RESUMEN
Regulation of gene expression is known to contribute to the long-term adaptations taking place in response to drugs of abuse. Recent studies highlighted the regulation of gene transcription in neurons by chromatin remodeling, a process in which posttranslational modifications of histones play a major role. To test the involvement of epigenetic regulation on drug-reinforcing properties, we submitted rats to the cocaine operant self-administration paradigm. Using the fixed ratio 1 schedule, we found that the histone deacetylase (HDAC) inhibitors trichostatin A and phenylbutyrate dose-dependently reduced cocaine self-administration. Under the progressive ratio schedule, both trichostatin A and depudecin significantly reduced the breaking point, indicating that HDAC inhibition attenuated the motivation of rats for cocaine. Conversely, HDAC inhibition did not decrease self-administration for the natural reinforcer sucrose. This observation was correlated with measurements of HDAC activity in the frontal cortex, which was inhibited in response to cocaine, but not to sucrose self-administration. Control experiments showed that the decrease in the motivation for the drug was not attributable to a general motivational dysfunction because trichostatin A had no adverse effect on locomotion during the habituation session or on cocaine-induced hyperlocomotion. It was not attributable to anhedonia because the inhibitor had no effect on the sucrose preference test. In contrast, trichostatin A completely blocked the cocaine-induced behavioral sensitization. Together, the data show that epigenetic regulation of gene transcription in adult brain is able to influence a motivated behavior and suggest that HDAC inhibition may counteract the neural sensitization leading to drug dependence.
Asunto(s)
Encéfalo/efectos de los fármacos , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Cocaína/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Animales , Encéfalo/enzimología , Química Encefálica/efectos de los fármacos , Química Encefálica/genética , Trastornos Relacionados con Cocaína/enzimología , Trastornos Relacionados con Cocaína/fisiopatología , Condicionamiento Operante , Metilación de ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Inhibidores de Captación de Dopamina/farmacología , Inhibidores Enzimáticos/uso terapéutico , Epigénesis Genética/efectos de los fármacos , Epigénesis Genética/genética , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Ácidos Hidroxámicos/farmacología , Locomoción/efectos de los fármacos , Locomoción/genética , Masculino , Fenilbutiratos/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Procesamiento Proteico-Postraduccional/genética , Ratas , Ratas Wistar , Autoadministración , Sacarosa/farmacologíaRESUMEN
Tryptophan metabolism through the kynurenine pathway leads to several neuroactive compounds, including kynurenic and picolinic acids. Xanthurenic acid (Xa) has been generally considered as a substance with no physiological role but possessing toxic and apoptotic properties. In the present work, we present several findings which support a physiological role for endogenous Xa in synaptic signalling in brain. This substance is present in micromolar amounts in most regions of the rat brain with a heterogeneous distribution. An active vesicular synaptic process inhibited by bafilomycin and nigericin accumulates xanthurenate into pre-synaptic terminals. A neuronal transport, partially dependant on adenosine 5'-triphosphate (ATP), sodium and chloride ions exists in NCB-20 neurons which could participate in the clearance of extracellular xanthurenate. Both transports (neuronal and vesicular) are greatly enhanced by the presence of micromolar amounts of zinc ions. Finally, electrical in vivo stimulation of A10-induced Xa release in the extracellular spaces of the rat prefrontal cortex. This phenomenon is reproduced by veratrine, K+ ions and blocked by EGTA and tetrodotoxin. These results strongly argue for a role for Xa in neurotransmission/neuromodulation in the rat brain, thus providing the existence of specific Xa receptors.
Asunto(s)
Química Encefálica/fisiología , Encéfalo/metabolismo , Neurotransmisores/metabolismo , Terminales Presinápticos/metabolismo , Transmisión Sináptica/fisiología , Xanturenatos/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Transporte Biológico Activo/efectos de los fármacos , Transporte Biológico Activo/fisiología , Encéfalo/anatomía & histología , Línea Celular , Cloruros/metabolismo , Estimulación Eléctrica , Masculino , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Terminales Presinápticos/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/farmacología , Ratas , Ratas Wistar , Sodio/metabolismo , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/efectos de los fármacos , Canales de Sodio/metabolismo , Transmisión Sináptica/efectos de los fármacos , Vesículas Sinápticas/efectos de los fármacos , Vesículas Sinápticas/metabolismo , Zinc/metabolismoRESUMEN
We compared the effect of conditioned taste aversion in rats by measuring the amount of sucrose that they drunk after conditioning, which differed according to whether rats had drunk the sucrose freely (SD: self drinking) during the conditioning session, or had been forced to drink it (IO: intra-oral administration through a chronically implanted cannula). The SD procedure delayed the extinction of conditioned taste aversion. Enhanced arousal, alertness, awareness or attention in the SD condition may have strengthened the memory of the taste. Brain noradrenergic networks are involved in such processes. We administered two noradrenergic drugs that produce opposite effects on noradrenaline release in the brain, methoxy-idazoxan, RX821002 (1mg/kg, i.p.), and guanfacine (0.12mg/kg, i.p.). We evaluated their effect (i) on the level of noradrenaline in the gustatory cortex using microdialysis, (ii) on glycaemia that is an essential factor of taste learning and (iii) on the comparative SD versus IO conditioned taste aversion protocol mentioned above. Injecting RX821001 increased the level of noradrenaline in the gustatory cortex up to two-fold of the baseline. This effect lasted 1h. The same dose of RX821002 did not elicit any alteration of glycaemia. It enhanced extinction of conditioned taste aversion in the SD group of rats. Injecting 0.12mg/kg of guanfacine produced the opposite effect. The noradrenaline level of the gustatory cortex decreased, but only down to 20% of the baseline. This decrease lasted 2h. Guanfacine increased glycaemia. Extinction of conditioned taste aversion was only marginally decreased by guanfacine in the SD group of rats. These results fit with Aston-Jones' point of view that the role of the noradrenergic coeruleo-cortical system may be to enhance arousal, alertness, awareness or attention to an event by a transient increase of cortical noradrenaline.
Asunto(s)
Reacción de Prevención/fisiología , Corteza Cerebral/metabolismo , Condicionamiento Clásico/fisiología , Extinción Psicológica/fisiología , Norepinefrina/metabolismo , Adrenérgicos/farmacología , Análisis de Varianza , Animales , Reacción de Prevención/efectos de los fármacos , Glucemia/fisiología , Condicionamiento Clásico/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Conducta de Ingestión de Líquido/fisiología , Extinción Psicológica/efectos de los fármacos , Guanfacina/farmacología , Idazoxan/análogos & derivados , Idazoxan/farmacología , Masculino , Microdiálisis , Ratas , Ratas Long-Evans , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismo , GustoRESUMEN
Gamma-hydroxybutyrate (GHB) is an endogenous neuromodulator with therapeutical applications in anesthesia, sleep disorders, and drug addiction. We report the cloning of a GHB receptor from a rat hippocampal cDNA library. This receptor has a molecular mass of 56 kDa and belongs to the seven-transmembrane receptor family. The peptidic sequence has no significant homology with any known receptor, including GABA(B) receptors. Its mRNA is restricted to the brain and is particularly abundant in the hippocampus, cortex, striatum, thalamus, olfactory bulbs, and cerebellum, matching the distribution of GHB binding sites in rat brain. Southern blot revealed the presence of homologous sequences in several species including the human. Binding assays on transfected CHO cells showed a dissociation constant (Kd) of 426 nM for GHB and no affinity for GABA, baclofen, or glutamate. In patch-clamp experiments, transfected CHO cells revealed a functional G-protein-coupled receptor as demonstrated by GTP-gamma-S-induced irreversible activation. Application of 0.1-15 microM GHB specifically induced an inward current at negative membrane potentials that was not reproduced by application of baclofen (10 microM). CGP-55845, a GABA(B) receptor antagonist, did not inhibit the GHB-induced response nor did the GHB receptor antagonist NCS-382, suggesting that the GHB receptor system includes several subtypes.
Asunto(s)
Química Encefálica , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Oxibato de Sodio/metabolismo , Animales , Células CHO , Clonación Molecular , Cricetinae , Humanos , Técnicas de Placa-Clamp , Estructura Secundaria de Proteína , ARN Mensajero/análisis , Ratas , Receptores de Superficie Celular/química , Homología de Secuencia de Aminoácido , TransfecciónRESUMEN
Gamma-hydroxybutyrate (GHB) is both a therapeutic agent and a recreative drug. It has sedative, anxiolytic and euphoric effects. These effects are believed to be due to GHB-induced potentiation of cerebral GABAergic and dopaminergic activities, but the serotonergic system might also be involved. In this study, we examine the effects of pharmacological doses of GHB on the serotonergic activity in rat brain. Administration of 4.0 mmol/kg i.p. GHB to rats induces an accumulation of tryptophan and 5-HIAA (5-hydroxyindole acetic acid) in the frontal cortex, striatum and hippocampus without causing significant change in the tissue serotonin content. In the extracellular space, GHB induced a slight decrease in serotonin release. The tryptophan and 5-HIAA accumulation induced by GHB is mimicked by the GHB receptor agonist para-chlorophenyl-transhydroxycrotonate (NCS-356) and blocked by NCS-382 (6,7,8,9-tetrahydro-5-[H]-benzocycloheptene-5-ol-4-ylidene acetic acid) a selective GHB receptor antagonist. GHB induces the accumulation of either a derivative of or [3H]-tryptophan itself in the extracellular space, possibly by increasing tryptophan transport across the blood-brain barrier. The blood content of certain neutral amino-acids, including tryptophan, is also increased by peripheral GHB administration. Some of the effect of GHB could be reproduced by baclofen and reduced by the GABAB antagonist CGP 35348. Taken together, these results indicate that the GHB-induced stimulation of tissue serotonin turnover may be due to an increase in tryptophan transport to the brain and in its uptake by serotonergic cells. As the serotonergic system may be involved in the regulation of sleep, mood and anxiety, the stimulation of this system by high doses of GHB may be involved in certain neuropharmacological events induced by GHB administration.
Asunto(s)
Encéfalo/efectos de los fármacos , Ácido Hidroxiindolacético/metabolismo , Oxibato de Sodio/farmacología , Triptófano/farmacocinética , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Agonistas del GABA/farmacología , Antagonistas del GABA/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Ratas , Ratas WistarRESUMEN
Rats with a neonatal ventral hippocampal lesion (NVHL) have been used to model certain features of schizophrenia because they display dopaminergic activity and behavioral alterations consistent with a dysfunctional prefrontal cortex after puberty. Microdialysis studies in normal rats demonstrated increased prefrontal dopamine release during the incentive phase of behavior in an experimental situation specifically designed to evidence this behavioral aspect: the so called "sensory-specific satiety" procedure. Our hypothesis is that if dopaminergic activity in the prefrontal cortex of NVHL rats differs from sham lesioned rats, the responsiveness to the aforementioned experimental situation should also be different. Extracellular medial prefrontal dopamine outflow increased in hungry control rats when they had access to food and decreased across satiety. It increased again when a new food was presented, even when the rats were satiated. NVHL rats also had increased dopamine prefrontal outflow in these conditions, but it remained high after the end of the consumption period. The food consumption behavior declined less rapidly and the reinstatement of food consumption, usually produced by new food, did not occur in NVHL rats, provided the lesions were large. These data were discussed in relation to several theoretical backgrounds developed about the incentive aspect of behavior and for understanding the pathophysiology of schizophrenia.
Asunto(s)
Dopamina/metabolismo , Hipocampo/fisiopatología , Corteza Prefrontal/metabolismo , Respuesta de Saciedad/fisiología , Animales , Animales Recién Nacidos , Ingestión de Alimentos/fisiología , Hipocampo/efectos de los fármacos , Ácido Iboténico/toxicidad , Microdiálisis , Corteza Prefrontal/fisiopatología , Ratas , Ratas Sprague-DawleyRESUMEN
Drug addiction is a chronic brain disease characterized by a persistent risk of relapse, even after a long period of abstinence. A current hypothesis states that relapse results from lasting neuroadaptations that are induced in response to repeated drug administration. The adaptations require gene expression, some of which being under the control of stable epigenetic regulations. We have previously demonstrated that pretreatment with histone deacetylase (HDAC) inhibitors reduces the cocaine reinforcing properties as well as the motivation of rats for cocaine. We show here that the same HDAC inhibitors, trichostatin A and phenylbutyrate, significantly reduced the cocaine-seeking behavior induced by the combination of a cocaine injection together with the exposure to a light cue previously associated with cocaine taking. Reinstatement of drug-seeking behavior was carried out after a 3-week withdrawal period, which came after ten daily sessions of cocaine intravenous self-administration. Our results suggest that pharmacological treatment aimed at modulating epigenetic regulation, and particularly treatment that would inhibit HDAC activity, could reduce the risk of relapse, a major drawback in the treatment of drug addiction.
RESUMEN
Abnormal signaling by retinoids or n-3 polyunsaturated fatty acids has been implicated in clinical depression. The converging point in activities of these two classes of molecules is transcriptional activation of retinoid X receptors (Rxr). We show here that ablation of Rxrgamma in mice leads to depressive-like behaviors including increased despair and anhedonia, which were accompanied by reduced expression of dopamine D2 receptor in the shell of nucleus accumbens (NAc) and altered serotonin signaling. While abnormal serotonin signaling is not sufficient to generate the depressive behaviors, increasing D2r expression by chronic fluoxetine (Prozac) treatment or adenoassociated virus type2 (AAV2) mediated expression of Rxrgamma or D2r in the NAc of Rxrgamma(-/-) mice normalizes depressive-like behaviors in Rxrgamma(-/-) animals. Conversely, NAc infusion of raclopride, a D2r antagonist prevents AAV2-Rxrgamma-mediated rescue of despair behaviors in Rxrgamma(-/-) mice. Combined, our data argue that control of NAc D2r expression is critical for Rxrgamma-mediated modulation of affective behaviors.
Asunto(s)
Dopamina/metabolismo , Regulación de la Expresión Génica/genética , Trastornos del Humor/genética , Receptor gamma X Retinoide/fisiología , Transducción de Señal/genética , Animales , Antidepresivos/uso terapéutico , Conducta Animal/fisiología , Recuento de Células/métodos , Dependovirus/fisiología , Modelos Animales de Enfermedad , Dopamina/genética , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Fluoxetina/uso terapéutico , Preferencias Alimentarias/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Haloperidol/farmacología , Pérdida de Tono Postural/fisiología , Ratones , Ratones Noqueados , Trastornos del Humor/tratamiento farmacológico , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Mensajero/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Ácido Retinoico/deficiencia , Receptor gamma X Retinoide/deficiencia , Serotonina/metabolismoRESUMEN
Alcohol administration is known to alter several brain functions and behaviors in humans and in laboratory animals. One of the targets of ethanol is the mesocorticolimbic dopaminergic reward pathway. We used the "alcohol deprivation effect" test as a rat model of alcohol craving and relapse. The effect is characterized by increased alcohol intake and preference after several weeks of voluntary alcohol consumption followed by a withdrawal phase. The alcohol deprivation effect was found to be considerably reduced by the injection in dopaminergic brain structures of the neuropeptide CNP. This peptide is the most abundant natriuretic peptide in the brain, and signals via an intracellular rise in cyclic GMP. The effect of CNP was observed whether the peptide was injected in situ into the ventral tegmental area or into the prefrontal cortex. It was partially reversed by the injection in the same structures of KT5823, a selective inhibitor of the cGMP-dependent protein kinase. The results indicate that changes of cyclic GMP levels in dopaminergic rat brain areas participate in the neurobiological mechanisms underlying alcohol craving after withdrawal and/or alcohol dependence.
Asunto(s)
Consumo de Bebidas Alcohólicas , Encéfalo/efectos de los fármacos , Dopamina/metabolismo , Péptido Natriurético Tipo-C/farmacología , Neuropéptidos/farmacología , Corteza Prefrontal/efectos de los fármacos , Área Tegmental Ventral/efectos de los fármacos , Trastornos Inducidos por Alcohol/metabolismo , Animales , Encéfalo/metabolismo , Carbazoles/metabolismo , GMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Etanol/metabolismo , Humanos , Masculino , Corteza Prefrontal/metabolismo , Ratas , Ratas Wistar , Síndrome de Abstinencia a Sustancias/metabolismo , Área Tegmental Ventral/metabolismoRESUMEN
Dopamine, a neurotransmitter released by the lateral olivocochlear efferents, has been shown tonically to inhibit the spontaneous and sound-evoked activity of auditory nerve fibres. This permanent inhibition probably requires the presence of an efficient transporter to remove dopamine from the synaptic cleft. Here, we report that the dopamine transporter is located in the lateral efferent fibres both below the inner hair cells and in the inner spiral bundle. Perilymphatic perfusion of the dopamine transporter inhibitors nomifensine and N-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidine into the cochlea reduced the spontaneous neural noise and the sound-evoked compound action potential of the auditory nerve in a dose-dependent manner, leading to both neural responses being completely abolished. We observed no significant change in cochlear responses generated by sensory hair cells (cochlear microphonic, summating potential, distortion products otoacoustic emissions) or in the endocochlear potential reflecting the functional state of the stria vascularis. This is consistent with a selective action of dopamine transporter inhibitors on auditory nerve activity. Capillary electrophoresis with laser-induced fluorescence (EC-LIF) measurements showed that nomifensine-induced inhibition of auditory nerve responses was due to increased extracellular dopamine levels in the cochlea. Altogether, these results show that the dopamine transporter is essential for maintaining the spontaneous activity of auditory nerve neurones and their responsiveness to sound stimulation.
Asunto(s)
Nervio Coclear/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Dopamina/metabolismo , Audición/fisiología , Neuronas Aferentes/metabolismo , Ganglio Espiral de la Cóclea/metabolismo , Estimulación Acústica , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Potenciales Microfónicos de la Cóclea/efectos de los fármacos , Potenciales Microfónicos de la Cóclea/fisiología , Nervio Coclear/citología , Nervio Coclear/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Vías Eferentes/efectos de los fármacos , Vías Eferentes/fisiología , Líquido Extracelular/efectos de los fármacos , Líquido Extracelular/metabolismo , Cobayas , Células Ciliadas Auditivas Internas/efectos de los fármacos , Células Ciliadas Auditivas Internas/metabolismo , Mecanotransducción Celular/efectos de los fármacos , Mecanotransducción Celular/fisiología , Neuronas Aferentes/efectos de los fármacos , Perilinfa/efectos de los fármacos , Perilinfa/metabolismo , Ganglio Espiral de la Cóclea/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
PURPOSE: The aim of this study was to investigate whether the nucleus parafascicularis (Pf) of the thalamus could be a relay of the control of epileptic seizures by the superior colliculus (SC). The Pf is one of the main ascending projections of the SC, the disinhibition of which has been shown to suppress seizures in different animal models and has been proposed as the main relay of the nigral control of epilepsy. METHODS: Rats with genetic absence seizures (generalized absence epilepsy rat from Strasbourg or GAERS) were used in this study. The effect of bilateral microinjection of picrotoxin, a gamma-aminobutyric acid (GABA) antagonist, in the SC on the glutamate and GABA extracellular concentration within the Pf was first investigated by using microdialysis. In a second experiment, the effect of direct activation of Pf neurons on the occurrence of absence seizures was examined with microinjection of low doses of kainate, a glutamate agonist. RESULTS: Bilateral injection of picrotoxin (33 pmol/side) in the SC suppressed spike-and-wave discharges for 20 min. This treatment resulted in an increase of glutamate but not GABA levels in the Pf during the same time course. Bilateral injection of kainate (35 pmol/side) into the Pf significantly suppressed spike-and-wave discharges for 20 min, whereas such injections were without effects when at least one site was located outside the Pf. CONCLUSIONS: These data suggest that glutamatergic projections to the Pf could be involved in the control of seizures by the SC. Disinhibition of these neurons could lead to seizure suppression and may be involved in the nigral control of epilepsy.
Asunto(s)
Epilepsia Tipo Ausencia/prevención & control , Epilepsia Tipo Ausencia/fisiopatología , Glutamatos/fisiología , Núcleos Talámicos Intralaminares/efectos de los fármacos , Núcleos Talámicos Intralaminares/fisiopatología , Colículos Superiores/efectos de los fármacos , Colículos Superiores/fisiopatología , Animales , Modelos Animales de Enfermedad , Electroencefalografía/estadística & datos numéricos , Agonistas de Aminoácidos Excitadores/farmacología , Líquido Extracelular/química , Líquido Extracelular/efectos de los fármacos , Antagonistas del GABA/farmacología , Glutamatos/análisis , Glutamatos/efectos de los fármacos , Núcleos Talámicos Intralaminares/química , Ácido Kaínico/administración & dosificación , Ácido Kaínico/farmacología , Masculino , Microdiálisis , Microinyecciones , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiopatología , Picrotoxina/administración & dosificación , Picrotoxina/farmacología , Ratas , Ratas Endogámicas , Sustancia Negra/fisiopatología , Ácido gamma-Aminobutírico/análisis , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
UNLABELLED: There is growing evidence that propofol acts on affective and reward processes. We designed this study to assess the effect of propofol on the concentration of dopamine in the nucleus accumbens, a main component of the mesolimbic system. The concentration of dopamine in the nucleus accumbens was assessed by using in vivo brain microdialysis in freely moving rats. A microdialysis probe was placed within guide cannulae previously placed during stereotaxic surgery. Fluid was perfused through the probe, and samples were collected every 20 min for measuring concentrations by high-pressure liquid chromatography. All rats served as their own controls and were randomized to four different doses of propofol, injected intraperitoneally: 0, 9, 60, or 100 mg/kg, according to a within design. Compared with the baseline value, dopamine concentration was decreased at the smallest dose of 9 mg/kg, whereas concentration was largely increased at the subanesthetic (60 mg/kg) and anesthetic (100 mg/kg) doses. This increase was of the same magnitude (+90%) for subanesthetic and anesthetic doses but was more prolonged at the anesthetic dose. Data show that only subanesthetic and anesthetic doses of propofol increase the concentration of dopamine in the nucleus accumbens, as previously described with drugs of potential abuse. IMPLICATIONS: Depending on the dose, propofol either increased or decreased the concentration of dopamine in the nucleus accumbens, as assessed during microdialysis in freely moving rats. Only large doses which display a pharmacological profile, such as propofol, may show promise.
Asunto(s)
Anestesia Intravenosa , Anestésicos Intravenosos/farmacología , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Propofol/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Anestésicos Intravenosos/administración & dosificación , Animales , Cromatografía Líquida de Alta Presión , Ácido Homovanílico/metabolismo , Masculino , Microdiálisis , Núcleo Accumbens/efectos de los fármacos , Propofol/administración & dosificación , Ratas , Ratas Long-EvansRESUMEN
Differential display reverse transcription-polymerase chain reaction was used to identify mRNAs that are differentially expressed in the brain of rats treated chronically with the reference tricyclic antidepressant, imipramine, in comparison with control rats. The gene encoding for a mutation suppressor for Sec4-8 yeast (Mss4) transcript is overexpressed in the amygdala of treated rats after 3 weeks of daily administration. This overexpression is also found in the hippocampus of rats treated chronically with either tianeptine or fluoxetine. Mss4 protein has the properties of a guanine nucleotide exchange factor, interacting with several members of the Rab family implicated in Ca(2+)-dependent exocytosis of neurotransmitters. Mss4 was also overexpressed in other brain structures as judged by in situ hybridization. The kinetics of the up-regulation of Mss4 gene expression measured by Northern blot during the imipramine, tianeptine, or fluoxetine treatments are consistent with an antidepressant effect that occurs after 3 weeks. In rats in which anhedonia was induced by chronic mild stress during 3 weeks, Mss4 transcripts were specifically down-regulated in hippocampus and amygdala compared with control rats. It is proposed that Mss4 protein, which stimulates exocytosis in vivo, participates in the potentiation of the activity of neurotransmitter pathways implicated in the action of several antidepressants and constitutes one of the common functional molecules induced after chronic antidepressant treatment.