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De nombreuses pathologies psychiatriques, telles que la schizophrénie, les troubles bipolaires ou la dépression majeure, bien que très différentes, ont en commun une dysfonction du système de récompense et de motivation en lien avec une altération de la transmission dopaminergique. Par ailleurs, ces pathologies s’accompagnent de modifications du métabolisme lipidique et en particulier d’une diminution des taux en acide docosahexaenoic (DHA), le principal acide gras polyinsaturé (AGPI) n-3 dans le système nerveux central. Cependant, bien que certaines études cliniques décrivent des effets bénéfiques de supplémentations en AGPI n-3 sur certains symptômes psychiatriques, ces résultats restent controversés, et l’implication de la modification du statut lipidique dans l’étiologie de ces pathologies reste très peu étudiée. Le but de ce travail a été d’établir s’il existe un lien causal entre une déficience en AGPI n-3 et certains endophénotypes neurobiologiques et comportementaux caractéristiques de pathologies psychiatriques. En particulier, nous avons fait l’hypothèse que la déficience en AGPI n-3 pourrait conduire à un dysfonctionnement de la transmission dopaminergique mésolimbique. Dans cette étude, des tâches de conditionnement opérant chez la souris nous ont permis de mettre en évidence un déficit motivationnel à l’âge adulte induit par une déficience développementale en AGPI n-3 qui est partiellement prévenu par une supplémentation en AGPI n-3 à la naissance, mais pas au sevrage. Ce déficit motivationnel s’accompagne d’une altération de la transmission dopaminergique comme le suggère la réduction de la sensibilité au psychostimulant, l’amphétamine. Plus précisément, nous avons pu montrer que la déficience en AGPI n-3 conduit à une dysfonction des propriétés électrophysiologiques des neurones épineux moyens (medium spinyneurons ou MSN) dans le noyau accumbens (NAc), population neuronale centrale pour la modulation de la motivation. En effet la carence en AGPI n-3 induit une réduction de l’excitabilité des MSNs de la voie directe (dMSNs) qui expriment le récepteur dopaminergique de type D1, associée à une augmentation de la transmission inhibitrice reçue par ces neurones. Ces modifications sont restaurées par l’application de l’agoniste des récepteurs dopaminergiques D2 (RD2), le quinpirole. Ces données nous ont amené à faire l’hypothèse que la diminution d’excitabilité des dMSNs sous déficience en AGPI n-3 résulte de l’augmentation de la transmission GABA issue des MSNs de la voie indirecte (iMSNs) exprimant le RD2. En accord avec ces résultats, par utilisation d’un transgène Cre-dépendant permettant l’expression de l’acide gras désaturase FAT1, nous démontrons que la normalisation des taux d’AGPI dans les iMSN sélectivement, est suffisante pour restaurer les propriétés électrophysiologiques des dMSNs. Par ailleurs, l’expression de la FAT1 dans les neurones exprimant le D2R – mais pas ceux exprimant le D1R - est suffisante pour normaliser le déficit motivationnel en situation de carence. Nos résultats montrent donc un lien causal entre des modifications de taux d’AGPI dans une sous-population neuronale spécifique et une altération comportementale. Par ailleurs, notre étude suggère que la diminution des taux d’AGPI décrite dans plusieurs pathologies psychiatriques pourrait directement participer à l’expression de certains symptômes tels que l’avolition ou l’apathie. / Various, though distinct psychiatric disorders, such as Schizophrenia, bipolar disorder or major depression are associated with a dysfunction of the reward system linked to an alteration of dopamine transmission. Furthermore, these pathologies are also accompanied by changes in lipid metabolism and in particular a decrease in the brain content of docosahexaenoic acid (DHA), the main n-3 polyunsaturated fatty acid (PUFA) in the nervous system. However, despite that n-3 PUFA supplementation seems to improve or prevent some psychiatric symptoms, these results are still controversial and the implication of brain lipid composition in the etiology of psychiatric endophenotypes has been overlooked. The aim of this study was to investigate a potential causal link between n-3 PUFA deficiency and common neurobiological and behavioral endophenotypes of psychiatric disorders. In particular, the hypothesis was that n-3 PUFA deficiency could lead to dysfunctions of mesolimbic dopamine transmission and associated behaviors. Using operant conditioning tasks in mice, we showed that developmental n-3 PUFA deficiency leads to a motivational deficit at adulthood, that is partially reversed by n-3 PUFA supplementation starting at birth, but not at weaning. This motivational deficit was associated with an alteration of dopaminergic transmission as revealed by the reduced sensitivity to the psychostimulant amphetamine. More precisely, we showed that n-3 PUFA deficiency leads to alterations in electrophysiological properties of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), main actors in motivational processes. Indeed, MSNs from the direct pathway (dMSNs), that express dopaminergic D1 receptors, displayed a decrease in neuronal excitability in parallel with an increase of inhibitory input onto these neurons. These alterations were reversed by the dopaminergic D2 receptor (D2R) agonist quinpirole. These data led us to hypothesize that the decreased dMSN excitability induced by n-3 PUFA deficiency could result from an increase of the inhibitory input of MSNs from the indirect pathway (iMSNs that expresses D2R), called lateral inhibition. Accordingly, using a transgenic approach that allows the expression of the fatty acid desaturase FAT1 in a credependent manner, we showed that rescuing appropriate PUFA levels in D2R-expressing neurons selectively (including iMSNs), was sufficient to reverse alterations in electrophysiological properties of MSNs induced by n-3 PUFA deficiency. Moreover, the selective expression of FAT1 in D2-expressing neurons – but not in D1-expressing neurons – reversed the motivational deficit observed in n-3 PUFA deficient mice. We demonstrated the existence of a causal link between modifications in PUFA levels in a discrete neuronal population and behavioral alterations. Overall, this study suggests that altered PUFA levels, observed in some psychiatric disorders, could directly participate in the development of symptoms such as avolition or apathy.

Rxry est l’un des récepteurs nucléaires impliqués dans la signalisation à l’acide rétinoïque. L’ablation de Rxry chez les souris provoque le développement de comportements de type dépressifs - désespoir et d’anhédonie. De tels déficits pouvaient être normalisés par des anti-dépresseurs tels que la fluoxetine, suggérant donc l’importance de telles données pour la recherche sur la dépression.Nous avons trouvé que le NAcSh est une structure impliquée dans le contrôle par Rxry des comportements motivés étant donné que la ré-expression de Rxry dans cette structure par le virus normalise les déficits comportementaux chez les souris Rxry-/-. Nous avons démontré que le récepteur Drd2 qui est sous-exprimé dans le NAcSh des souris Rxry-/- est nécessaire dans le contrôle des comportements affectifs étant donné que le blocage des activités du Drd2 par infusion de raclopride dans le NAcSh empêche le rétablissement du phénotype Rxry-/- par le virus AAV2-RxryCette observation est étayée par le rétablissement fonctionnel des déficits comportementaux par injection de virus ou traitement à la fluoxetine qui augmentent l’expression du Drd2 dans le NAcSh chez les souris Rxry-/-. Ces données sont la première démonstration que les récepteurs aux rétinoides sont impliqués dans le contrôle des comportements affectifs chez la souris.Nous avons observé que l’ablation de Rxry provoquent une hyperactivité du NAcSh. Nous avons observé des phénomènes similaires dans un modèle de stresse par défaite sociale. L’existence de telle corrélation dans deux modèles animaux distincts de comportements dépressifs suggère que l’hyperactivité du NacSh pourrait être un phénomène commun sous-tendant la dépression. / Rxry is one of nuclear receptors involved in retinoic acid signalling. Ablation of this receptor in mice leads to development of depressive-like behaviours - despair and anhedonia. Importantly, such deficits could be normalized by antidepressant, fluoxetine chronic treatment, suggesting thus the relevance of such data for research into depression. We identified that NAcSh is a key structure implicated in Rxry control of motivated behaviours as virus mediated re-expression of Rxry in this brain region normalized behavioural deficits of Rxry-/- mice. We demonstrated that dopaminergic D2 receptor – Drd2, which is underexpressed in the NAcSh of Rxry-/- mice is necessary for Rxry control of affective behaviours since blocking of Drd2 activities by infusion of raclopride into the NAcSh prevented AAV2-Rxry mediated rescue of Rxry-/- phenotype. This observation was further supported by functional rescue of behavioral deficits by virus mediated or chronic fluoxetine treatment increase of Drd2 expression in the NAcSh of Rxry-/- mice. Such data provide the first evidence that retinoid receptors are implicated in the control of affective behaviours in mice.We also identified that molecular changes caused by Rxry ablation lead to hyperactivity of the NAcSh. Importantly, we observed similar phenomenon in etiologically different model of depression – social defeat stress model. Existence of such correlation in two distinct animal models of depressive behaviours, suggests that NAcSh hyperactivity might be a common phenomenon underlying depression.

The therapeutic benefits attributed to activation of peripheral mechanoreceptors are poorly understood. There is growing evidence that mechanical stimulation modulates substrates in the supraspinal central nervous system (CNS) that are outside the canonical somatosensory circuits. This work demonstrates that activation of peripheral mechnoreceptors via mechanical stimulation (MStim) is sufficient to increase dopamine release in the nucleus accumbens (NAc), alter neuron firing rate in the ventral tegmental area (VTA) and increase membrane translocation of delta opioid receptors (DORs) in the NAc. Further, we demonstrate that these effects are dependent on DORs and acetylcholine receptors. Additionally, MStim can block neuronal markers of chronic ethanol dependence including ethanol-induced changes to VTA GABA neuron firing during withdrawal, and DA release profiles after reinstatement ethanol during withdrawal. These are presented in tandem with evidence that MStim also ameliorates behavioral indices of ethanol withdrawal. Finally, exercise, a modality that includes a mechanosensory component, is shown to alter expression of kappa opioid receptors (KORs) in the NAc. This change substantively depresses KORs influence over evoked DA release in direct contraversion to the effects of chronic ethanol. These changes translate into reduced drinking behavior.

No description available.

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Alcohol and cocaine are commonly co-abused drugs, and those meeting criteria for both cocaine and alcohol use disorders experience more severe behavioral and health consequences than those with a single disorder. Chronic alcohol (ethanol) drinking increased the reinforcing and dopamine (DA) neuronal stimulating effects of ethanol within mesolimbic regions of the central nervous system (CNS) of alcohol-preferring (P) rats. The objectives of the current study were to determine if chronic continuous ethanol drinking produced: (1) alterations in the sensitivity of the nucleus accumbens shell (AcbSh) to the reinforcing effects of cocaine, (2) changes in the magnitude and time course of the local stimulating effects of cocaine on posterior ventral tegmental area (pVTA) DA neurons, and (3) a persistence of alterations in the stimulating effects of cocaine after a period of protracted abstinence. Female P rats received continuous, free-choice access to water and 15% v/v ethanol for at least 10 wk (continuous ethanol-drinking; CE) or access to water alone (ethanol-naïve; N). A third group of rats received the same period of ethanol access followed by 30 d of protracted abstinence from ethanol (ethanol-abstinent; Ab). CE and Ab rats consumed, on average, 6-7 g/kg/d of ethanol. Animals with a single cannula aimed at the AcbSh responded for injections of cocaine into the AcbSh during four initial operant sessions. Cocaine was not present in the self-infused solution for the subsequent three sessions, and cocaine access was restored during one final session. Animals with dual ipsilateral cannulae aimed at the AcbSh and the pVTA were injected with pulsed microinfusions of cocaine into the pVTA while DA content was collected for analysis through a microdialysis probe inserted into the AcbSh. During the initial four sessions, neither CE nor N rats self-infused artificial cerebrospinal fluid (aCSF) or 0.1 mM cocaine into the AcbSh. CE, but not N, rats self-administered 0.5 mM cocaine into the AcbSh, whereas both groups self-infused concentrations of 1.0, 2.0, 4.0, or 8.0 mM cocaine. When cocaine access was restored in Session 8, CE rats responded more on the active lever and obtained more infusions of 0.5, 1.0, 2.0, or 4.0 mM cocaine compared to N rats. Microinjection of aCSF into the pVTA did not alter AcbSh DA levels in N, CE, or Ab rats. Microinjections of 0.25 mM cocaine into the pVTA did not significantly alter AcbSh DA levels in N animals, moderately increased DA levels in CE rats, and greatly increased DA levels in Ab rats. Microinjections of 0.5 mM cocaine into the pVTA modestly increased AcbSh DA levels in N animals, robustly increased DA levels in CE rats, and did not significantly alter DA levels in Ab rats. Microinjections of 1.0 or 2.0 mM cocaine into the pVTA modestly increased AcbSh DA levels in N animals but decreased DA levels in CE and Ab rats. Overall, long-term continuous ethanol drinking by P rats enhanced both the reinforcing effects of cocaine within the AcbSh and the stimulatory and inhibitory effects of cocaine on pVTA DA neurons. Alterations in the stimulatory and inhibitory effects of cocaine on pVTA DA neurons were not only enduring, but also enhanced, following a period of protracted abstinence from ethanol exposure. Translationally, prevention of chronic and excessive alcohol intake in populations with a genetic risk for substance abuse may reduce the likelihood of subsequent cocaine use.

Les comportements motivés dont l‟addiction aux drogues d‟abus, mettent en jeu le système dopaminergique mésolimbique. Aussi connu sous le nom de système de la récompense, celui-ci comprend les neurones à dopamine de l‟aire tegmentale ventrale qui projettent, entre autres, vers le noyau accumbens. Tout comme les neurones de l‟hypothalamus, les neurones à dopamine de l‟aire tegmentale ventrale répondent aux hormones telles que la leptine, l‟insuline et la ghréline pour modifier la prise alimentaire, la motivation ou encore le tonus dopaminergique. Ceci indique que le système dopaminergique mésolimbique est sensible aux signaux hormonaux circulants et suggère que les neurones de l‟aire tegmentale ventrale pourraient percevoir les signaux métaboliques comme le glucose ou les acides gras. De plus, plusieurs études chez les humains et les rongeurs démontrent que l‟obésité et les diètes riches en gras affectent négativement la fonction dopaminergique mésolimbique. Étant donné les lacunes qui demeurent quant aux mécanismes impliqués dans la dysfonction du système dopaminergique mésolimbique induite par la nourriture riche en gras, nous avons cherché à évaluer les effets de l‟acide oléique et de l‟acide palmitique, deux des acides gras les plus abondants dans l‟organisme et l‟alimentation contemporaine, sur le système de la récompense. Ces deux acides gras, l‟un saturé (acide palmitique) et l‟autre mono-insaturé (acide oléique), se distinguent par leurs effets différentiels sur la prise alimentaire, la signalisation hormonale ou encore leur métabolisme intracellulaire mais aussi sur la santé cardiovasculaire et mentale. Nous avons dans un premier temps évalué la capacité du système dopaminergique mésolimbique à détecter les acides gras. Nous avons comparé les effets de l‟injection d‟acide oléique ou d‟acide palmitique dans l‟aire tegmentale ventrale sur la prise alimentaire, la motivation et l‟activité électrique des neurones à dopamine de l‟aire tegmentale ventrale. Nos résultats montrent que l‟acide oléique, mais pas l‟acide palmitique, diminue la prise alimentaire et le comportement motivé. L‟acide oléique inhibe également l‟activité électrique des neurones à dopamine, ces effets semblent dépendre de son entrée dans la cellule. De plus, nous montrons que les neurones à dopamine de l‟aire tegmentale ventrale expriment plusieurs 3 gènes de protéines importantes pour le transport et le métabolisme des acides gras et qu‟ils sont capables de d‟incorporer les acides gras. Nous avons dans un second temps évalué les effets de l‟acide oléique et de l‟acide palmitique dérivés de l‟alimentation. Nous avons soumis des rats à l‟une de ces trois diètes : une riche en gras enrichie en acide oléique, une riche en gras enrichie en acide palmitique ou une contrôle faible en gras. Après huit semaines, et en l‟absence d‟obésité ou d‟altérations métaboliques majeures, la diète enrichie en acide palmitique, mais pas la diète isocalorique enrichie en acide oléique, induit une hyposensibilité aux effets récompensants et locomoteurs de l‟amphétamine, associée, entre autres, à la diminution de la signalisation du récepteur à la dopamine D1R et de l‟expression du transporteur de la dopamine. Nous avons finalement exploré l‟impact de ces diètes sur l‟activité de l‟axe hypothalamo-hypophysaire-surrénalien. Les résultats montrent que la diète enrichie en acide palmitique altère aussi la fonction de l‟axe et l‟expression de plusieurs gènes cibles des corticostéroïdes, sans toutefois modifier le comportement anxieux. Ce travail de doctorat vient compléter les connaissances sur les dysfonctions du système dopaminergique mésolimbique induites par la nourriture riche en gras. Il met en lumière les effets différentiels des classes d‟acides gras et les mécanismes par lesquels ils modulent les comportements motivés et alimentaires. De façon chronique, avant l‟apparition d‟obésité et d‟altérations métaboliques, les acides gras saturés, et non les acides gras mono-insaturés, issus de l‟alimentation perturbent le fonctionnement de l‟axe hypothalamo-hypophysaire-surrénalien et réduisent la fonction dopaminergique. Ceci pourrait contribuer à perpétuer la recherche et la prise de ce type d‟acides gras afin de compenser ce déficit. / The mesolimbic dopamine system, also known as the reward system, is well recognized for its role in motivated reward-related behaviours such as drug addiction. It consists of dopamine neurons originating in the ventral tegmental area that project, among others, to the nucleus accumbens. Similar to neurons in the hypothalamus, dopamine neurons in the ventral tegmental area can detect circulating hormones such as leptin, insulin and ghrelin to adjust food intake, motivation and dopamine tone. This suggests that they could also perceive nutritional signals like glucose and fatty acids. Moreover, several lines of evidence exist showing that palatable food enriched in fat and obesity reduce mesolimbic dopamine function. Given the many unknowns regarding the mechanisms of obesity-induced dopamine dysfunction, and given that fatty acids differentially influence cardiovascular and mental health according to their class, we sought to determine the effects of the monounsaturated fatty acid oleic acid and the saturated fatty acid palmitic acid, two of the most abundant fatty acids in the body and foods, on mesolimbic dopamine function. Notably palmitic acid and oleic acid differ in their intracellular metabolic fate as well as in their effects on food intake and leptin and insulin signaling at the level of the hypothalamus. We first evaluated the fatty acid sensing properties of the mesolimbic dopamine system. We looked at the effects of the injection of oleic acid or palmitic acid in the ventral tegmental area on food intake, motivation and dopamine neurons activity. Our results demonstrate that oleic acid, but not palmitic acid, reduces basal and motivated feeding behavior and neuronal activity. Those effects seem to be dependent on its entry into the cell. Moreover, using a neurons culture system we show that dopamine neurons can uptake fatty acids. We then examined the effect of food-derived oleic and palmitic acid on mesolimbic dopamine function. We assigned rats to a low-fat control diet or to one or the other of a high-fat diet: one enriched in oleic acid or one enriched in palmitic acid. The two high-fat diets are isocaloric and differed only in the fat source. Following eight weeks of feeding, the palmitic 5 acid-enriched high-fat diet, but not the oleic acid-enriched diet, decreased the sensitivity to the rewarding and locomotor-sensitizing effects of amphetamine. This was associated with a reduction of dopamine receptor D1R signaling and dopamine transporter expression. Importantly this occured independently of weight gain and hormonal changes. Lastly, we explored the impact of those diets on the activity of the hypothalamus-pituitary-adrenal axis. Results show that the saturated fat diet alters the function of the axis as well as the expression of several keys genes targeted by glucocorticoids in the hypothalamus but without affecting anxiety-related behavior. This work provides further insight into how the mesolimbic dopamine system is altered by high-fat food consumption. It brings light to the differential effects of two classes of fatty acids and the mechanisms by which they modulate food intake and motivation. The prolonged intake of saturated fat, but not mono-unsaturated fat, disrupts the hypothalamus-pituitary-adrenal axis and decreases mesolimbic dopamine function prior to the onset of obesity and major metabolic alterations. Dysfunction of dopaminergic systems induced by saturated fat consumption could promote further intake of such palatable food as a means to compensate for reward hyposensitivity.

Les médicaments antipsychotiques améliorent les symptômes de la schizophrénie, mais peuvent perdre leur efficacité à long terme en sensibilisant le système dopaminergique. Les mécanismes sous-tendant cette sensibilisation ne sont pas connus. Le neuropeptide neurotensine module le système dopaminergique et est régulé par les antipsychotiques dans le noyau accumbens. Dans cette région, la neurotensine peut avoir des effets anti- et pro-dopaminergiques via les récepteurs NTS1. Nous avions pour hypothèse que la neurotensine du noyau accumbens module l’expression de la sensibilisation dopaminergique induite par les antipsychotiques. Ainsi, nous avons traité par intermittence ou continuellement des rats à l’antipsychotique halopéridol. Seule l’administration continue sensibilise le système dopaminergique et donc sensibilise aux effets locomoteurs de l’amphétamine. Des microinjections de neurotensine dans le noyau accumbens ont diminué l’hyperlocomotion induite par l’amphétamine chez les rats témoins et ceux traités par intermittence aux antipsychotiques. Au contraire, la sensibilisation dopaminergique induite par un traitement continu serait liée à une augmentation des effets pro-dopaminergiques de la neurotensine. Ceci est indépendant d’un changement de densité des récepteurs NTS1 dans le noyau accumbens. Un traitement intermittent n’a pas d’effet sur cette mesure également. De plus, autant un traitement antipsychotique continu qu’intermittent augmentent la transcription de proneurotensine. Donc, seule l’altération de la fonction de la neurotensine du noyau accumbens corrèle avec la sensibilisation dopaminergique. En parallèle, dans le caudé-putamen, un traitement continu augmente la transcription de proneurotensine et un traitement intermittent augmente la densité des récepteurs NTS1. En somme, la neurotensine du noyau accumbens module la sensibilisation dopaminergique induite par les antipsychotiques. / Antipsychotic medications improve schizophrenia symptoms, but they can also sensitize the dopamine system over time, consequently leading to impaired treatment efficacy. The mechanisms underlying antipsychotic-evoked dopamine supersensitivity are not known. The neuropeptide neurotensin regulates the dopamine system and can be modulated by antipsychotics, particularly in the nucleus accumbens. In this area, neurotensin has both anti- and pro-dopaminergic effects via an interaction with NTS1 receptors. In the present study, we hypothesized that neurotensin in the nucleus accumbens can modulate the expression of dopamine supersensitivity-evoked by an antipsychotic treatment. We treated rats with the antipsychotic haloperidol administered either intermittently or continuously. Continuous, but not intermittent, haloperidol treatment induces dopamine supersensitivity as shown by an increased locomotor activity induced by amphetamine. Microinjections of neurotensin in the nucleus accumbens diminish amphetamine-induced locomotion in control and intermittently antipsychotic-treated rats. Dopamine supersensitivity-evoked by a continuous antipsychotic treatment is linked to a potential enhancement of the pro-dopaminergic effects of neurotensin. This is not caused by any change in NTS1 receptor levels in the nucleus accumbens. An intermittent treatment did not alter NTS1 receptor levels as well in this area. Also, both continuous and intermittent treatment increased neurotensin transcription in the nucleus accumbens. Thus, only neurotensin altered function correlates with dopamine supersensitivity. In the caudate-putamen, continuous antipsychotic treatment increased neurotensin transcription, whereas intermittent treatment increased NTS1 receptor levels. In summary, neurotensin in the nucleus accumbens can modulate the expression of dopamine supersensitivity-evoked by antipsychotics.

O efeito ansiolítico dos benzodiazepínicos (BZDs) é reduzido depois da primeira exposição ao labirinto em cruz elevado (LCE). Várias hipóteses tem sido formuladas para explicar este fenômeno chamado one-trial tolerance (OTT), entretanto, nenhuma delas é conclusiva. No presente estudo, examinamos este fenômeno através da análise etofarmacológica de ratos submetidos ao LCE em duas sessões (T1 e T2), e do conteúdo de monoaminas presentes no córtex pré-frontal, amígdala, hipocampo e núcleo accumbens através da técnica de Cromatografia Líquida de Alta Pressão. Ratos machos Wistar foram tratados com salina ou midazolam (0,5 mg/Kg, i.p.) antes de T1 e T2 e imediatamente depois, seus encéfalos foram dissecados e as estruturas analisadas. Como controle à análise neuroquímica foram incluídos animais tratados com salina e não expostos ao LCE. A administração de midazolam antes de T1 promoveu efeito ansiolítico, aumentando a exploração dos braços abertos, porcentagem de entradas e tempo de permanência nos mesmos. Em T2 foi observado redução da exploração dos braços abertos em relação a T1. Esses resultados sugerem que há uma mudança no estado emocional do animal em T2, que é resistente a ação ansiolítica dos BZDs. Com relação aos resultados dos estudos neuroquímicos, foi observado redução dos conteúdos de serotonina (5- HT) e noradrenalina (NA) no córtex pré-frontal, na amígdala, no hipocampo e no núcleo accumbens depois de T1 e T2. Houve também, redução do conteúdo de dopamina (DA) na amígdala depois de ambas sessões. Não ocorreram mudanças nas taxas de renovação dessas monoaminas em nenhuma das estruturas analisadas. Através desses resultados, pode-se inferir que a estimulação aversiva do LCE causa alterações na neurotransmissão monoaminérgica da amígdala, como também das outras estruturas límbicas estudadas neste trabalho. Essas alterações neuroquímicas depois da primeira exposição ao LCE, devem representar alterações adaptativas na neurotransmissão do sistema límbico que podem estar associadas ao fenômeno da OTT. / Numerous reports have demonstrated that a single exposure to a variety of stressful experiences enhances fearful reactions when behavior is subsequently tested in current animal models of anxiety. Until now, no study has examined the neurochemical changes during the test and retest sessions of freely-behaving rats in the elevated plus-maze (EPM), one of the most traditional tests of anxiety. This work is a new approach looking at the changes in dopamine (DA), serotonin (5-HT) and noradrenaline (NA) levels in the prefrontal cortex, amygdala, hippocampus and nucleus accumbens during one-trial learning development. We used high pressure liquid chromatography to assess the concentrations of these neurotransmitters and their metabolites in animals injected with saline or midazolam upon single or double exposure to the EPM. For the biochemical analysis an extra control group treated with saline and not exposed to EPM was added. The data showed that stressful stimuli present in the maze were able to elicit one-trial learning to midazolam on re-exposure. Significant decreases in 5-HT and NA contents in the prefrontal cortex, amygdala, hippocampus and nucleus accumbens occurred in saline and midazolam injected animals submitted to the first and second trials. Significant decreases in DA content were also observed in the amygdala after both trials. There was no change in the turnover of these monoamines in any structure studied. It is suggested that aversive stimuli inherent to the EPM cause primary changes in the neurochemical mechanisms of the amygdala and also influence the activity of monoaminergic neurotransmission in the prefrontal cortex, hippocampus and nucleus accumbens. The observed reduction in monoaminergic transmission in limbic structures after the first stressful experience in the EPM seems to represent adaptive changes and may be associated to the phenomenon of ?one-trial tolerance?.