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1.
Neuropharmacology ; 158: 107745, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31445017

RESUMEN

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 24 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 , Vigilia
2.
Neuropharmacology ; 142: 219-230, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29221792

RESUMEN

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/metabolismo
3.
Biol Psychiatry ; 76(12): 937-45, 2014 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-25038984

RESUMEN

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.


Asunto(s)
Neuronas GABAérgicas/efectos de los fármacos , Alucinógenos/farmacología , Fenciclidina/farmacología , Tálamo/citología , Potenciales de Acción/efectos de los fármacos , Análisis de Varianza , Animales , Clozapina/farmacología , Antagonistas del GABA/farmacología , Masculino , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Parvalbúminas/metabolismo , Corteza Prefrontal/citología , Ratas , Ratas Wistar
4.
Biol Psychiatry ; 69(10): 918-27, 2011 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-21251645

RESUMEN

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.


Asunto(s)
Antipsicóticos/farmacología , Corteza Cerebral/efectos de los fármacos , Clozapina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Fenciclidina/farmacología , Tálamo/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Mapeo Encefálico , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Interacciones Farmacológicas , Potenciales Evocados/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Neuronas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Mensajero/metabolismo , Ratas , Tálamo/citología , Tálamo/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/genética , Proteína 1 de Transporte Vesicular de Glutamato/metabolismo
5.
Biol Psychiatry ; 64(5): 392-400, 2008 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-18436196

RESUMEN

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 DOI's psychotomimetic action. The reversal by clozapine and haloperidol indicates that antipsychotic drugs may reduce psychotic symptoms by normalizing an altered PFC function.


Asunto(s)
Anfetaminas/farmacología , Antipsicóticos/farmacología , Relojes Biológicos/efectos de los fármacos , Clozapina/farmacología , Alucinógenos/farmacología , Corteza Prefrontal/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Electroencefalografía , Electrólisis/métodos , Potenciales Evocados/efectos de los fármacos , Fluorobencenos/farmacología , Análisis de Fourier , Masculino , Neuronas/efectos de los fármacos , Piperidinas/farmacología , Corteza Prefrontal/citología , Ratas , Ratas Wistar , Antagonistas de la Serotonina/farmacología , Tálamo/lesiones , Tálamo/fisiología
6.
Cereb Cortex ; 15(1): 1-14, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15238448

RESUMEN

Serotonin is involved in psychiatric disorders exhibiting abnormal prefrontal cortex (PFC) function (e.g. major depression, schizophrenia). We examined the effect of the stimulation of the dorsal and median raphe nuclei (DR and MnR, respectively) on the activity of PFC neurons. Electrical stimulation of DR/MnR inhibited 66% (115/173) of pyramidal neurons in the medial PFC (mPFC). The rest of the cases exhibited orthodromic excitations, either pure (13%) or preceded by short-latency inhibitions (20%). Excited neurons had a lower pre-stimulus firing rate than those inhibited. Excitations evoked by MnR stimulation had a shorter latency than those evoked by DR stimulation. WAY-100635 [a 5-hydroxytryptamine1A (5-HT1A) antagonist] and the selective gamma aminobutyric acidA (GABAA) antagonist picrotoxinin partially antagonized DR/MnR-evoked inhibitions, suggesting the involvement of 5-HT1A- and GABAA-mediated components. The presence of a direct DR/MnR-mPFC GABAergic component is suggested by the short latency of evoked inhibitions (9 +/- 1 ms), faster than those evoked in the secondary motor area (20 +/- 3 ms), and that of antidromic spikes evoked by DR/MnR stimulation in mPFC pyramidal neurons (15 +/- 1 ms). Stimulation of the DR/MnR with paired pulses enhanced the duration of inhibitions and turned some excitations into inhibitions. Thus, the DR/MnR control the activity of mPFC pyramidal neurons in vivo in a complex manner, involving 5-HT-mediated excitations and GABA- and 5-HT-mediated inhibitions.


Asunto(s)
Corteza Prefrontal/citología , Células Piramidales/fisiología , Núcleos del Rafe/citología , Serotonina/fisiología , Ácido gamma-Aminobutírico/fisiología , Animales , Estimulación Eléctrica , Potenciales Evocados/efectos de los fármacos , Potenciales Evocados/fisiología , Masculino , Corteza Motora/citología , Corteza Motora/fisiología , Inhibición Neural/fisiología , Vías Nerviosas , Piperazinas/farmacología , Corteza Prefrontal/fisiología , Piridinas/farmacología , Núcleos del Rafe/fisiología , Ratas , Ratas Wistar , Antagonistas de la Serotonina/farmacología
7.
Cereb Cortex ; 14(12): 1365-75, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15166106

RESUMEN

Serotonin (5-hydroxytryptamine, 5-HT) controls pyramidal cell activity in prefrontal cortex (PFC) through various receptors, in particular, 5-HT1A and 5-HT2A receptors. Here we report that the physiological stimulation of the raphe nuclei excites local, putatively GABAergic neurons in the prelimbic and cingulate areas of the rat PFC in vivo. These excitations had a latency of 36 +/- 4 ms and a duration of 69 +/- 9 ms and were blocked by the i.v. administration of the 5-HT3 receptor antagonists ondansetron and tropisetron. The latency and duration were shorter than those elicited through 5-HT2A receptors in pyramidal neurons of the same areas. Double in situ hybridization histochemistry showed the presence of GABAergic neurons expressing 5-HT3 receptor mRNA in PFC. These cells were more abundant in the cingulate, prelimbic and infralimbic areas, particularly in superficial layers. The percentages of GAD mRNA-positive neurons expressing 5-HT3 receptor mRNA in prelimbic cortex were 40, 18, 6 and 8% in layers I, II-III, V and VI, respectively, a distribution complementary to that of cells expressing 5-HT2A receptors. Overall, these results support an important role of 5-HT in the control of the excitability of apical dendrites of pyramidal neurons in the medial PFC through the activation of 5-HT3 receptors in GABAergic interneurons.


Asunto(s)
Interneuronas/fisiología , Corteza Prefrontal/fisiología , Receptores de Serotonina 5-HT3/fisiología , Ácido gamma-Aminobutírico/fisiología , Animales , Estimulación Eléctrica/métodos , Interneuronas/efectos de los fármacos , Masculino , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Wistar , Antagonistas del Receptor de Serotonina 5-HT3 , Antagonistas de la Serotonina/farmacología
8.
Cereb Cortex ; 13(8): 870-82, 2003 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12853374

RESUMEN

The activation of 5-HT(2A) receptors in medial prefrontal cortex (mPFC) by the hallucinogen DOI increases the firing activity of dorsal raphe (DR) 5-HT neurons and prefrontal 5-HT release. Here we show that the i.v. administration of DOI markedly affected the firing rate of identified pyramidal neurons recorded extracellularly. DOI excited (481%) 21/56 neurons, inhibited (11%) 17/56 neurons and left the rest unaffected (overall 2.4-fold increase in firing rate). Both effects were antagonized by 5-HT(2A) receptor blockade. 5-HT(2A)-mediated orthodromic excitations were recorded in pyramidal neurons projecting to DR after electrical stimulation of this nucleus. We also examined whether the effects of DOI in mPFC involve thalamic excitatory inputs. The disinhibition of the mediodorsal and centromedial nuclei of the thalamus by local bicuculline resembled the effects of DOI as it increased pyramidal cell firing and 5-HT release in mPFC. However, the selective activation of prefrontal micro -opioid and mGlu II receptors counteracted the effects of the thalamic disinhibition but not those of DOI. Moreover, extensive thalamic lesions did not alter the effect of DOI on pyramidal cell firing and 5-HT release. We conclude that DOI increases the activity of the mPFC-DR circuit by an action on postsynaptic 5-HT(2A) receptors unrelated to thalamocortical afferents.


Asunto(s)
Corteza Cerebral/fisiología , Indofenol/análogos & derivados , Corteza Prefrontal/fisiología , Células Piramidales/fisiología , Receptores de Serotonina/fisiología , Tálamo/fisiología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiología , Animales , Corteza Cerebral/efectos de los fármacos , Indofenol/farmacología , Masculino , Corteza Prefrontal/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT2A , Tálamo/efectos de los fármacos
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