Masculino , Metoxidimetiltriptaminas/antagonistas & inhibidores , Corteza Prefrontal/irrigación sanguínea , Corteza Prefrontal/fisiología , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Ratas , Risperidona/farmacología , Corteza Visual/irrigación sanguínea , Corteza Visual/fisiologíaRESUMEN
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.
Asunto(s)
Conducta Animal , Encéfalo/fisiopatología , Indofenol/análogos & derivados , Fenciclidina , Corteza Prefrontal/fisiopatología , Esquizofrenia/inducido químicamente , Psicología del Esquizofrénico , Núcleos Talámicos/fisiopatología , Animales , Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Humanos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Núcleos Talámicos/efectos de los fármacos , Núcleos Talámicos/metabolismoRESUMEN
5-HT(1A) receptors (5-HT1AR) are expressed by pyramidal and γ-aminobutyric acidergic (GABAergic) neurons in medial prefrontal cortex (mPFC). Endogenous serotonin inhibits mPFC pyramidal neurons via 5-HT1AR while 5-HT1AR agonists, given systemically, paradoxically excite ventral tegmental area-projecting pyramidal neurons. This enhances mesocortical dopamine function, a process involved in the superior efficacy of atypical antipsychotic drugs on negative and cognitive symptoms of schizophrenia. Moreover, the 5-HT1AR-induced increase of pyramidal discharge may also contribute to the maintenance of activity patterns required for working memory, impaired in schizophrenia. Given the importance of these processes, we examined the neurobiological basis of pyramidal activation through 5-HT1AR using the prototypical agent 8-OH-DPAT. (±)8-OH-DPAT (7.5 µg/kg i.v.) increased discharge rate and c-fos expression in rat mPFC pyramidal neurons. Local blockade of GABA(A) inputs with gabazine (SR-95531) avoided (±)8-OH-DPAT-induced excitations of pyramidal neurons. Moreover, (±)8-OH-DPAT administration reduced the discharge rate of mPFC fast-spiking GABAergic interneurons at doses exciting pyramidal neurons. Activation of other 5-HT1AR subpopulations (raphe nuclei or hippocampus) does not appear to contribute to pyramidal excitations. Overall, the present data suggest a preferential action of (±)8-OH-DPAT on 5-HT1AR in GABAergic interneurons. This results in pyramidal disinhibition and subsequent downstream excitations of subcortical structures reciprocally connected with PFC, such as midbrain dopaminergic neurons.
Asunto(s)
Potenciales de Acción/fisiología , Interneuronas/fisiología , Vías Nerviosas/fisiología , Corteza Prefrontal/fisiología , Células Piramidales/fisiología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Ácido gamma-Aminobutírico/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Masculino , Vías Nerviosas/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Antipsychotic drugs of different chemical/pharmacological families show preferential dopamine (DA) D2 receptor (D2-R) vs. D1 receptor (D1-R) affinity, with the exception of clozapine, the gold standard of schizophrenia treatment, which shows a comparable affinity for both DA receptors. Here, we examined the ability of Lu AF35700 (preferential D1-R>D2-R antagonist), to reverse the alterations in thalamo-cortical activity induced by phencyclidine (PCP), used as a pharmacological model of schizophrenia. Lu AF35700 reversed the PCP-induced alteration of neuronal discharge and low frequency oscillation (LFO, 0.15-4 Hz) in thalamo-cortical networks. Likewise, Lu AF35700 prevented the increased c-fos mRNA expression induced by PCP in thalamo-cortical regions of awake rats. We next examined the contribution of D1-R and D2-R to the antipsychotic reversal of PCP effects. The D2-R antagonist haloperidol reversed PCP effects on thalamic discharge rate and LFO. Remarkably, the combination of sub-effective doses of haloperidol and SCH-23390 (DA D1-R antagonist) fully reversed the PCP-induced fall in thalamo-cortical LFO. However, unlike with haloperidol, SCH-23390 elicited different degrees of potentiation of the effects of low clozapine and Lu AF35700 doses. Overall, the present data support a synergistic interaction between both DA receptors to reverse the PCP-induced alterations of oscillatory activity in thalamo-cortical networks, possibly due to their simultaneous blockade in direct and indirect pathways of basal ganglia. The mild potentiation induced by SCH-23390 in the case of clozapine and Lu AF35700 suggests that, at effective doses, these agents reverse PCP effects through the simultaneous blockade of both DA receptors.
Asunto(s)
Antipsicóticos , Clozapina , Ratas , Animales , Fenciclidina/farmacología , Clozapina/farmacología , Haloperidol/farmacología , Dopamina , Antipsicóticos/farmacología , Antagonistas de Dopamina/farmacología , Receptores de Dopamina D1RESUMEN
Derangements of the prefrontal cortex (PFC) and of brainstem monoaminergic systems occur in depression and schizophrenia. Anatomical and functional evidence supports a PFC control of the brainstem monoaminergic systems. Similarly, the PFC contains a high density of monoamine receptors for which antipsychotic drugs exhibit high affinity. This raises the possibility that pathological or drug-induced changes in PFC may subsequently alter monoaminergic activity. Recent data indicate that a substantial proportion of PFC pyramidal neurons projecting to the ventral tegmental area (VTA) or the dorsal raphe nucleus (DR) express the 5-HT2A receptor mRNA, which suggests that atypical antipsychotic drugs affect serotonergic and dopaminergic function by targeting PFC 5-HT2A receptors. Using electrophysiological and tract-tracing techniques we examined whether PFC pyramidal neurons projecting to DR are segregated from those projecting to the VTA. Sequential electrical stimulation of these nuclei in anaesthetized rats evoked antidromic potentials from both areas in the same pyramidal neurons of the medial PFC (60%, n=30). A similar percentage of dual DR+VTA projection neurons (50%) was obtained using the reciprocal collision test (n=85). Similarly, tracer application (Fluoro-Gold in VTA and cholera toxin B in DR, or vice versa) retrogradely labelled pyramidal neurons in PFC projecting to VTA (81±18), to DR (52±9) and to both nuclei (31±4, n=5 rats). Overall, these results indicate that the PFC may simultaneously coordinate the activity of dopaminergic and serotonergic systems within a short temporal domain, supporting a concerted modulation of the ascending serotonergic and dopaminergic activity during antipsychotic drug treatment.
Asunto(s)
Antipsicóticos/farmacología , Tronco Encefálico/fisiología , Vías Nerviosas/fisiopatología , Neuronas/fisiología , Corteza Prefrontal/citología , Corteza Prefrontal/fisiología , Animales , Tronco Encefálico/citología , Toxina del Cólera/metabolismo , Dopamina/fisiología , Fenómenos Electrofisiológicos , Colorantes Fluorescentes/metabolismo , Masculino , Núcleos del Rafe/fisiología , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT2A/metabolismo , Serotonina/fisiología , Estilbamidinas/metabolismo , Área Tegmental Ventral/fisiologíaRESUMEN
Anxiety and depression exhibit high comorbidity and share the alteration of the amygdala-hippocampal-prefrontal network, playing different roles in the ventral and dorsal hippocampi. Deep brain stimulation of the infralimbic cortex in rodents or the human equivalent-the subgenual cingulate cortex-constitutes a fast antidepressant treatment. The aim of this work was: (1) to describe the oscillatory profile in a rodent model of anxiety, and (2) to deepen the therapeutic basis of infralimbic deep brain stimulation in mood disorders. First, the anxiogenic drug FG-7142 was administered to anaesthetized rats to characterize neural oscillations within the amygdala and the dorsoventral axis of the hippocampus. Next, deep brain stimulation was applied. FG-7142 administration drastically reduced the slow waves, increasing delta, low theta, and beta oscillations in the network. Moreover, FG-7142 altered communication in these bands in selective subnetworks. Deep brain stimulation of the infralimbic cortex reversed most of these FG-7142 effects. Cross-frequency coupling was also inversely modified by FG-7142 and by deep brain stimulation. Our study demonstrates that the hyperactivated amygdala-hippocampal network associated with the anxiogenic drug exhibits an oscillatory fingerprint. The study contributes to comprehending the neurobiological basis of anxiety and the effects of infralimbic deep brain stimulation.
RESUMEN
Major depressive disorder (MDD) is a chronic and disabling psychiatric disorder characterized by a wide range of signs/symptoms, including cognitive dysfunction. Vortioxetine (VOR) is a multimodal antidepressant drug with pro-cognitive actions in animal models and MDD patients. The VOR-mediated blockade of 5-HT3-R in a subpopulation of GABA interneurons enhances pyramidal neuron activity in rat medial prefrontal cortex, an effect possibly underlying its pro-cognitive action. Brain oscillations are involved in regulation of cognitive function. We therefore examined VOR effects on oscillatory activity in four brain areas of freely-moving rats (prelimbic cortex, PrL; nucleus accumbens, NAc; dorsal hippocampus, dHPC; paraventricular thalamic nucleus, PVA), in standard and in serotonin-depleted rats showing recognition memory deficits. 4-chloro-dl-phenylalanine (pCPA) markedly reduced low frequency oscillations (LFO, mainly 1 Hz oscillations) and enhanced theta oscillations in PrL and NAc. It also reduced gamma and high frequency oscillations (HFO) in PVA. Subchronic VOR and escitalopram (ESC) treatments had little effect on oscillatory activity in standard rats. However, VOR -but not ESC- prevented recognition memory deficits in 5-HT-depleted rats, and normalized LFO and theta powers in PrL and NAc. In parallel, VOR -but not ESC- prevented the deficit in PrL-dHPC gamma coherence, but not the decrease in gamma and HFO powers in PVA. Overall, this supports a prominent role of serotonergic neurotransmission on brain oscillatory activity, particularly in cortico-striatal pathways linked to short-term recognition memory. Further, VOR prevented pCPA-induced cognitive deficits by normalizing oscillatory activity at lower frequencies in the PrL-NAc pathway, also normalizing the PrL-dHPC coherence at gamma frequencies.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ritmo Circadiano/efectos de los fármacos , Citalopram/administración & dosificación , Trastornos de la Memoria/metabolismo , Serotonina/metabolismo , Vortioxetina/administración & dosificación , Animales , Antidepresivos de Segunda Generación/administración & dosificación , Ritmo Circadiano/fisiología , Fenclonina/toxicidad , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Ratas , Ratas Wistar , Antagonistas del Receptor de Serotonina 5-HT3/administración & dosificación , Antagonistas de la Serotonina/toxicidadRESUMEN
Non-competitive N-methyl-d-aspartate receptor antagonists mimic schizophrenia symptoms and produce immediate and persistent antidepressant effects. We investigated the effects of ketamine and phencyclidine (PCP) on thalamo-cortical network activity in awake, freely-moving male Wistar rats to gain new insight into the neuronal populations and brain circuits involved in the effects of NMDA-R antagonists. Single unit and local field potential (LFP) recordings were conducted in mediodorsal/centromedial thalamus and in medial prefrontal cortex (mPFC) using microelectrode arrays. Ketamine and PCP moderately increased the discharge rates of principal neurons in both areas while not attenuating the discharge of mPFC GABAergic interneurons. They also strongly affected LFP activity, reducing beta power and increasing that of gamma and high-frequency oscillation bands. These effects were short-lasting following the rapid pharmacokinetic profile of the drugs, and consequently were not present at 24â¯h after ketamine administration. The temporal profile of both drugs was remarkably different, with ketamine effects peaking earlier than PCP effects. Although this study is compatible with the glutamate hypothesis for fast-acting antidepressant action, it does not support a local disinhibition mechanism as the source for the increased pyramidal neuron activity in mPFC. The short-lasting increase in thalamo-cortical activity is likely associated with the rapid psychotomimetic action of both agents but could also be part of a cascade of events ultimately leading to the persistent antidepressant effects of ketamine. Changes in spectral contents of high-frequency bands by the drugs show potential as translational biomarkers for target engagement of NMDA-R modulators.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Neuronas GABAérgicas/efectos de los fármacos , Núcleos Talámicos Intralaminares/efectos de los fármacos , Ketamina/farmacología , Núcleo Talámico Mediodorsal/efectos de los fármacos , Fenciclidina/farmacología , Corteza Prefrontal/efectos de los fármacos , Animales , Neuronas GABAérgicas/metabolismo , Interneuronas/efectos de los fármacos , Interneuronas/metabolismo , Núcleos Talámicos Intralaminares/citología , Núcleos Talámicos Intralaminares/metabolismo , Núcleo Talámico Mediodorsal/citología , Núcleo Talámico Mediodorsal/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Corteza Prefrontal/citología , Corteza Prefrontal/metabolismo , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Tálamo , VigiliaRESUMEN
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-D-aspartate (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 in c-fos expression. Examination of the effects of PCP on other brain areas revealed an increased c-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.
Asunto(s)
Antipsicóticos/farmacología , Fenciclidina/farmacología , Corteza Prefrontal/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Núcleos Talámicos/efectos de los fármacos , Animales , Corteza Cerebral/metabolismo , Clozapina/farmacología , Haloperidol/farmacología , Masculino , Vías Nerviosas , Fenciclidina/antagonistas & inhibidores , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiología , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Células Piramidales/fisiología , Ratas , Ratas Wistar , Corteza Somatosensorial/metabolismo , Núcleos Talámicos/metabolismoRESUMEN
Major depressive disorder (MDD) is a severe psychiatric syndrome with high prevalence and socioeconomic impact. Current antidepressant treatments are based on the blockade of serotonin (5-hydroxytryptamine, 5-HT) and/or noradrenaline transporters. These drugs show slow onset of clinical action and limited efficacy, partly due to the activation of physiological negative feed-back mechanisms operating through autoreceptors (5-HT1A, 5-HT1B, α2-adrenoceptors) and postsynaptic receptors (e.g., 5-HT3). As a result, clinically-relevant doses of reuptake inhibitors increase extracellular (active) 5-HT concentrations in the midbrain raphe nuclei but not in forebrain, as indicated by rodent microdialysis studies and by PET-scan studies in primate/human brain. The prevention of these self-inhibitory mechanisms by antagonists of the above receptors augments preclinical and clinical antidepressant effects. Hence, the mixed ß-adrenoceptor/5-HT1A antagonist pindolol accelerated, and in some cases enhanced, the clinical action of selective serotonin reuptake inhibitors (SSRI). This strategy has been incorporated into two new multi-target antidepressant drugs, vilazodone and vortioxetine, which combine 5-HT reuptake inhibition and partial agonism at 5-HT1A receptors. Vortioxetine shows also high affinity for other 5-HT receptors, including excitatory 5-HT3 receptors located in cortical and hippocampal GABA interneurons. 5-HT3 receptor blockade by vortioxetine enhances pyramidal neuron activity in prefrontal cortex as well as cortical and hippocampal 5-HT release. It is still too soon to know whether these new antidepressants will represent a real advance over existing drugs in the real world. However, their development opened the way to future antidepressant drugs based on the prevention of local and distal self-inhibitory mechanisms attenuating monoamine activity.
Asunto(s)
Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Neurotransmisores/farmacología , Neurotransmisores/uso terapéutico , Animales , Monoaminas Biogénicas/metabolismo , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/metabolismo , HumanosRESUMEN
BACKGROUND: Deep Brain Stimulation (DBS) of the subgenual cingulate cortex (SCC) is a promising therapeutic alternative to treat resistant major depressive disorder. In preclinical studies, DBS of the ventromedial prefrontal cortex (vmPFC, the rodent SCC correlate) provokes an antidepressant-like effect, along with changes in noradrenaline levels at the site of stimulation. Hence, DBS appears to activate the noradrenergic-locus coeruleus (LC) system. OBJECTIVE/HYPOTHESIS: The aim of this study was to evaluate the effect of vmPFC DBS on the electrical activity of noradrenergic LC neurons, cortical oscillations and coherence between both brain areas in male rats. METHODS: The antidepressant-like effect of vmPFC DBS was evaluated through the forced swimming test. Tonic and evoked activity of LC neurons, LC activity of alpha2-adrenoceptors, local field potentials from LC and electrocorticogram signals were studied after DBS by electrophysiological recordings in anaesthetized rats. The effect of DBS on tyrosine hydroxylase (TH), noradrenaline transporters (NAT), phosphorylation of the extracellular signal-regulated kinase (ERK) and corticotropin releasing factor (CRF) expression in the LC were measured by western blot assays. RESULTS: DBS induced an antidepressant-like effect increasing climbing behaviour in the FST that was accompanied by a robust increase of TH expression in the rat LC. The tonic and evoked activity of LC neurons was enhanced by DBS, which impaired alpha2-adrenoceptors activity. DBS also promoted an increase in slow LC oscillations, as well as a shift in LC-cortical coherence. CONCLUSION: DBS of the vmPFC appears to affect the LC, producing changes that may underlie its antidepressant-like effects.
Asunto(s)
Estimulación Encefálica Profunda , Depresión/terapia , Locus Coeruleus/citología , Locus Coeruleus/fisiología , Norepinefrina/metabolismo , Corteza Prefrontal/fisiología , Animales , Trastorno Depresivo Mayor/terapia , Giro del Cíngulo/fisiología , Masculino , Ratas , Ratas Wistar , NataciónRESUMEN
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'.
Asunto(s)
Alucinógenos/farmacología , Metoxidimetiltriptaminas/farmacología , Corteza Prefrontal/efectos de los fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Tálamo/efectos de los fármacos , Corteza Visual/efectos de los fármacos , Animales , Ondas Encefálicas/efectos de los fármacos , Ondas Encefálicas/fisiología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Piperazinas/farmacología , Corteza Prefrontal/metabolismo , Piridinas/farmacología , Receptor de Serotonina 5-HT1A/genética , Receptor de Serotonina 5-HT2A/genética , Antagonistas de la Serotonina/farmacología , Tálamo/metabolismo , Corteza Visual/metabolismoRESUMEN
BACKGROUND: Sub-anesthetic doses of the non-competitive N-methyl-d-aspartate receptor (NMDA-R) antagonist ketamine evoke transient psychotomimetic effects, followed by persistent antidepressant effects in treatment-resistant depressed patients and rodents through still poorly understood mechanisms. Since phencyclidine (PCP) disinhibits thalamo-cortical networks by blocking NMDA-Rs on GABAergic neurons of the reticular thalamic nucleus (RtN), we examined ketamine's actions in the same areas. METHODS: Single units and local field potentials were recorded in chloral hydrate anesthetized male Wistar rats. The effects of cumulative ketamine doses (0.25-5â¯mg/kg, i.v.) on neuronal discharge and oscillatory activity were examined in RtN, mediodorsal and centromedial (MD/CM) thalamic nuclei, and layer VI of the medial prefrontal cortex (mPFC). RESULTS: Ketamine (1, 2 and 5â¯mg/kg, i.v.) significantly decreased the discharge of MD/CM, RtN and layer VI mPFC pyramidal neurons. Simultaneously, ketamine decreased the power of low frequency oscillations in all areas examined and increased gamma oscillations in mPFC and MD/CM. Lower ketamine doses (0.25 and 0.5â¯mg/kg, i.v.) were ineffective. CONCLUSIONS: As observed for PCP, ketamine markedly inhibited the activity of RtN neurons. However, unlike PCP, this effect did not translate into a disinhibition of MD/CM and mPFC excitatory neurons, possibly due to a more potent and simultaneous blockade of NMDA-Rs by ketamine in MD/CM and mPFC neurons. Hence, the present in vivo results show that ketamine evokes an early transient inhibition of neuronal discharge in thalamo-cortical networks, following its rapid pharmacokinetics, which is likely associated to its psychotomimetic effects. The prolonged increase in gamma oscillations may underlie its antidepressant action.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/farmacología , Ritmo Gamma/efectos de los fármacos , Ketamina/farmacología , Neuronas/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Núcleos Talámicos/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/sangre , Ritmo Gamma/fisiología , Ketamina/sangre , Masculino , Inhibición Neural/efectos de los fármacos , Neuronas/fisiología , Fenciclidina/farmacología , Corteza Prefrontal/fisiología , Ratas Wistar , Núcleos Talámicos/fisiologíaRESUMEN
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.
Asunto(s)
Antidepresivos/administración & dosificación , Citalopram/administración & dosificación , Piperazinas/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Sulfuros/administración & dosificación , Potenciales de Acción/efectos de los fármacos , Animales , Masculino , Corteza Prefrontal/fisiología , Células Piramidales/fisiología , Ratas , Ratas Wistar , VortioxetinaRESUMEN
Brexpiprazole (BREX), a recently approved antipsychotic drug in the US and Canada, improves cognitive dysfunction in animal models, by still largely unknown mechanisms. BREX is a partial agonist at 5-HT1A and D2 receptors and antagonist at α1B- and α2C-adrenergic and 5-HT2A receptors all with a similar potency. The NMDA receptor antagonist phencyclidine (PCP), used as pharmacological model of schizophrenia, activates thalamocortical networks and decreases low frequency oscillations (LFO; <4 Hz). These effects are reversed by antipsychotics. Here we assessed the ability of BREX to reverse PCP-induced hyperactivity of thalamocortical circuits, and the involvement of 5-HT1A receptors in its therapeutic action. BREX reversed PCP-induced neuronal activation at a lower dose in centromedial/mediodorsal thalamic nuclei (CM/MD; 0.5mg/kg) than in pyramidal medial prefrontal cortex neurons (mPFC, 2mg/kg), perhaps due to antagonism at α1B-adrenoceptors, abundantly expressed in the thalamus. Conversely, a cumulative 0.5 mg/kg dose reversed a PCP-induced LFO decrease in mPFC but not in CM/MD. BREX reduced LFO in both areas, yet with a different dose-response, and moderately excited mPFC neurons. The latter effect was reversed by the 5-HT1A receptor antagonist WAY-100635. Thus, BREX partly antagonizes PCP-induced thalamocortical hyperactivity, differentially in mPFC versus CM/MD. This regional selectivity may be related to the differential expression of α1B-, α2C-adrenergic and 5-HT2A receptors in both regions and/or different neuronal types. Furthermore, the pro-cognitive properties of BREX may be related to the 5-HT1A receptor-mediated increase in mPFC pyramidal neuron activity. Overall, the present data provide new insight on the brain elements involved in BREX's therapeutic actions.
Asunto(s)
Antipsicóticos/farmacología , Vías Nerviosas/efectos de los fármacos , Neuronas/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Quinolonas/farmacología , Núcleos Talámicos/efectos de los fármacos , Tiofenos/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Ondas Encefálicas/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Análisis de Fourier , Masculino , Vías Nerviosas/fisiología , Fenciclidina/farmacología , Piperazinas/farmacología , Corteza Prefrontal/citología , Piridinas/farmacología , Ratas , Ratas Wistar , Antagonistas de la Serotonina/farmacología , Núcleos Talámicos/citologíaRESUMEN
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.
Asunto(s)
Antidepresivos/farmacología , Antipsicóticos/farmacología , Trastornos Mentales/fisiopatología , Vías Nerviosas/fisiopatología , Antidepresivos/uso terapéutico , Antipsicóticos/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/fisiopatología , Industria Farmacéutica , Humanos , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatologíaRESUMEN
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 microg/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 microM) and reduced it at a higher concentration (30 microM). 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.