RESUMEN
BACKGROUND: Based on the pivotal role of astrocytes in brain homeostasis and the strong metabolic cooperation existing between neurons and astrocytes, it has been suggested that astrocytic dysfunctions might cause and/or contribute to neuroinflammation and neurodegenerative processes. Therapeutic approaches aimed at both neuroprotection and neuroinflammation reduction may prove particularly effective in slowing the progression of these diseases. The endogenous lipid mediator palmitoylethanolamide (PEA) displayed neuroprotective and anti(neuro)inflammatory properties, and demonstrated interesting potential as a novel treatment for Alzheimer's disease. OBJECTIVE AND METHODS: We firstly evaluated whether astrocytes could participate in regulating the Aß42-induced neuronal damage, by using primary mouse astrocytes cell cultures and mixed astrocytes-neurons cultures. Furthermore, the possible protective effects of PEA against Aß42-induced neuronal toxicity have also been investigated by evaluating neuronal viability, apoptosis, and morphometric parameters. RESULTS: The presence of astrocytes pre-exposed to Aß42 (0.5µM; 24âh) induced a reduction of neuronal viability in primary mouse astrocytes-neurons co-cultures. Furthermore, under these experimental conditions, an increase in the number of neuronal apoptotic nuclei and a decrease in the number of MAP-2 positive neurons were observed. Finally, astrocytic Aß42 pre-exposure induced an increase in the number of neurite aggregations/100µm as compared to control (i.e., untreated) astrocytes-neurons co-cultures. These effects were not observed in neurons cultured in the presence of astrocytes pre-exposed to PEA (0.1µM), applied 1âh before and maintained during Aß42 treatment. CONCLUSION: Astrocytes contribute to Aß42-induced neurotoxicity and PEA, by blunting Aß42-induced astrocyte activation, improved neuronal survival in mouse astrocyte-neuron co-cultures.
Asunto(s)
Péptidos beta-Amiloides/farmacología , Antiinflamatorios no Esteroideos/farmacología , Astrocitos/efectos de los fármacos , Etanolaminas/farmacología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Ácidos Palmíticos/farmacología , Fragmentos de Péptidos/farmacología , Amidas , Análisis de Varianza , Animales , Animales Recién Nacidos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/citología , Técnicas de Cocultivo , Ratones , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos/metabolismo , Factores de TiempoRESUMEN
The effects of nanomolar cocaine concentrations, possibly not blocking the dopamine transporter activity, on striatal D2-σ1 heteroreceptor complexes and their inhibitory signaling over Gi/o, have been tested in rat striatal synaptosomes and HEK293T cells. Furthermore, the possible role of σ1 receptors (σ1Rs) in the cocaine-provoked amplification of D2 receptor (D2R)-induced reduction of K+-evoked [3H]-DA and glutamate release from rat striatal synaptosomes, has also been investigated. The dopamine D2-likeR agonist quinpirole (10nM-1µM), concentration-dependently reduced K+-evoked [3H]-DA and glutamate release from rat striatal synaptosomes. The σ1R antagonist BD1063 (100nM), amplified the effects of quinpirole (10 and 100nM) on K+-evoked [3H]-DA, but not glutamate, release. Nanomolar cocaine concentrations significantly enhanced the quinpirole (100nM)-induced decrease of K+-evoked [3H]-DA and glutamate release from rat striatal synaptosomes. In the presence of BD1063 (10nM), cocaine failed to amplify the quinpirole (100nM)-induced effects. In cotransfected σ1R and D2LR HEK293T cells, quinpirole had a reduced potency to inhibit the CREB signal versus D2LR singly transfected cells. In the presence of cocaine (100nM), the potency of quinpirole to inhibit the CREB signal was restored. In D2L singly transfected cells cocaine (100nM and 10µM) exerted no modulatory effects on the inhibitory potency of quinpirole to bring down the CREB signal. These results led us to hypothesize the existence of functional D2-σ1R complexes on the rat striatal DA and glutamate nerve terminals and functional D2-σ1R-DA transporter complexes on the striatal DA terminals. Nanomolar cocaine concentrations appear to alter the allosteric receptor-receptor interactions in such complexes leading to enhancement of Gi/o mediated D2R signaling.
Asunto(s)
Cocaína/administración & dosificación , Cuerpo Estriado/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores sigma/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Dopamina/metabolismo , Agonistas de Dopamina/administración & dosificación , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Ácido Glutámico/metabolismo , Células HEK293 , Humanos , Complejos Multiproteicos/efectos de los fármacos , Complejos Multiproteicos/genética , Terminaciones Nerviosas/efectos de los fármacos , Terminaciones Nerviosas/metabolismo , Quinpirol/administración & dosificación , Ratas , Receptores de Dopamina D2/química , Receptores de Dopamina D2/genética , Receptores sigma/química , Receptores sigma/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Receptor Sigma-1RESUMEN
The long-lasting effects of gestational cannabinoids exposure on the adult brain of the offspring are still controversial. It has already been shown that pre- or perinatal cannabinoids exposure induces learning and memory disruption in rat adult offspring, associated with permanent alterations of cortical glutamatergic neurotransmission and cognitive deficits. In the present study, the risk of long-term consequences induced by perinatal exposure to cannabinoids on rat hippocampal GABAergic system of the offspring, has been explored. To this purpose, pregnant rats were treated daily with Delta9-tetrahydrocannabinol (Δ9-THC; 5mg/kg) or its vehicle. Perinatal exposure to Δ9-THC induced a significant reduction (p<0.05) in basal and K+-evoked [3H]-GABA outflow of 90-day-old rat hippocampal slices. These effects were associated with a reduction of hippocampal [3H]-GABA uptake compared to vehicle exposed group. Perinatal exposure to Δ9-THC induced a significant reduction of CB1 receptor binding (Bmax) in the hippocampus of 90-day-old rats. However, a pharmacological challenge with either Δ9-THC (0.1µM) or WIN55,212-2 (2µM), similarly reduced K+-evoked [3H]-GABA outflow in both experimental groups. These reductions were significantly blocked by adding the selective CB1 receptor antagonist SR141716A. These findings suggest that maternal exposure to cannabinoids induces long-term alterations of hippocampal GABAergic system. Interestingly, previous behavioral studies demonstrated that, under the same experimental conditions as in the present study, perinatal cannabinoids exposure induced cognitive impairments in adult rats, thus resembling some effects observed in humans. Although it is difficult and sometimes misleading to extrapolate findings obtained from animal models to humans, the possibility that an alteration of hippocampus aminoacidergic transmission might underlie, at least in part, some of the cognitive deficits affecting the offspring of marijuana users, is supported.
Asunto(s)
Dronabinol/farmacología , Neuronas GABAérgicas/efectos de los fármacos , Hipocampo/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/metabolismo , Receptor Cannabinoide CB1/metabolismo , Transmisión Sináptica/efectos de los fármacos , Animales , Benzoxazinas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Femenino , Neuronas GABAérgicas/metabolismo , Hipocampo/metabolismo , Masculino , Morfolinas/farmacología , Naftalenos/farmacología , Embarazo , Unión Proteica/efectos de los fármacos , Ratas , Transmisión Sináptica/fisiologíaRESUMEN
In this study, the functional role of individual striatal receptors for adenosine (A2AR), dopamine (D2R), and the metabotropic glutamate receptor mGlu5R in regulating rat basal ganglia activity was characterized in vivo using dual-probe microdialysis in freely moving rats. In particular, intrastriatal perfusion with the D2R agonist quinpirole (10 µM, 60 min) decreased ipsilateral pallidal GABA and glutamate levels, whereas intrastriatal CGS21680 (A2AR agonist; 1 µM, 60 min) was ineffective on either pallidal GABA and glutamate levels or the quinpirole-induced effects. Intrastriatal perfusion with the mGlu5R agonist (RS)-2-chloro-5-hydroxyphenylglycine (600 µM, 60 min), by itself ineffective on pallidal GABA and glutamate levels, partially counteracted the effects of quinpirole. When combined with CGS21680 (1 µM, 60 min), (RS)-2-chloro-5-hydroxyphenylglycine (CHPG; 600 µM, 60 min) fully counteracted the quinpirole (10 µM, 60 min)-induced reduction in ipsilateral pallidal GABA and glutamate levels. These effects were fully counteracted by local perfusion with the mGlu5R antagonist MPEP (300 µM) or the A2AR antagonist ZM 241385 (100 nM). These results suggest that A2ARs and mGlu5Rs interact synergistically in modulating the D2R-mediated control of striatopallidal GABA neurons. Using dual-probe microdialysis, we characterized the functional role of striatal adenosine A2A receptor (A2AR), dopamine D2 receptor (D2R), and metabotropic glutamate receptor 5 (mGluR5) interactions in regulating rat basal ganglia activity. The results suggest the possible usefulness of using an A2AR antagonist and mGluR5 antagonist combination in the treatment of Parkinson's disease to increase the inhibitory D2 signaling on striatopallidal GABA neurons.
Asunto(s)
Cuerpo Estriado/metabolismo , Receptor del Glutamato Metabotropico 5/metabolismo , Receptores de Dopamina D2/metabolismo , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Dopamina/farmacología , Agonistas de Dopamina/farmacología , Ácido Glutámico/farmacología , Masculino , Microdiálisis/métodos , Neostriado/metabolismo , Ratas Sprague-Dawley , Receptor del Glutamato Metabotropico 5/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacosRESUMEN
Neurotensin is a tridecapeptide originally identified in extracts of bovine hypothalamus. This peptide has a close anatomical and functional relationship with the mesocorticolimbic and nigrostriatal dopamine system. Neural circuits containing neurotensin were originally proposed to play a role in the mechanism of action of antipsychotic agents. Additionally, neurotensin-containing pathways were demonstrated to mediate some of the rewarding and/or sensitizing properties of drugs of abuse.This review attempts to contribute to the understanding of the role of neurotensin and its receptors in drug abuse. In particular, we will summarize the potential relevance of neurotensin, its related compounds and neurotensin receptors in substance use disorders, with a focus on the preclinical research.
Asunto(s)
Neurotensina/metabolismo , Receptores de Neurotensina/metabolismo , Trastornos Relacionados con Sustancias/fisiopatología , Animales , Antipsicóticos/farmacología , Encéfalo/metabolismo , Dopamina/metabolismo , Humanos , RecompensaRESUMEN
AIMS: N-[(4-trifluoromethyl) benzyl] 4-methoxybutyramide (GET73) may be considered a promising therapeutic agent for the treatment of alcohol use disorders. The compound displayed anti-alcohol and anxiolytic properties in rat. In the present study, an in vitro experimental model of chronic ethanol treatment was used to investigate the ability of the compound to counteract the ethanol-induced neurotoxicity. METHODS: Primary cultures of rat hippocampal neurons were exposed to ethanol (75 mM; 4 days) and the neuroprotective effects of GET73 were assessed by evaluating cell viability, cell morphology, glutamate levels and reactive oxygen species production. RESULTS: The exposure to ethanol induced a reduction of cell viability, an alteration of cytoskeleton, a decrease in extracellular glutamate levels and an increase of reactive oxygen species production. The addiction of GET73 (1 and 10 µM) 1 h before and during chronic ethanol exposure prevented all the above ethanol-induced effects. Based on the proposed GET73 mechanism of action, the effects of mGlu5 receptor negative allosteric modulator, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), on ethanol-induced reduction of cell viability were also assessed. The results indicated that the addiction of MPEP (100 µM) 1 h before and during chronic ethanol exposure prevented the ethanol-induced cell viability reduction. CONCLUSION: The present findings provide the first evidence that GET73 shows a neuroprotective role against ethanol-induced neurotoxicity in primary cultures of rat hippocampal neurons. Together with previous findings, these results suggest that GET73 possesses multifaceted properties thus lending further support to the significance of developing GET73 as a therapeutic tool for use in the treatment of alcohol use disorders.
Asunto(s)
Anilidas/farmacología , Etanol/toxicidad , Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Animales Recién Nacidos , Células Cultivadas , Hipocampo/metabolismo , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Considering the heterogeneity of pathological changes occurring in Alzheimer's disease (AD), a therapeutic approach aimed both to neuroprotection and to neuroinflammation reduction may prove effective. Palmitoylethanolamide (PEA) has attracted attention for its anti-inflammatory/neuroprotective properties observed in AD animal models. OBJECTIVE AND METHODS: We evaluated the protective role of PEA against amyloid-ß42 (Aß42) toxicity on cell viability and glutamatergic transmission in primary cultures of cerebral cortex neurons and astrocytes from the triple-transgenic murine model of AD (3xTg-AD) and their wild-type littermates (non-Tg) mice. RESULTS: Aß42 (0.5 µM; 24 h) affects the cell viability in cultured cortical neurons and astrocytes from non-Tg mice, but not in those from 3xTg-AD mice. These effects were counteracted by the pretreatment with PEA (0.1 µM). Basal glutamate levels in cultured neurons and astrocytes from 3xTg-AD mice were lower than those observed in cultured cells from non-Tg mice. Aß42-exposure reduced and increased glutamate levels in non-Tg mouse cortical neurons and astrocytes, respectively. These effects were counteracted by the pretreatment with PEA. By itself, PEA did not affect cell viability and glutamate levels in cultured cortical neurons and astrocytes from non-Tg or 3xTg-AD mice. CONCLUSION: The exposure to Aß42 induced toxic effects on cultured cortical neurons and astrocytes from non-Tg mice, but not in those from 3xTg-AD mice. Furthermore, PEA exerts differential effects against Aß42-induced toxicity in primary cultures of cortical neurons and astrocytes from non-Tg and 3xTg-AD mice. In particular, PEA displays protective properties in non-Tg but not in 3xTg-AD mouse neuronal cultured cells overexpressing Aß.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/efectos adversos , Antiinflamatorios no Esteroideos/farmacología , Astrocitos/efectos de los fármacos , Etanolaminas/farmacología , Neuronas/efectos de los fármacos , Ácidos Palmíticos/farmacología , Amidas , Animales , Células Cultivadas , Corteza Cerebral/citología , Modelos Animales de Enfermedad , Ácido Glutámico/sangre , Ratones , Ratones Transgénicos , Proteínas tau/metabolismoRESUMEN
The tridecapeptide neurotensin (NT) acts as neurotransmitter in the central nervous system and in the periphery. NT and NT receptors are largely localized in dopamine (DA)-enriched regions of the mammalian brain. Accordingly, numerous studies indicate the presence of close functional interactions between DA neurons and the peptide. Among others mechanisms, it has been suggested that NT could modulate nigrostriatal, mesolimbic and meso-cortical DA transmission through an antagonistic receptor-receptor interaction between the NT receptor subtype 1 (NTS1) and the dopamine D2 receptor (D2R). In particular, it was originally demonstrated that the peptide reduces the D2R agonist affinity in striatal sections and in striatal membrane preparations. These effects could be a consequence of the direct allosteric NTS1/D2 receptor interactions leading to a decrease in the DA agonist affinity at the D2 receptor. Several neurochemical, biochemical and co-immunoprecipitation data have successively reinforced the indication of the presence of direct NTS1-D2 receptor interactions in the mammalian brain. The present mini-review attempts to provide a summary of current knowledge, mainly emerging from our microdialysis studies, supporting the presence of a NTS1/D2 receptor heteromer in the brain. The pre and post-synaptic mechanisms underlying the involvement of this heteromer in the striatopallidal GABA and mesocorticolimbic DA neurotransmission are discussed especially for their relevance in Parkinson's disease and schizophrenia, respectively.
Asunto(s)
Encéfalo/metabolismo , Enfermedad de Parkinson/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Neurotensina/metabolismo , Esquizofrenia/metabolismo , Animales , Dopamina/metabolismo , Humanos , Neurotensina/metabolismo , Transmisión Sináptica , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Striatal dopamine adenosine A2A and D2 receptors interact to modulate some aspects of motor and motivational function. The demonstration of A2A/D2 receptor heteromerization in living cells constituted a progress for understanding the neurobiology of dopamine D2 and adenosine A2A receptors. In fact, the existence of putative striatalA2A/D2 receptor heteromers has been suggested to be important for striatal function under both normal and pathological conditions, such as Parkinson's disease. Consequently, the antagonistic A2A-D2 receptor interactions in a putative striatal receptor heteromer on striato-pallidal GABA neuron led to the introduction of A2A receptor antagonists as possible anti- Parkinsonian drugs. The present mini-review briefly summarizes the main findings supporting the presence of antagonistic A2A-D2 receptor interactions in putative receptor heteromers in the basal ganglia. Special emphasis is given to in vivo microdialysis findings demonstrating the functional role putative A2A/D2 heteromers on striato-pallidal GABA neurons play in the modulation of this pathway, in which A2A receptors inhibit D2 receptor signaling. The possible relevance of compounds targeting the putative striatal A2A/D2 heteromer in the Parkinson's disease pharmacological treatment is also discussed.
Asunto(s)
Enfermedad de Parkinson/metabolismo , Receptor de Adenosina A2A/metabolismo , Receptores de Dopamina D2/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Antagonistas del Receptor de Adenosina A2/farmacología , Animales , Antiparkinsonianos/farmacología , Descubrimiento de Drogas , Humanos , Terapia Molecular Dirigida , Enfermedad de Parkinson/tratamiento farmacológico , Multimerización de Proteína , Receptor de Adenosina A2A/química , Receptores de Dopamina D2/químicaRESUMEN
The tryptophan metabolite kynurenic acid (KYNA) is an endogenous antagonist of the α7 nicotinic acetylcholine receptor (α7nAChR) and, at higher concentrations, inhibits ionotropic glutamate receptors. Increases in KYNA levels are seen in brain and cerebrospinal fluid in individuals with schizophrenia (SZ) and may be causally related to cognitive deficits in SZ and other psychiatric diseases. As dysfunction of circuits involving GABAergic neurons in the prefrontal cortex (PFC) likely plays a role in the cognitive impairments seen in these disorders, we examined the effects of KYNA on extracellular GABA in this brain area. Applied to awake rats for 2 h by reverse dialysis, KYNA concentration-dependently and reversibly reduced extracellular GABA levels, with 300 nM KYNA causing a nadir of â¼45% of baseline concentrations. This effect was not duplicated by reverse dialysis of the selective glycineB receptor antagonist 7-Cl-KYNA (100 nM) or the AMPA/kainate receptor antagonist CNQX (100 µM), and was prevented by co-application of galantamine (5 µM), a positive allosteric modulator of the α7nAChR. Conversely, inhibition of endogenous KYNA formation by reverse dialysis of (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 5 mM) reversibly increased GABA levels in the PFC, reaching a peak of â¼160% of baseline concentrations. Co-infusion of 30 nM KYNA neutralized this effect. Taken together, these results demonstrate a role for endogenous KYNA in the bi-directional control of GABAergic neurotransmission in the PFC. Pharmacological manipulation of KYNA may therefore be useful in the treatment of GABAergic impairments in SZ and other brain disorders involving the PFC.
Asunto(s)
Espacio Extracelular/metabolismo , Ácido Quinurénico/metabolismo , Corteza Prefrontal/metabolismo , Ácido gamma-Aminobutírico/metabolismo , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Animales , Fármacos del Sistema Nervioso Central/farmacología , Colinérgicos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Espacio Extracelular/efectos de los fármacos , Galantamina/farmacología , Ácido Glutámico/metabolismo , Ácido Quinurénico/antagonistas & inhibidores , Masculino , Microdiálisis , Corteza Prefrontal/efectos de los fármacos , Ratas Sprague-Dawley , Receptores de Glicina/antagonistas & inhibidores , Receptores de Glicina/metabolismo , Bases de Schiff/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/metabolismoRESUMEN
Although several findings indicate an association between adolescent cannabis abuse and the risk to develop schizophrenia later in life, the evidence for a causal relationship is still inconclusive. In the present study, we investigated the emergence of psychotic-like behavior in adult female rats chronically exposed to delta-9-tetrahydrocannabinol (THC) during adolescence. To this aim, female Sprague-Dawley rats were treated with THC during adolescence (PND 35-45) and, in adulthood (PND 75), a series of behavioral tests and biochemical assays were performed in order to investigate the long-term effects of adolescent THC exposure. Adolescent THC pretreatment leads to long-term behavioral alterations, characterized by recognition memory deficits, social withdrawal, altered emotional reactivity and sensitization to the locomotor activating effects of acute PCP. Moreover, since cortical disinhibition seems to be a key feature of many different animal models of schizophrenia and GABAergic hypofunction in the prefrontal cortex (PFC) has been observed in postmortem brains from schizophrenic patients, we then investigated the long-lasting consequences of adolescent THC exposure on GABAergic transmission in the adult rat PFC. Biochemical analyses revealed that adolescent THC exposure results in reduced GAD67 and basal GABA levels within the adult PFC. GAD67 expression is reduced both in parvalbumin (PV)- and cholecystokinin (CCK)-containing interneurons; this alteration may be related to the altered emotional reactivity triggered by adolescent THC, as silencing PFC GAD67 expression through a siRNA-mediated approach is sufficient to impact rats' behavior in the forced swim test. Finally, the cellular underpinnings of the observed sensitized response to acute PCP in adult THC-treated rats could be ascribed to the increased cFos immunoreactivity and glutamate levels in the PFC and dorsal striatum. The present findings support the hypothesis that adolescent THC exposure may represent a risk factor for the development of a complex psychotic-like behavior in adulthood.
Asunto(s)
Agonistas de Receptores de Cannabinoides/toxicidad , Dronabinol/toxicidad , Corteza Prefrontal/metabolismo , Trastornos Psicóticos/etiología , Trastornos Psicóticos/patología , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/metabolismo , Factores de Edad , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Glutamato Descarboxilasa/metabolismo , Actividad Motora/efectos de los fármacos , Fenciclidina/farmacología , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reconocimiento en Psicología/efectos de los fármacos , Conducta Estereotipada/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacosRESUMEN
N-[(4-trifluoromethyl) benzyl] 4-methoxybutyramide (GET73) is a newly synthesized compound displaying anti-alcohol and anxiolytic properties. In light of the importance of the hippocampal CA1 subregion in alcohol addiction and anxiety-like behaviors-this in vivo microdialysis study characterized the effect of GET73 on extracellular GABA levels in the hippocampal CA1 region of the freely moving rat-including a possible role for mGlu5 receptor in mediating this effect. Both intraperitoneal administration (2-10 mg/kg) and local intra-hippocampal CA1 perfusion with GET73 (50-1000 nM) were associated with a transient, step-wise increase in dialysate hippocampal CA1 GABA levels. The GET73 (10 mg/kg)-induced increase in GABA levels was not affected by intra-CA1 perfusion with either the GABA reuptake inhibitor SKF89976A (0.5 mM) or by local GABAA (bicuculline; 1µM) and GABAB (CGP35348; 500 µM) receptor antagonists. On the contrary, the GET73-induced increase in GABA levels was partially counteracted by the intra-CA1 perfusion with the mGlu5 receptor negative allosteric modulator MPEP (300 µM). Interestingly, GET73 at the lowest (2 mg/kg) dose tested, by itself ineffective, fully counteracted the increase in GABA levels induced by the mGlu5 receptor agonist CHPG (1000 µM). Taken together, these findings suggest that the GET73-induced increase in hippocampal CA1 GABA levels operates independently of local GABA reuptake and/or GABAA or GABAB receptors. Furthermore, the present data lead to hypothesize a possible interaction between GET73 and mGluR5-mediated regulation of hippocampal CA1 GABA transmission, an effect which may be relevant to the ability of GET73 to reduce alcohol intake in an alcohol-preferring rat strain.
Asunto(s)
Anilidas/farmacología , Ansiolíticos/farmacología , Región CA1 Hipocampal/efectos de los fármacos , Espacio Extracelular/metabolismo , Receptor del Glutamato Metabotropico 5/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Anilidas/administración & dosificación , Animales , Ansiolíticos/administración & dosificación , Región CA1 Hipocampal/metabolismo , Inhibidores de Recaptación de GABA/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Antagonistas de Receptores de GABA-B/farmacología , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Kynurenic acid (KYNA) is an astrocyte-derived non-competitive antagonist of the α7 nicotinic acetylcholine receptor (α7nAChR) and inhibits the NMDA receptor (NMDAR) competitively. The main aim of the present study was to examine the possible effects of KYNA (30 - 1000 nm), applied locally by reverse dialysis for 2 h, on extracellular GABA levels in the rat striatum. KYNA concentration-dependently reduced GABA levels, with 300 nm KYNA causing a maximal reduction to ~60% of baseline concentrations. The effect of KYNA (100 nm) was prevented by co-application of galantamine (5 µm), an agonist at a site of the α7nAChR that is very similar to that targeted by KYNA. Infusion of 7-chlorokynurenic acid (100 nm), an NMDAR antagonist acting selectively at the glycineB site of the receptor, affected neither basal GABA levels nor the KYNA-induced reduction in GABA. Inhibition of endogenous KYNA formation by reverse dialysis of (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 1 mm) increased extracellular GABA levels, reaching a peak of 156% of baseline levels after 1 h. Co-infusion of 100 nm KYNA abolished the effect of ESBA. Qualitatively and quantitatively similar, bi-directional effects of KYNA on extracellular glutamate were observed in the same microdialysis samples. Taken together, the present findings suggest that fluctuations in endogenous KYNA levels, by modulating α7nAChR function, control extracellular GABA levels in the rat striatum. This effect may be relevant for a number of physiological and pathological processes involving the basal ganglia.
Asunto(s)
Antagonistas Colinérgicos/farmacología , Cuerpo Estriado/metabolismo , Espacio Extracelular/metabolismo , Ácido Quinurénico/farmacología , Receptores Nicotínicos/metabolismo , Animales , Agonistas Colinérgicos/farmacología , Cuerpo Estriado/efectos de los fármacos , Espacio Extracelular/efectos de los fármacos , Galantamina/farmacología , Ácido Glutámico/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Nicotínicos/efectos de los fármacos , Bases de Schiff/farmacología , Receptor Nicotínico de Acetilcolina alfa 7 , Ácido gamma-Aminobutírico/metabolismoRESUMEN
CHF5074, a new microglial modulator, attenuates memory deficit in Alzheimer's disease transgenic mice. In this study, the effect of an acute or subacute CHF5074 treatment on in vivo novel object recognition test and on [³H]Acetylcholine (ACh) and GABA release in pre-plaque (7-month-old) Tg2576 mice have been compared with those induced by the γ-secretase inhibitor LY450139 (semagacestat). Vehicle-treated Tg2576 mice displayed an impairment of recognition memory compared with wild-type animals. This impairment was recovered in transgenic animals acutely treated with CHF5074 (30 mg/kg), while LY450139 (1, 3, 10 mg/kg) was ineffective. In frontal cortex synaptosomes from vehicle-treated Tg2576 mice, Kâº-evoked [³H]ACh release was lower than that measured in wild-type mice. This reduction was absent in transgenic animals subacutely treated with CHF5074 (30 mg/kg daily for 8 days), while it was slightly, not significantly, amplified by LY450139 (3 mg/kg daily for 8 days). There were no differences between the groups on spontaneous [³H]ACh release as well as spontaneous and Kâº-evoked GABA release. These results suggest that CHF5074 has beneficial effects on visual memory and cortical cholinergic dysfunctions in pre-plaque Tg2576 mice. Together with previous findings, these data suggest that CHF5074 could be a possible candidate for early Alzheimer's disease therapeutic regimens.
Asunto(s)
Acetilcolina/metabolismo , Corteza Cerebral/efectos de los fármacos , Ciclopropanos/farmacología , Flurbiprofeno/análogos & derivados , Memoria/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Sinaptosomas/efectos de los fármacos , Enfermedad de Alzheimer/metabolismo , Animales , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Femenino , Flurbiprofeno/farmacología , Humanos , Ratones , Ratones TransgénicosRESUMEN
Modafinil, (RS)-2-(diphenylmethylsulfinyl)acetamide derivative (Modiodal, Provigil), is a vigilance-promoting agent which reduces sleep episodes by improving wakefulness. It is approved by the USA FDA for narcolepsy, shiftwork sleep disorder and obstructive sleep apnoea with residual excessive sleepiness despite optimal use of continuous positive airway pressure. Unlike classical psychostimulants such as amphetamine and amphetamine-like compounds, the awaking effect of modafinil is not associated with a disturbance of nighttime sleep, tolerance, and sensitization. Its precise mechanism of action is still unclear. In animal studies, modafinil and its analogues have been shown to modify dopaminergic, noradrenergic, glutamatergic, GABAergic, serotoninergic, orexinergic, and histaminergic pathways. Besides the approved use in sleep disorders, modafinil has been investigated for the treatment of fatigue, impaired cognition and some symptoms in a number of other disorders. In particular, clinical studies seem to indicate that the drug could be particularly successful in the treatment of depression and its use in major depressive and bipolar disorders, has been suggested. However, the molecular mechanisms underlying this possible effect are still unknown. The present review firstly summarizes the structure-activity relationship studies and the mechanism of action of modafinil and its related compounds. Then, it focuses on data demonstrating that modafinil interacts with serotonin neuronal activity in rat frontal cortex and dorsal raphe nucleus, two brain areas linked together and involved in depression. Preclinical and clinical evidence of a positive interaction between modafinil and classical antidepressant drugs, is also summarized.
Asunto(s)
Antidepresivos/química , Compuestos de Bencidrilo/química , Corteza Prefrontal/efectos de los fármacos , Núcleos del Rafe/efectos de los fármacos , Serotonina/metabolismo , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , Modelos Animales de Enfermedad , Dopamina/metabolismo , Humanos , Trastornos Mentales/tratamiento farmacológico , Modafinilo , Corteza Prefrontal/metabolismo , Núcleos del Rafe/metabolismo , Transducción de Señal , Relación Estructura-ActividadRESUMEN
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is considered one of the most toxic dioxin-like compounds. It is ubiquitous in foodstuffs of animal origin and accumulates in the fatty tissues of animals and humans. Prenatal TCDD exposure has been associated, beside other effects, with persistent impaired cognitive development. In the present study, the effects of maternal exposure to TCDD during pregnancy on cortical neuron development at birth and cortical glutamate transmission in new-born, 14- and 60-day-old rat offspring, were investigated. A single dose (0.7 µg/kg) of TCDD dissolved in corn oil was orally administrated to the dams on gestational day 18; controls dams were treated with the vehicle. All the experiments have been performed on the male offspring from vehicle-treated (i.e. control group) and TCDD-treated dams. Primary cultures of cerebral cortical neurons obtained from 1-day-old rats born from mothers exposed to TCDD displayed a reduction in cell viability (MTT assay) and an increase in the number of apoptotic nuclei (nuclear staining with Hoechst 33258) possibly associated with altered dendrite outgrowth (MAP2-immunoreactivity) with respect to control cell cultures. These changes were associated with impairment in cortical glutamate transmission, characterized by a reduction in basal and K(+)-evoked outflow as well as a decrease in [(3)H]glutamate uptake. Interestingly, the prenatal TCDD-induced alteration of cortical glutamate signaling is persistent since it was also present in 14- and 60-day-old offspring. Taken together, these results suggest that a single prenatal exposure to TCDD produces alterations in cortical neuron development associated with a long-term dysfunction of glutamate transmission in rat cerebral cortex. The possible relevance of these findings for the understanding of the long-lasting cognitive deficit observed in the offspring from mothers exposed to the toxicant during pregnancy, is discussed.
Asunto(s)
Corteza Cerebral/metabolismo , Ácido Glutámico/efectos adversos , Neurogénesis/fisiología , Neuronas/metabolismo , Dibenzodioxinas Policloradas/toxicidad , Efectos Tardíos de la Exposición Prenatal/metabolismo , Animales , Animales Recién Nacidos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/crecimiento & desarrollo , Femenino , Ácido Glutámico/fisiología , Masculino , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Ratas , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Factores de TiempoRESUMEN
Recent in vitro results suggest that cocaine may exert direct and/or indirect allosteric enhancing actions at dopamine (DA) D(2) receptors (D(2)Rs). In the present paper we tested the hypothesis that cocaine in vivo can enhance the effects of the D(2)-likeR agonist quinpirole in rats by using microdialysis and pharmacological behavioral studies. Furthermore, in vitro D(2)-likeR binding characteristics and Gα(i/o)-protein coupling, in the absence and in the presence of cocaine, have been investigated in rat striatal membranes. Intra-nucleus accumbens perfusion of the D(2)-likeR agonist quinpirole (10 µM) reduced local dialysate glutamate levels, whereas cocaine (10 and 100 nM) was ineffective. At a low concentration (100 nM), cocaine significantly enhanced quinpirole-induced reduction of accumbal extracellular glutamate levels. The behavioral experiments showed that cocaine (0.625 mg/kg), but not the DA uptake blocker GBR 12783 (1.25 mg/kg), enhanced quinpirole (1 mg/kg)-induced hyperlocomotion. Finally, cocaine (100 nM), but not GBR 12783 (200 nM), produced a small, but significant increase in the efficacy of DA to stimulate binding of GTPγS to striatal D(2)-likeRs, whereas the D(2)-likeR binding characteristics were unchanged in striatal membranes by cocaine in the nM range. The significant increase in the maximal response to DA-stimulated GTPγS binding to D(2)-likeRs by 100 nM cocaine remained in the presence of GBR 12783. The observed cocaine-induced enhancement of the Gα(i/o)-protein coupling of D(2)Rs may be in part because of allosteric direct and/or indirect enhancing effects of cocaine at these receptors. These novel actions of cocaine may have relevance for understanding the actions of cocaine upon accumbal DA, and/or glutamate transmission and thus its rewarding as well as relapsing effects.
Asunto(s)
Cocaína/farmacología , Quinpirol/farmacología , Receptores de Dopamina D2/fisiología , Animales , Cocaína/administración & dosificación , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/farmacología , Sinergismo Farmacológico , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Ácido Glutámico , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Locomoción/efectos de los fármacos , Masculino , Microinyecciones , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Piperazinas/farmacología , Quinpirol/administración & dosificación , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismoRESUMEN
The present manuscript mainly summarizes the basic concepts and the molecular mechanisms underlying adenosine A(2A)-dopamine D(2) receptor-receptor interactions in the basal ganglia. Special emphasis is placed on neurochemical, behavioral and electrophysiological findings supporting the functional role that A(2A)/D(2) heteromeric receptor complexes located on striato-pallidal GABA neurons and corticostriatal glutamate terminals play in the regulation of the so called "basal ganglia indirect pathway". Furthermore, the role of A(2A)/mGluR(5) synergistic interactions in striatal neuron function and dysfunction is discussed. The functional consequences of the interactions between striatal adenosine A(2A), mGluR(5) and dopamine D(2) receptors on striatopallidal GABA release and motor behavior dysfunctions suggest the possibility of simultaneously targeting these receptors in Parkinson's disease treatment. This article is part of a Special Issue entitled Brain Integration. This article is part of a Special Issue entitled: Brain Integration.
Asunto(s)
Aminoácidos/metabolismo , Cuerpo Estriado/metabolismo , Enfermedad de Parkinson , Receptor de Adenosina A2A/genética , Receptores de Dopamina D2/genética , Transducción de Señal/genética , Animales , Humanos , Modelos Biológicos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patologíaRESUMEN
The current microdialysis study elucidates a functional interaction between the striatal neurotensin NTS(1) receptor and the striatal dopamine D(2) and N-methyl-d-aspartic acid (NMDA) receptors in the regulation of striatopallidal gamma-aminobutyric acid (GABA) and glutamate levels after an ipsilateral intranigral 6-hydroxydopamine-induced lesion of the ascending dopamine pathways to the striatum. Lateral globus pallidus GABA levels were higher in the lesioned group while no change was observed in striatal GABA and glutamate levels. The 6-hydroxydopamine-induced lesion did not alter the ability of intrastriatal NT (10 nm) to counteract the decrease in pallidal GABA and glutamate levels induced by the dopamine D(2) -like receptor agonist quinpirole (10 µm). A more pronounced increase in the intrastriatal NMDA- (10 µm) induced increase in pallidal GABA levels was observed in the lesioned group while it attenuated the increase in striatal glutamate levels and amplified the increase in pallidal glutamate levels compared with that observed in the controls. NT enhanced the NMDA-induced increase in pallidal GABA and glutamate and striatal glutamate levels; these effects were counteracted by the NTS(1) antagonist SR48692 (100 nm) in both groups. These findings demonstrate an inhibitory striatal dopamine D(2) and an excitatory striatal NMDA receptor regulation of striatopallidal GABA transmission in both groups. These actions are modulated by NT via antagonistic NTS(1) /D(2) and facilitatory NTS(1) /NMDA receptor-receptor interactions, leading to enhanced glutamate drive of the striatopallidal GABA neurons associated with motor inhibition, effects which all are counteracted by SR48692. Thus, NTS(1) antagonists in combination with conventional treatments may provide a novel therapeutic strategy in Parkinson's disease.
Asunto(s)
Ácido Glutámico/metabolismo , Trastornos Parkinsonianos/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de N-Metil-D-Aspartato/fisiología , Receptores de Neurotensina/metabolismo , Ácido gamma-Aminobutírico/biosíntesis , Adrenérgicos/toxicidad , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Globo Pálido/efectos de los fármacos , Globo Pálido/metabolismo , Masculino , Microdiálisis , Vías Nerviosas/metabolismo , Oxidopamina/toxicidad , Trastornos Parkinsonianos/fisiopatología , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica/fisiologíaRESUMEN
The aim of the present in vivo microdialysis study was to investigate whether the tridecapeptide neurotensin (NT) influences the N-methyl-D-aspartate (NMDA) receptor-mediated increase of cortical glutamate transmission in freely moving rats. Intracortical perfusion with NT influenced local extracellular glutamate levels in a bell-shaped, concentration-dependent manner. One hundred and three hundred nanomolar NT concentrations increased glutamate levels (151% ± 7% and 124% ± 3% of basal values, respectively). Higher (1,000 nM) and lower (10 nM) NT concentrations did not alter extracellular glutamate levels. The NT receptor antagonist SR48692 (100 nM) prevented the NT (100 nM)-induced increase in glutamate levels. NMDA (100 and 500 µM) perfusion induced a concentration-dependent increase in extracellular glutamate levels, the lower 10 µM NMDA concentration being ineffective. When NT (10 nM, a concentration by itself ineffective) was added in combination with NMDA (100 µM) to the perfusion medium, a significant greater increase in extracellular glutamate levels (169% ± 7%) was observed with respect to the increase induced by NMDA (100 µM) alone (139% ± 4%). SR48692 (100 nM) counteracted the increase in glutamate levels induced by the treatment with NT (10 nM) plus NMDA (100 µM). The enhancement of cortical glutamate levels induced by NMDA (100 and 500 µM) was partially antagonized by the presence of SR48692, at a concentration (100 nM) that by itself was ineffective in modulating glutamate release. These findings indicate that NT plays a relevant role in the regulation of cortical glutamatergic transmission, especially by modulating the functional activity of cortical NMDA receptors. A possible role in glutamate-mediated neurotoxicity is suggested.