Les antipsychotiques sont administrés chroniquement pour prévenir de nouveaux épisodes psychotiques dans la schizophrénie. Ces médicaments diminuent l’activité des récepteurs dopaminergiques de type 2. Diminuer chroniquement la transmission dopaminergique induit des compensations pouvant mener à une sensibilisation du système dopaminergique. Cette sensibilisation pourrait diminuer l’efficacité des antipsychotiques et exacerber la psychose. Chez le rat, la sensibilisation dopaminergique induite par les antipsychotiques augmente les effets psychomoteurs et motivationnels des agonistes dopaminergiques. Le premier objectif de la présente thèse était de caractériser les substrats neuronaux régulant l’expression de la sensibilisation dopaminergique évoquée par les antipsychotiques. Ceci est important afin d’améliorer le traitement à long terme de la schizophrénie. Pour ce faire, des rats ont reçu un traitement cliniquement pertinent à l’antipsychotique halopéridol. Ce traitement sensibilise aux effets psychomoteurs de l’agoniste dopaminergique d-amphétamine. Cet indice comportemental de sensibilisation dopaminergique a été utilisé pour déterminer les contributions spécifiques du système dopaminergique et l’implication des effets centraux de la d-amphétamine. Puisqu’il y a une relation étroite entre le stress et l’activité dopaminergique, les réponses liées au stress ont également été mesurées. Ceci est important, puisque le stress exacerbe la psychose. La présente thèse démontre que les récepteurs dopaminergiques régulent de manière distincte la sensibilisation dopaminergique. En effet, la transmission via les récepteurs de type 2 exacerbe cette sensibilisation, alors que la transmission via les récepteurs de type 1 la tempère. Également, la présente thèse suggère que des processus périphériques sont nécessaires à l’expression de la sensibilisation dopaminergique. De plus, la sensibilisation pourrait augmenter les réponses au stress. En effet, cette sensibilisation est renversée lorsque la synthèse de l’hormone de stress corticostérone est inhibée, en plus d’être associée à certains comportements suggérant un stress augmenté. Chez le rat, la sensibilisation dopaminergique évoquée par les antipsychotiques potentialise également les effets motivationnels des stimuli conditionnés prédisant des récompenses. Lorsque ces stimuli acquièrent trop de valeur motivationnelle, ils peuvent motiver des comportements pathologiques. Ainsi, une potentialisation de la valeur motivationnelle des stimuli conditionnés provoquée par les antipsychotiques pourrait avoir des implications importantes dans des processus motivationnels anormaux dans la schizophrénie, tels que la psychose et la forte prévalence de toxicomanie. Ainsi, le deuxième objectif de la présente thèse était d’étudier les mécanismes neurobiologiques régulant les effets comportementaux des stimuli conditionnés, particulièrement le rôle du noyau basolatéral de l’amygdale. Ici, le rôle de ce noyau a été étudié chez des animaux non traités aux antipsychotiques, puisque sa contribution reste incomprise. Ce travail pourrait révéler des mécanismes neurobiologiques potentiellement impliqués dans la sensibilisation dopaminergique évoquée par les antipsychotiques. La présente thèse démontre que l’activation optogénétique de l’amygdale basolatérale potentialise les effets comportementaux des stimuli conditionnés, en augmentant leur valeur motivationnelle et leur capacité à guider le comportement vers des récompenses imminentes. Ainsi, une activité excessive de l’amygdale basolatérale pourrait attribuer trop de pouvoir aux stimuli conditionnés, et ceci pourrait jouer un rôle dans l’état motivationnel anormal provoqué par les antipsychotiques. La présente thèse identifie de nouveaux mécanismes par lesquels les antipsychotiques et les stimuli conditionnés favorisent des réponses pathologiques. / Schizophrenia requires long-term antipsychotic treatment to prevent psychosis relapse. Antipsychotic drugs temper psychotic symptoms by reducing dopamine D2 receptor-mediated signalling. Chronically decreasing dopamine transmission produces neuronal compensation leading to supersensitivity to dopamine stimulation. In patients, this dopamine supersensitivity would compromise antipsychotic efficacy and exacerbate psychotic symptoms. In laboratory animals, antipsychotic-evoked dopamine supersensitivity enhances the psychomotor and reward-enhancing effects of dopamine agonists. The first objective of the present thesis was to characterize the biological substrates mediating the expression of antipsychotic-evoked dopamine supersensitivity, a necessary work for developing better long-term treatment strategies. To do so, rats were chronically exposed to a clinically relevant antipsychotic treatment regimen, using the drug haloperidol. Haloperidol produces dopamine supersensitivity, as indicated by an exaggerated psychomotor response to the dopamine agonist d-amphetamine. This behavioural index of supersensitivity was used to examine the specific contributions of the dopamine system and the central effects of d-amphetamine. Given that there is a close relationship between stress and dopamine activity, it was also determined whether antipsychotic-evoked dopamine supersensitivity alters stress-like responses. This is important to consider because stress is a contributing factor to psychosis relapse. The present thesis first reveals that D1- and D2-mediated transmissions contribute distinctively to the expression of antipsychotic-evoked dopamine supersensitivity, with D2 transmission promoting this supersensitivity and D1 transmission tempering it. The present thesis also provides evidence that peripheral processes play a necessary role in dopamine supersensitivity. Additionally, antipsychotic-evoked dopamine supersensitivity could potentiate stress-like responses. Indeed, the expression of supersensitivity is reversed by inhibition of the synthesis of the stress hormone corticosterone and is linked with some signs of heightened stress-related behaviours. In rats, antipsychotic-evoked dopamine supersensitivity potentiates the incentive motivational effects of reward-predictive conditioned stimuli. When these stimuli acquire too much motivational value, they motivate maladaptive responses. Hence, the increased motivational value of conditioned stimuli elicited by antipsychotic exposure could be involved in impaired motivational processes found in schizophrenia, such as psychosis and the greater vulnerability to drug addiction. Thereby, the last goal of the present thesis was to investigate the neurobiological substrates mediating the behavioural effects of reward-predictive stimuli, with a special focus on the role of the basolateral nucleus of the amygdala. This was investigated in antipsychotic-naïve rats because there are important caveats in our current understanding of the functional role of the basolateral amygdala. Such investigation could give novel insights on the neurobiological effects of antipsychotic-evoked dopamine supersensitivity. Here it is shown that optogenetic stimulation of basolateral amygdala neurons potentiates the behavioural effects of conditioned stimuli, by increasing their motivational value and their ability to guide behaviour toward impending rewards. The implication for this is that excessive activity in the basolateral amygdala could attribute too much motivational power to conditioned stimuli, and this could be involved in the abnormal motivational state produced by antipsychotic drugs. Taken together, the present thesis provides novel mechanisms by which antipsychotic drugs and reward-predictive stimuli promote maladaptive responses.

Increases in basolateral amygdala (BLA) activity drive avoidance-seeking behavior that may be associated with stress induced drug seeking. Activity of BLA pyramidal neurons is regulated by local and paracapsular gamma aminobutyric acid (GABA) interneurons. The lateral paracapsular interneurons (LPCs) border the external capsule, receive dense cortical/thalamic input and provide feed-forward inhibition onto BLA principle neurons. The GABAergic LPCs also express high concentrations of g-protein coupled µ-opioid receptors (MORs). Therefore, the effects of opiates on LPC activity and local GABA release were examined. Fluorescently double labeled LPCs were observed in glutamate decarboxylase (GAD) 65-mcherry/GAD67-green fluorescent protein (GFP) transgenic mice. Whole-cell electrophysiology experiments demonstrated that acute exposure to [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO; a synthetic selective MOR agonist), reduced LPC firing and spontaneous inhibitory postsynaptic current (sIPSC) frequency in LPCs, with no apparent effect on spontaneous excitatory currents (sEPSCs). Current injection induced firing in LPC neurons, but less effectively than in saline controls. Morphine-exposed mice (10mg/kg/day, across 5 days, 1-2 days off) had increased sIPSCs compared to saline-injected controls, as well as enhanced adenylyl cyclase (AC) activity. Together these data show that LPC neurons are a highly sensitive targets for opiate-induced inhibition, and that long-term opiate exposure results in impaired LPC excitability, possibly contributing to anxiety observed during opiate withdrawal.

Indiana University-Purdue University Indianapolis (IUPUI) / Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder that affects roughly 1 in 3500 individuals. In addition to physical features (e.g., neurofibromas), developmental disorders are also common that can affect cognition, learning, attention and social function. The NF1 gene encodes neurofibromin, a GTPase activating protein (GAP)-like protein that negatively regulates Ras GTPase activation. Mutation at the NF1 locus increases the output of MAPK and PI3K signal transduction from the cellular membrane to the nucleus. Similar to humans, Nf1+/- mice show spatial learning abnormalities that are potentially correlated with increases in GABA-mediated inhibition and deficits in long-term potentiation in the hippocampus. Here, we demonstrate for the first time that Nf1+/- mice exhibit a selective loss of long-term social learning / memory and increased GABAergic inhibition in the basolateral amygdala, a critical brain region for regulating social behaviors. Next, utilizing a genetic intercross, we show that the co-deletion of p21-activated kinase type 1 (Pak1-/-), which positively regulates MAPK activation, restores Nf1+/--dependent MAPK hyperactivation in neurons cultured from the frontal cortex. We found that the co-deletion of Pak1 in Nf1+/- mice (Nf1+/- / Pak1-/-) also restores the deficits in long-term social learning / memory seen in Nf1+/- mice and normalizes the increases in GABA-mediated inhibition in the BLA, as compared to Nf1+/- mice. Together, these findings establish a role for Nf1 and Pak1 genes in the regulation of social learning in Nf1-deficient mice. Furthermore, proteomic studies identify dysregulation of F-actin and microtubule dynamics in the prefrontal cortex, and implicate proteins associated with vesicular release as well as neurite formation and outgrowth (e.g., LSAMP, STXBP1, DREB). In the BLA, disintegrin and metalloproteinase domain-containing protein 22 (ADAM22) was identified, and ADAM22 may play a role in the regulation of AMPA receptors. Finally, due to the increased co-occurrence of NF1 and autism, these findings may also have important implications for the pathology and treatment of NF1-related social deficits and some forms of autism.

Extensos dados na literatura têm assinalado a importância da serotonina (5-HT) na modulação de comportamentos de medo e ansiedade em roedores, a grande maioria utilizando ratos machos como sujeitos experimentais. No presente trabalho, foi analisada a influência da neurotransmissão 5-HT periférica e central sobre a expressão da resposta de medo condicionado e incondicionado de ratos machos e fêmeas, previamente selecionados pelo fenótipo como animais de baixa (BA) ou de alta (AA) reatividade emocional. Para este fim foi utilizado o teste do sobressalto potencializado pelo medo (SPM). A influência global e central de 5-HT foi avaliada pela utilização da administração sistêmica ou intraventricular aguda do inibidor irreversível da enzima triptofano hidroxilase PCPA (p-clorofenilalanina) nas doses de 200 mg/mL (i.p.) e 200 µg/5 µL (i.v.), ou através de infusões locais de 5-HT (10 nmol/0.2 µL) ou do agonista seletivo de receptores 5-HT1A 8-hidroxi-2-(di-n-propilamino)-tetralina (8-OH-DPAT) na dose de 0,3 µg/0.2 µL, diretamente em áreas encefálicas conhecidas por sua influência na modulação do medo e ansiedade a saber: o córtex pré-limbico (CPL), o núcleo basolateral da amígdala (BLA), e a substância cinzenta periaqueductal dorsal (SCPd) do mesencéfalo. As variáveis dependentes registradas foram a amplitude e a latência das respostas incondicionadas e condicionadas de sobressalto e a amplitude do SPM. / Extensive data in the literature have signaled the importance of serotonin (5-HT) on the modulation of fear and anxiety-like behaviors in rodents. In the present study, we have analyzed the influence of peripheral and central 5-HT neurotransmission on the expression of the conditioned and unconditioned fear, and on the fear-potentiated startle in male and female rats previously selected as low- (LA) or high-anxiety (HA). For this purpose, we used the fear-potentiated startle (FPS) test. The global and central influence of 5-HT was evaluated by using the acute systemic or intraventricular administration of the irreversible tryptophan hydroxylase inhibitor PCPA (p-chlorophenylalanine - 200 mg/mL i.p., or 200 µg/5 µL i.v.). Local effects were evaluated through local infusions of 5-HT itself (10 nmol/0.2 µL) or the selective 5-HT1A receptors agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT 0.3 µg/0.2 µL) in the prelimbic cortex (PrL), basolateral amygdala (BLA) or the dorsal periaqueductal gray (DPAG). These brain regions were chosen for the present study based on their great importance in the modulation and expression of conditioned and unconditioned fear. Dependent variables recorded were the amplitude and latency of unconditioned and conditioned fear, and fear-potentiated startle (FPS).

Extensos dados na literatura têm assinalado a importância da serotonina (5-HT) na modulação de comportamentos de medo e ansiedade em roedores, a grande maioria utilizando ratos machos como sujeitos experimentais. No presente trabalho, foi analisada a influência da neurotransmissão 5-HT periférica e central sobre a expressão da resposta de medo condicionado e incondicionado de ratos machos e fêmeas, previamente selecionados pelo fenótipo como animais de baixa (BA) ou de alta (AA) reatividade emocional. Para este fim foi utilizado o teste do sobressalto potencializado pelo medo (SPM). A influência global e central de 5-HT foi avaliada pela utilização da administração sistêmica ou intraventricular aguda do inibidor irreversível da enzima triptofano hidroxilase PCPA (p-clorofenilalanina) nas doses de 200 mg/mL (i.p.) e 200 µg/5 µL (i.v.), ou através de infusões locais de 5-HT (10 nmol/0.2 µL) ou do agonista seletivo de receptores 5-HT1A 8-hidroxi-2-(di-n-propilamino)-tetralina (8-OH-DPAT) na dose de 0,3 µg/0.2 µL, diretamente em áreas encefálicas conhecidas por sua influência na modulação do medo e ansiedade a saber: o córtex pré-limbico (CPL), o núcleo basolateral da amígdala (BLA), e a substância cinzenta periaqueductal dorsal (SCPd) do mesencéfalo. As variáveis dependentes registradas foram a amplitude e a latência das respostas incondicionadas e condicionadas de sobressalto e a amplitude do SPM. / Extensive data in the literature have signaled the importance of serotonin (5-HT) on the modulation of fear and anxiety-like behaviors in rodents. In the present study, we have analyzed the influence of peripheral and central 5-HT neurotransmission on the expression of the conditioned and unconditioned fear, and on the fear-potentiated startle in male and female rats previously selected as low- (LA) or high-anxiety (HA). For this purpose, we used the fear-potentiated startle (FPS) test. The global and central influence of 5-HT was evaluated by using the acute systemic or intraventricular administration of the irreversible tryptophan hydroxylase inhibitor PCPA (p-chlorophenylalanine - 200 mg/mL i.p., or 200 µg/5 µL i.v.). Local effects were evaluated through local infusions of 5-HT itself (10 nmol/0.2 µL) or the selective 5-HT1A receptors agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT 0.3 µg/0.2 µL) in the prelimbic cortex (PrL), basolateral amygdala (BLA) or the dorsal periaqueductal gray (DPAG). These brain regions were chosen for the present study based on their great importance in the modulation and expression of conditioned and unconditioned fear. Dependent variables recorded were the amplitude and latency of unconditioned and conditioned fear, and fear-potentiated startle (FPS).

Bien que la neurotransmission glutamatergique joue un rôle pivot dans le développement et l’expression de la sensibilisation comportementale aux amphétamines, le rôle spécifique de certaines structures glutamatergiques qui projettent sur l’aire tegmentale ventrale et/ou le noyau accumbens n’est pas encore bien caractérisé. Nous montrons que l’hippocampe dorsal, la partie prélimbique du cortex préfrontal et l’amygdale basolatérale joue un rôle prépondérant dans les réponses locomotrices induites par l’administration aiguë (développement de la sensibilisation) et chronique (expression de la sensibilisation) d’amphétamines, suggérant les réponses locomotrices aux amphétamines impliquent un ensemble de structures glutamatergiques corticolimbiques. Par la suite, nous nous sommes intéressés au rôle de la neurotransmission glutamatergique associée aux récepteurs NMDA dans le noyau accumbens, qui est considéré comme le noyau clé de l’expression de la sensibilisation, sur le développement à court terme de la sensibilisation aux amphétamines. De plus, nous montrons le développement de la sensibilisation à court terme aux amphétamines requiert l’activation concomitante de certains récepteurs NMDA au glutamate et nicotiniques à l’acétylcholine dans le noyau accumbens. De plus, l’activation concomitante de ces récepteurs sous tend également la libération de dopamine induite par les amphétamines dans le noyau accumbens. L’ensemble de ces données montre que la neurotransmission glutamatergique, et les structures glutamatergiques qui projettent sur l’aire tegmentale ventrale et/ou le noyau accumbens, joue un rôle majeur dans la sensibilisation comportementale à court terme aux amphétamines. / Although it is well admitted that the glutamatergic neurotransmission plays a pivotal role in the development and expression of behavioral sensitization to amphetamine, the specific role of glutamatergic structures that project to the ventral tegmental and/or the nucleus accumbens is less well studied. We showed that the dorsal hippocampus, the prelimbic part of the prefrontal cortex and the basolateral amygdala play a critical role in both acute (development of sensitization) and chronic (expression of sensitization) locomotor responses induced by amphetamine, suggesting that behavioral responses to amphetamine are mediated by circuitry of corticolimbic glutamatergic structures. Next, we investigated the role of glutamatergic NMDA receptors contained in the nucleus accumbens, which is seen as the key structure for the expression of sensitization, in the development of short term sensitization to amphetamine. Interestingly, we showed that, contrasting with the current dichotomous thinking that has attributed specialized functions to the ventral tegmental area and the nucleus accumbens, respectively in the development and the expression of behavioral sensitization, concomitant activation of certain types of NMDA and nicotinic receptors in the nucleus accumbens is also required for the development of short term sensitization. Furthermore, we showed that concomitant activation of these receptors sustained the amphetamine-induced dopamine release in the nucleus accumbens. All these data show that glutamatergic neurotransmission, and glutamatergic structures which project onto mésoaccumbens system, plays a major role in short-term behavioral sensitization to amphetamine.

La maladie de Parkinson est caractérisée par la manifestation de symptômes moteursprincipalement dus à la dégénérescence du système dopaminergique. Malgré l'accent mis surles déficits moteurs, la maladie de Parkinson est également caractérisée par des symptômesnon moteurs, incluant l'anxiété et la dépression, qui sont sous-étudiés et de ce fait pas bientraités. Alors que certaines études cliniques ont suggéré que l'anxiété et la dépressionpourraient être associées à la dégénérescence des neurones dopaminergiques, d'autres ontsuggéré l'implication de la dégénérescence des neurones noradrénergiques etsérotoninergiques dans les troubles observés mais également dans les effets induits par laLévodopa et la stimulation cérébrale profonde du noyau sous-thalamique.Dans un premier temps, nous avons étudié le rôle respectif de la dopamine, de lanoradrénaline et de la sérotonine dans la manifestation des déficits parkinsoniens moteurs etnon moteurs chez le rat. L’ensemble de nos résultats démontre que malgré l’importance dusystème dopaminergique, la perturbation des trois systèmes monoaminergiques joue un rôleimportant à la fois dans la manifestation des troubles moteurs et non moteurs.Nous avons également étudier l’impact des monoamines sur l’efficacité des traitementsantiparkinsoniens, à savoir, la Lévodopa et la stimulation cérébrale profonde du noyau sousthalamique,sur les troubles observés. Nos résultats montrent que la déplétion combinée dessystèmes monoaminergiques peut altérer l’efficacité de la Lévodopa ainsi que de lastimulation cérébrale profonde sur certains troubles. Ces résultats peuvent expliquer lemanque d’efficacité des traitements antiparkinsoniens chez certains patients et la difficulté àtraiter tous les symptômes.Pour finir, nous avons voulu mettre en évidence le lien entre le noyau sous-thalamique,structure excitatrice des ganglions de la base et les troubles moteurs, ainsi que l’amygdalebasolatérale et l’habénula latérale, structures impliquées dans les comportements émotionnels,et les troubles non moteurs. Nous avons mis en évidence le parallèle existant entre lesmodifications du mode de décharge des neurones du NST et les troubles moteurs, leschangements de l’amygdale basolatérale et les troubles anxieux ainsi que ceux de l’habénulalatérale et les troubles dépressifs.Les résultats de ces travaux de thèse ont donc permis d’apporter de nouvelles évidences surl’implication des trois systèmes monoaminergiques dans la physiopathologie et la thérapie dela maladie de Parkinson. / Parkinson’s disease is characterized by the manifestation of motor symptoms mostlyassociated with the degeneration of dopaminergic neurons. While Parkinson’s disease is oftenfocused on motor deficits, the disease is also characterized by non-motor deficits, includinganxiety and depression, which are under studied and consequently are not well treated.Whereas some clinical studies suggested that anxiety and depression could be linked to thedegeneration of dopaminergic neurons, others suggested the involvement of norepinephrineand serotonin in the observed symptoms and also in the efficacy of Levodopa and deep brainstimulation of the subthalamic nucleus.In a first time, we investigated the respective role of the neuronal degeneration of dopamine,noradrenaline and serotonin in the manifestation of motor and non-motor parkinsonian-likedisorders in the rat. Our results demonstrate that despite the importance of the dopaminergicsystem, the disturbances in the three-monoaminergic systems play a key role in themanifestation of motor and non-motor deficits.In a second time, we studied the impact of monoamine depletions on the efficacy ofantiparkinsonian treatments, the Levodopa and deep brain stimulation of the subthalamicnucleus. Our results showed that the combined depletions could deteriorate the efficacy of theLevodopa and of the deep brain stimulation on some deficits. Together, these results canexplain the lack of efficacy of the antiparkinsonian treatments in some patients and thedifficulty to treat all the symptoms.Finally, we investigated the link between the subthalamic nucleus, which is an excitatorystructure of the basal ganglia, and the motor deficits, as well as the involvement of thebasolateral amygdala and the lateral habenula in emotional control of the behavior, and nonmotordeficits. We showed the parallel between changes in the neuronal activity of thesubthalamic nucleus and the motor deficits, of the basolateral amygdala and anxiety and ofthe lateral habenula and depression.Results from this thesis provide new evidences on the involvement of the threemonoaminergicsystems in the pathophysiology and the therapy of Parkinson’s disease.

Les stimuli conditionnés (CS) guident les animaux vers des récompenses essentielles à leur survie, telle que la quête de nourriture et d'eau. Ils peuvent également promouvoir la poursuite excessive de récompense, comme dans l’addiction. La transmission glutamatergique dans l’amygdale basolatérale (BLA) régule les effets des CS. Cependant, le rôle des récepteurs glutamatergiques métabotropes du groupe II (mGlu2/3) de la BLA est inconnu. Les mGlu2/3 sont principalement localisés au niveau extrasynaptique sur les terminaisons neuronales. L’activation de ces récepteurs diminue la libération synaptique de glutamate. Ainsi, nous avons émis l’hypothèse que l'activation des mGlu2/3 dans la BLA diminue la capacité des CS à potentialiser la recherche de récompense via la réduction de la libération de glutamate. La méthode de transfert Pavlovien-à-instrumental (PIT) a été utilisée pour tester cette hypothèse. Nous avons d'abord confirmé un effet PIT chez des rats mâles. Les rats ont initialement appris à appuyer sur un levier pour obtenir de l’eau comme récompense. Ils ont ensuite appris qu'un stimulus auditif (CS+) prédit la livraison non-contingente d'eau, tandis qu’un stimulus auditif différent (CS-) ne signale aucune récompense. Le jour du test PIT, les rats ont pu appuyer sur le levier sous extinction (eau omise) et nous avons évalué l’influence des CS+ et CS- sur ce comportement. Les rats ont appuyé davantage sur le levier pendant le CS+ comparé au CS-, indiquant que le CS+ incite les rats à rechercher la récompense. Chez un nouveau groupe de rats mâles, les mêmes méthodes ont été appliquées avec un agoniste des mGlu2/3, le LY379268 (0, 3 ou 6 μg/hémisphère) injecté dans la BLA avant le test PIT. Le LY379268 a diminué la capacité du CS+ à inciter l’appui sur le levier. Dans une dernière étude, nous avons examiné l’influence d’une administration systémique de LY379268 (0, 0.3 ou 1 mg/kg, sous-cutanée) sur l’effet PIT chez un groupe de rats mâles et femelles. Les effets motivationnels du CS+ sur la recherche de récompense étaient similaires entre les rats mâles et femelles. De plus, l’injection systémique de LY379268 a diminué ces effets chez les deux sexes. Ces résultats indiquent que les mGlu2/3 régulent les propriétés motivationnelles des CS chez les deux sexes. / Conditioned stimuli (CS) guide animals towards rewards needed for survival, such as food and water. In parallel, they can also promote maladaptive reward seeking, as in addiction. Glutamate signaling within the basolateral amygdala (BLA) modulates the effects of cues. However, the role of metabotropic group II glutamate (mGlu2/3) receptors in the BLA is unknown. mGlu2/3 are localized predominantly extrasynaptically on presynaptic terminals. The activation of these receptors suppresses synaptic glutamate release. Thus, we hypothesized that activating BLA mGlu2/3 receptors would attenuate cue-triggered increases in incentive motivation for reward, via reduced glutamate release. The Pavlovian-to-Instrumental transfer (PIT) method was used to test this hypothesis. We first confirmed a PIT effect in a cohort of male rats. Rats initially learned to press a lever to obtain a water reward. Then, they learned that one auditory cue predicts noncontingent delivery of water (CS+), while a second different auditory cue does not (CS-). On PIT test day, the rats could lever press under extinction (water deliveries omitted), and we assessed changes in lever pressing in response to CS+ and CS-. The rats pressed more on the lever during CS+ versus CS-, indicating cue-triggered potentiation of incentive motivation. In a separate cohort of male rats, the methods were repeated with the mGlu2/3 agonist LY379268 (0, 3 or 6 μg/hemisphere) infused into the BLA prior to PIT testing. LY379268 abolished CS+ potentiated pressing on the water-associated lever. In a last study, we examined the influence of systemic administration of LY379268 (0, 0.3 or 1 mg/kg, subcutaneous) on PIT, in a cohort of female and male rats. We found that cue-triggered increases in incentive motivation was similar across sexes, and that systemic injection of LY379268 decreased this effect in both sexes. These results indicate that mGlu2/3 receptors mediate the motivational effects of cues in both sexes.

很多行為的建構基礎是來自酬賞動機，而個體的行為表現通常是動態的歷程，其中對酬賞物的“價值”比較，是決定行為是否輸出或輸出多少的重要關鍵。在鼠類的動物行為模式中，可以利用甜液舔飲來進行這種對比(contrast)歷程的實驗。在受試可先後獲得兩次舔飲機會的實驗情境中，若兩管濃度皆為4%的蔗糖液先後間隔特定時距出現，受試會隨訓練天數增加而增加對兩管糖液的舔飲表現。若第一管4%蔗糖液之後會呈現濃度較高的32%蔗糖液，受試舔飲第一管同為濃度4%蔗糖液的表現會隨訓練天數增加而先增後減。這兩組受試對第一管糖液的舔飲量差異，即稱為預期性對比效果。一般認為此現象是受試等待與預期較高酬賞價值的糖液，而抑制當前較低酬賞價值糖液的舔飲。過去對此現象的研究主要關注在行為層面的探討，然而其相關神經機制的研究並不多，本研究的目的即在於探討與習得或形成預期性對比行為有關的神經機制。一般認為預期性對比效果的習得包含多階段的歷程，可能與多種心理行為面向有關，因此很有可能是經由多元性的神經機制參與。預期性對比效果的形成與否與兩糖液呈現的間距長短有很大的關係。本研究實驗一以0.5分鐘、2分鐘以及6分鐘三個不同的糖液間距引發的預期對比效果，從當中選取可有效形成預期性對比效果的0.5分鐘為實驗二糖液間距的依據。實驗二分別以興奮性神經毒素破壞依核核心區、眶前額皮質區以及杏仁體基側核區等三個神經區域。結果顯示杏仁核基側核區破壞不影響預期性對比效果的習得，而依核核心區以及眶前額皮質的破壞使受試無法習得預期性對比效果。綜合以上結果，預期性對比效果的習得是依靠有效的糖液呈現間距去進行酬賞比較，腦中依核核心區及眶前額皮質區與該種對比有關。 / Many types of behavior are constructed on the basis of reward motivation, which can be run in dynamic processes. Among those processes potentially involved, the reward comparison is a key determinant for the magnitude of behavioral output. The licking of sweet solution in the rat can be used as an animal model to investigate the contrast effect derived from reward comparison. In which, the subjects presented two sweet solutions in a sequential order each day may suppress intake of the first solution if the second solution is preferred. This phenomenon is termed anticipatory contrast effect (ACE). It is hypothesized that ACE could be built via an inhibition process associated with subject’s waiting for a preferred solution as presented by a less preferred solution. Most of the previous studies were mainly focused on the behavioral aspects of ACE. The present study intended to investigate the neural mechanisms of ACE. In considering that the formation of ACE requires multiple-stage processes, this study presumed that more than one brain area could be involved in mediating those psycho-behavioral processes. Experiment 1 was intended to establish behavioral model by manipulating the effectiveness of different inter-solution interval (ISI; 0.5, 2.0, and 6.0 min). The results showed that the ISI of 0.5 min is the critical parameters for the successful formation of ACE, which was then applied in Experiment 2. Experiment 2 investigated the effects of excitotoxin lesion conducted by ibotenic acid in the nucleus accumbens core (NACc), orbitofrontal cortex (OFC) or basolateral amygdala (BLA) on the acquisition of ACE. The result showed the rats with NACc or OFC lesion significantly failed to acquire ACE, but no such impairment appeared to BLA lesion. Together, these data suggest that the formation of ACE is depended upon the ISI leading to an effective reward comparison, and the NACc or OFC is involved in such a contrast processing.

Ciliary neurotrophic factor (CNTF) is produced by astrocytes which have been implicated in regulating stress responses. We found that CNTF in the medial amygdala (MeA) promotes despair or passive coping, i.e., immobility in an acute forced swim stress, in female mice, while having no effect in males. Neutralizing CNTF antibody injected into the MeA of wildtype females reduced activation of downstream STAT3 (Y705) 24 and 48 h later. In concert, the antibody reduced immobility in the swim test in females and only after MeA injection, but not when injected in the central or basolateral amygdala. Antibody injected into the male MeA did not affect immobility. These data reveal a unique role of CNTF in female MeA in promoting despair or passive coping behavior. Moreover, 4 weeks of chronic unpredictable stress (CUS) increased immobility in the swim test and reduced sucrose preference in wildtype CNTF+/+, but not CNTF-/- littermate, females. Following CUS, 10 min of restraint stress increased plasma corticosterone levels only in CNTF+/+ females. In males, the CUS effects were present in both genotypes. Further, CUS increased CNTF expression in the MeA of female, but not male, mice. CUS did not alter CNTF in the female hippocampus, hypothalamus and bed nucleus of stria terminalis. This suggests that MeA CNTF has a female-specific role in promoting CUS-induced despair or passive coping, behavioral anhedonia and neuroendocrine responses. Compared to CNTF+/+ mice, CNTF-/- mice did not show differences in CUS-induced anxiety-like behavior and sensorimotor gating function as measured by elevated T-Maze, open field and pre-pulse inhibition of the acoustic startle response. Together, this study reveals a novel CNTF-mediated female-specific mechanism in stress responses and points to opportunities for developing treatments for stress-related disorders in women.