The basal ganglia (BG) are a group of nuclei in the basal forebrain critical in movement, goal directed behaviour and action selection. Cortical projections to the largest BG nucleus, the striatum, are highly important in theories of BG function. Therefore, we have investigated the role of striatal neurons in modulating the activity of corticostriatal synapses. In an in-vitro preparation of rodent brain slices, we conducted whole-cell patch clamp recordings of single and pairs of striatal neurons and recorded responses of medium spiny neurons (MSNs) to stimulation of corticostriatal fibres. In the presence of opioid, GABAA, NK1 and cholinergic receptor antagonists, antidromic stimulation of a population of MSNs (5 stims, 50 Hz) caused suppression of subsequently evoked EPSPs in MSNs. This suppression was dependent upon the interval between antidromic MSN stimulation and the stimulation of evoked EPSPs; suppression was larger at 500 ms intervals than at 1 or 2 s intervals. These effects were completely blocked by the GABAB antagonist CGP 52432. Bursts of evoked action potentials (5 APs, 50 Hz) in a single MSN were insufficient to cause these effects in a nearby MSN. Similar spikes in single fast spiking interneurons and low threshold spiking interneurons (LTSIs) were also insufficient. Conversely, single neurogliaform interneurons (NGFIs) could suppress evoked EPSPs in nearby MSNs in a GABAB-dependent manner. This suppression was more likely in NGFI-MSN pairs that exhibited direct GABAergic interactions. We also tested long depolarisations in LTSIs, a protocol that preferentially releases NO, which was shown to suppress evoked EPSPs through a non-GABAergic mechanism. Finally, we tested the application of exogenous NPY to slices, which also inhibited corticostriatal transmission. These results provide the first demonstration of how GABAB receptors at corticostriatal synapses are activated by endogenous GABA released by striatal neurons. They also reveal novel mechanisms through which striatal factors influence these synapses.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-01-13T12:57:19Z No. of bitstreams: 1 IvaniBrys_TESE.pdf: 3588483 bytes, checksum: 5c0061be283212e032029bd78a38bd8c (MD5) / Approved for entry into archive by Elisangela Moura (lilaalves@gmail.com) on 2016-01-15T14:47:46Z (GMT) No. of bitstreams: 1 IvaniBrys_TESE.pdf: 3588483 bytes, checksum: 5c0061be283212e032029bd78a38bd8c (MD5) / Made available in DSpace on 2016-01-15T14:47:46Z (GMT). No. of bitstreams: 1 IvaniBrys_TESE.pdf: 3588483 bytes, checksum: 5c0061be283212e032029bd78a38bd8c (MD5) Previous issue date: 2014-09-26 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico - CNPq / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / A Doen?a de Parkinson (DP) est? associada a sintomas motores e ? perda de neur?nios dopamin?rgicos na via nigroestriatal. A prote?na alfa-sinucle?na ? o principal componente dos corpos de Lewy, marcadores biol?gicos da doen?a, e tem sido associada a casos de Parkinson heredit?rio. Recentemente, a estimula??o da medula espinhal (EME) tem se mostrado um m?todo de neuromodula??o efetivo em aliviar os sintomas parkinsonianos em modelos animais e pacientes humanos da DP. Nesse projeto, caracterizamos os efeitos motores e eletrofisiol?gicos da express?o de alfa-sinucle?na na subst?ncia nigra de ratos. Al?m disso, investigamos os efeitos da administra??o de AMPT, L-dopa e da aplica??o de EME nesse modelo. M?todo: Ratos Sprague-Dawley receberam inje??o unilateral de vetor viral vazio ou para expressar alfa-sinucle?na na subst?ncia nigra e foram avaliados semanalmente na tarefa do campo aberto e do cilindro. Um grupo separado de animais implantados com matrizes bilaterais de eletrodos no c?rtex motor e no estriado foram registrados semanalmente no campo aberto, durante as sess?es de EME e nos experimentos farmacol?gicos. Resultados: A express?o de alfa-sinucle?na resultou em assimetria motora, observada na redu??o do uso da pata contralateral na tarefa do cilindro. Os animais apresentaram aumento da atividade de potencial de campo local estriatal em beta ap?s tr?s e quatro semanas de express?o de alfa-sinucle?na, que desapareceu a partir da quinta semana. A administra??o de AMPT resultou em um quadro parkinsoniano severo, com redu??o da atividade locomotora e significativo aparecimento do pico de atividade oscilat?ria em beta no estriado e no cortex desse modelo. A EME mostrou-se efetiva em aliviar a assimetria motora em longo prazo, mas n?o reduziu as oscila??es corticostriatais de baixa frequ?ncia observadas 24 hs ap?s a administra??o de AMPT. Essas oscila??es foram atenuadas pela administra??o de L-dopa que, de forma semelhante ? EME, n?o foi efetiva em restaurar a atividade locomotora dos animais durante esse quadro de deple??o severa de dopamina. Discuss?o: O modelo alfa-sinucle?na da DP reproduz o preju?zo motor e a condi??o progressiva do processo neurodegenerativo. N?s demonstramos, pela primeira vez, que esse modelo apresenta tamb?m aumento da atividade corticostriatal oscilat?ria na banda beta compat?vel com as caracter?sticas da doen?a e que a EME tem efeito terap?utico sobre o sintoma motor desse modelo. / Parkinson disease (PD) is associated with motor symptoms and dopaminergic cell loss in the nigrostriatal pathway. Alpha-synuclein is the major component of the Lewy bodies, the biological hallmarks of disease, and has been associated with familial cases of PD. Recently, the spinal cord stimulation (SCS) showed to be effective to alleviate the Parkinson symptoms in animal models and human patients. In this project, we characterized the motor and electrophysiological effects of alpha-synuclein overexpression in the substantia nigra of rats. We further investigated the effects of spinal electrical stimulation, AMPT and L-dopa administration in this model. Method: Sprague-Dawley rats were injected with empty viral vector or the vector carrying the gene for alpha-synuclein in the substantia nigra, and were tested weekly for 10 weeks in the open field and cylinder tests. A separated group of animals implanted with bilateral electrode arrays in the motor cortex and the striatum were recorded in the open field, during the SCS sessions and the pharmacological experiments. Results: Alpha-synuclein expression resulted in motor asymmetry, observed as the reduction in use of contralateral forepaw in the cylinder test. Animals showed an increase of local field potential activity in beta band three and four weeks after the virus injection, that was not evident after the 5th week. AMPT resulted in a sever parkinsonian state, with reduction in the locomotor activity and significant peak of oscillatory activity in cortex and striatum. SCS was effective to alleviate the motor asymmetry at long term, but did not reduce the corticostriatal low frequency oscillations observed 24 hs after the AMPT administration. These oscillations were attenuated by L-dopa that, even as SCS, was not effective to restore the locomotor activity during the severe dopaminergic depletion period. Discussion: The alpha-synuclein model reproduces the motor impairment and the progressive neurodegenerative process of PD. We demonstrated, by the first time, that this model also presents the increase in low frequency oscillatory activity in the corticostriatal circuit, compatible with parkinsonian condition; and that SCS has a therapeutic effect on motor symptom of this model.

<p>The development of alcohol use disorder (AUD) is believed to involve functional adaptations in corticostriatal projections which regulate the reinforcing properties of ethanol (EtOH). To further our understanding of how repeated EtOH consumption impacts the corticostriatal circuit, extracellular electrophysiological recordings (local field potentials; LFPs) were gathered from the nucleus accumbens and prefrontal cortex of female and male C57BL/6J mice voluntarily consuming EtOH or water using ‘drinking-in-the-dark’ (DID) procedures. Mice were given 15 consecutive days of two-hours of access to EtOH (20% v/v), three hours into the dark cycle while LFPs were recorded. To determine the impact of repeated EtOH consumption on neural activity between these brain regions, theta phase-locking value (PLV, a measure of synchrony) was calculated. Specifically, theta PLV was calculated during active drinking periods (bouts) and average PLV during the first bout was compared to the last bout to determine within session changes in synchrony. Results indicated significantly lower PLV during the last bout than the first bout. Additionally, longer bouts predicted lower PLV during the last bout, but not the first bout when mice were consuming EtOH. These results may suggest that alcohol intoxication decreases corticostriatal synchrony over a drinking period. Results considering changes in theta power spectral density (PSD) indicated an increase in PSD when mice were given access to water during the typical EtOH access time following the 15-day EtOH drinking history. This effect was not seen when mice were drinking water prior to EtOH access and may be indicative of a successive negative contrast effect. This work identifies unique functional characteristics of corticostriatal communication associated with binge-like EtOH intake and sets the stage for identifying the biological mechanisms subserving them.</p>

Alcohol use disorder (AUD) is a chronic, relapsing condition with a complex etiology and heritable susceptibility factors interact with environmental factors to produce and maintain the disease. One goal of current neuroscience research is to identify the neuroadaptations mediating the propensity to consume high amounts of alcohol, of either innate or environmental origin. Dysfunctional neuronal communication between prefrontal cortical regions and the nucleus accumbens (NAcc) have been implicated in excessive alcohol drinking and proposed to play a critical role in AUD. However, the exact mechanism by which altered prefrontostriatal transmission may perpetuate excessive drinking is poorly understood. In addition, the exact role of dopamine receptor 1 (D1R) or dopamine receptor 2 (D2R)-expressing medium spiny neurons in the NAcc is unclear and adds another layer of complexity to this framework. This thesis concerns pituitary adenylate cyclase-activating polypeptide (PACAP), a highly conserved 38 amino acid neuropeptide, and its receptor PAC1R. Studies in rodents and humans have implicated PACAP and PAC1R in the actions of drugs of abuse, including more recently, alcohol. Notably, the PACAP/PAC1R system has also been shown to increase glutamatergic neurotransmission in several circuits. The overall hypothesis of this project was that the PACAP/PAC1 system in the prefrontal cortex-NAcc pathway regulates excessive drinking and the long-lasting neuroplastic changes observed in alcohol addiction, via the modulation of the glutamatergic system. Using alcohol-preferring rats, a hereditary model of AUD, we found that intracerebroventricular administration of a PAC1R antagonist blocked excessive alcohol drinking, motivation to drink, and alcohol seeking behavior selectively in this line and not in outbred rats. Alcohol-preferring rats displayed a higher number of PAC1R positive cells in the NAcc Core. Blockade of PAC1R in the NAcc Core, via pharmacology or gene knockdown, resulted in reduced alcohol drinking. Conversely, we found that knockdown of the PAC1R in the NAcc Shell led to increased alcohol drinking and motivation to drink in alcohol-preferring rats, suggesting that the PACAP/PAC1R system may play an opposite role in these two NAcc subregions. Using a mouse exposure model of excessive drinking, a glutamatergic projection from PACAP-expressing cells in the prelimbic portion of the prefrontal cortex (PrL) to the NAcc Core circuit was found to be recruited by alcohol exposure. Inhibition of these neurons, as well as PACAP neuron ablation or PACAP deletion, led to decreased alcohol intake that was specific to male mice. Systemic PAC1R antagonism, and specific knockdown of PAC1R in the NAcc Core, also decreased alcohol intake in male mice. Using slice electrophysiology and channelrhodopsin assisted circuit mapping, we found that this pathway is biased to D1R-expressing neurons in the NAcc Core following alcohol exposure in males, and that PACAP application increases post-synaptic measures of glutamatergic transmission in this circuit. Overall, these data describe a key role for the corticostriatal PACAP/PAC1R system in aberrant alcohol drinking in both hereditary- and exposure-based models of AUD and give novel insights into the underlying mechanisms of alcohol addiction. / 2025-01-23T00:00:00Z

The overall aim of the current research was to investigate the corticostriatal system in developmental language impairment (DLI) at the behavioral and neuroanatomical levels. Two groups of young adults, one with DLI (N = 25) and the other without (N = 23), participated in the behavioral study. A sample of procedural learning and reinforcement learning (RL) tasks was selected. Each task represents a unique aspect of procedural memory, and learning processes during these tasks have been linked, at least partially, to the functionality of the corticostriatal system. Findings showed that individuals with DLI demonstrated relatively poor performance on different aspects of procedural learning and on RL. Correlation results provide further evidence for a close relationship between individual differences in implicit learning and individual differences in language. These results implicate an abnormal corticostriatal system in DLI. In the structural imaging study, two subgroups of participants from the first study, one with DLI (n = 10) and the other without (n = 10), were matched on age, gender, and handedness. Conventional magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were used to investigate the subcortical components of the corticostriatal system in individuals with DLI. Results showed pathological enlargement in the bilateral putamen, the right globus pallidus, and the bilateral nucleus accumbens of individuals with DLI. In addition, the DLI group revealed decreased FA in the globus pallidus and in the thalamus, indicating abnormal white matter integrity in the two subcortical regions. These imaging results underpin the behavioral results, showing corticostriatal abnormalities in DLI at both macrostructural and microstructural levels. In addition to subcortical regions, the four cerebral lobes were also included for an exploratory analysis. Findings showed that individuals with DLI had global diffusion abnormalities in cerebral white matters in the absence of volumetric alterations, and these abnormalities were closely associated with impaired language performance. The results support a role of white matter integrity in language function. In conclusion, individuals with DLI have an abnormal corticostriatal system, which may lead to compromise of a wide variety of cognitive learning, including procedural learning, RL, and certain aspects of language learning.

Long-term potentiation (LTP) and depression (LTD) are activity dependent long-lasting changes in synaptic efficacy and have been proposed as mechanisms for learning and memory. Although the exact relationship of LTP and LTD to memory is not known, they do share some properties and mechanisms that relate to memory, such as the strengthening and weakening of synapses. LTP and LTD have been studied extensively in hippocampal brain-slice preparations, due to its relatively organized structure, ease of induction, and its critical function in memory storage. Less work has been done in the neocortex despite the belief that it is heavily involved in the storage of long-term memories. Activity dependent plasticity has also been demonstrated in the basal ganglia in vivo and in vitro, but the results have been somewhat inconsistent. The experiments presented in this thesis explore a novel form of neural plasticity in two excitatory pathways (corticostriatal and thalamocortical) of the basal ganglia motor loop in the intact brain in awake, freely behaving rats. In thalamocortical slice preparations, simultaneous presynaptic stimulation and postsynaptic depolarization can induce L TP in animals prior to the critical period. However the results presented in this thesis show that applied stimulation to the thalamocortical pathway failed to produce either LTP or LTD in the awake freely moving animal.Corticostriatal LTD has been shown in slice preparations following direct tetanic stimulation of the striatum. In the current experiment, cortical stimulation failed to induce LTD although there was an observable decrease in the evoked potential following low-frequency stimulation. Corticostriatal L TP has been shown to depend on the type of stimulation applied. High-frequency and theta burst stimulation produced long-lasting changes in response amplitude in the corticostriatal pathway, with theta burst stimulation appearing to be the more effective stimulation protocol for inducing LTP in both the early and late components. Paired stimulation of the substantia nigra pars compacta and cortex indicated a modulatory action of dopamine on corticostriatal synaptic plasticity. Pairing led to a stable increase in the amplitude of LTP of both early and late components. We also report that a temporal relationship exists in the striatum with respect to the release of nigral dopamine and cortical glutamate. Simultaneous stimulation produced a more robust L TP compared to the two other conditions in which there was an applied stimulation delay to either the corticostriatal or nigrostriatal pathway. The results demonstrate the mechanistic differences, not only between the thalamocortical and corticostriatal pathways, but also slice and anesthetized preparations. The results also emphasize the need for further study on mechanisms of L TP and LTD in the various excitatory and inhibitory pathways of the basal ganglia motor loop. / Thesis / Doctor of Philosophy (PhD)

Les antipsychotiques sont utilisés en clinique depuis plus de 50 ans pour pallier aux symptômes de la schizophrénie. Malgré une recherche intensive, les mécanismes cellulaires et moléculaires responsables de l’effet clinique de cette médication demeurent encore nébuleux. Ces drogues sont reconnues comme des antagonistes des récepteurs D2 de la dopamine et peuvent moduler la transcription génique dans le striatum. Au cours des recherches qui ont mené à l'écriture de cette thèse, nous avons exploré l’expression de Nur77, un facteur de transcription de la famille des récepteurs nucléaires, afin de caractériser le rôle de la dopamine, la sérotonine, l’adénosine et le glutamate dans la régulation génique contrôlée par les antagonistes D2. En premier lieu, nous avons examiné l’impact de la co-administration d’agents sérotonergiques et adrénergiques sur l’expression de l’ARNm de Nur77 induite par l’halopéridol, un antipsychotique de première génération. Nous avons observé que le 8-OH-DPAT et le MDL11939 préviennent partiellement l’induction de Nur77 dans le striatum. Au contraire, l’idazoxan potentialise l’effet de l’halopéridol sur l’expression de Nur77 alors que le prazosin reste sans effet. Ces résultats démontrent que l’expression striatale de Nur77 induite par l’halopéridol peut être modulée à la baisse avec un agoniste 5-HT1A ou un antagoniste 5-HT2A. Par la suite, nous avons évalué dans divers paradigmes expérimentaux l’effet de l’éticlopride, un antagoniste spécifique D2, afin d’explorer davantage le mécanisme de l’effet transcriptionnel des antagonistes D2. Étonnamment, la suppression de l’isoforme D2L chez la souris D2L KO ne réduit pas la réponse de l’éticlopride dans le striatum. Par contre, une lésion corticale avec l’acide iboténique bloque l’effet de l’éticlopride sur la transcription de Nur77, suggérant un rôle du glutamate. La combinaison d’un antagoniste des récepteurs métabotropes du glutamate de types 5 (mGluR5) et d’un antagoniste des récepteurs de l’adénosine A2A abolit complètement l’augmentation de la transcription de Nur77 induit par l’éticlopride dans le striatum. La modulation directe de l’expression striatale de Nur77 par les récepteurs mGluR5 et A2A a été confirmée dans un modèle de cultures organotypiques de tranches cérébrales. Ces résultats démontrent clairement que la modulation de l’expression génique dans le striatum, à la suite d’un traitement avec un antagoniste D2 pourrait être indépendante d’une interaction directe avec les récepteurs D2 post-synaptiques, et reposerait plutôt sur son interaction avec les récepteurs D2 hétérosynaptiques des afférences corticostriées et l’activation subséquente des récepteurs post-synaptiques du glutamate et de l’adénosine. En résumé, nos résultats suggèrent que l’interaction des antipsychotiques atypiques avec les récepteurs 5-HT2A et 5-HT1A pourrait expliquer la différence dans le patron d’expression génique induit par ces drogues en comparaison avec les antipsychotiques typiques. De plus, nos résultats révèlent un nouveau mécanisme d’action des antagonistes D2 et supportent un rôle primordial du glutamate et de l’adénosine dans les effets des antipsychotiques de première génération. / Antipsychotic drugs have been used to alleviate schizophrenia symptoms for more than 50 years. Despite extensive research, little is known about the molecular and cellular mechanism responsible for their clinical outcome. These drugs are usually recognized as dopamine D2 antagonists and are known to modulate gene expression in the striatum. In the present thesis, we used the expression of Nur77, a transcription factor of the orphan nuclear receptor family, to explore the role of dopamine, serotonin, glutamate and adenosine receptors in the effect of a dopamine D2 antagonist in the striatum. First, we examined the abilities of serotoninergic and adrenergic receptor drugs to modify the pattern of Nur77 mRNA expression induced by haloperidol, a first generation antipsychotic drug. We observed that 8-OH-DPAT and MDL11939 partially prevent haloperidol-induced Nur77 upregulation. On the contrary, idazoxan consistently potentiated haloperidol-induced Nur77 mRNA levels in the striatum whereas prazosin remained without effect. Taken together, these results show the ability of a 5-HT1A agonist or a 5-HT2A antagonist to reduce haloperidol-induced Nur77 striatal expression. Subsequently, we evaluated in different experimental designs the effect of eticlopride, a specific D2 antagonist, to provide additional information on the mechanism by which D2 antagonist controls transcriptional activity in the striatum. Surprisingly, deletion of the D2L receptor isoform did not reduce eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. However, cortical lesions with ibotenic acid strongly reduced eticlopride-induced upregulation of Nur77 mRNA, suggesting a role for glutamate neurotransmission. A combination of a metabotropic glutamate type 5 (mGluR5) antagonist with an antagonist of its synergistic partner adenosine A2A receptor abolished eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Direct modulation of striatal Nur77 expression by glutamate and adenosine receptors was confirmed using corticostriatal organotypic cultures. Taken together, these results indicate that modulation of gene expression in the striatum, following a D2 antagonist, might not involve a direct interaction of the drug at postsynaptic D2 receptors, but rather relies on its interaction with corticostriatal presynaptic D2 receptors and subsequent activation of postsynaptic glutamate and adenosine receptors in the striatum. In summary, our results suggest that interaction of atypical antipsychotic drugs with 5-HT2A and 5-HT1A receptors participate in the differential pattern of gene expression induced by these drugs when compared with typical antipsychotic drugs. Moreover, our results uncover a new mechanism of action of D2 antagonists and support a prominent role of glutamate and adenosine in the effect of classic antipsychotic drugs.

Les antipsychotiques sont utilisés en clinique depuis plus de 50 ans pour pallier aux symptômes de la schizophrénie. Malgré une recherche intensive, les mécanismes cellulaires et moléculaires responsables de l’effet clinique de cette médication demeurent encore nébuleux. Ces drogues sont reconnues comme des antagonistes des récepteurs D2 de la dopamine et peuvent moduler la transcription génique dans le striatum. Au cours des recherches qui ont mené à l'écriture de cette thèse, nous avons exploré l’expression de Nur77, un facteur de transcription de la famille des récepteurs nucléaires, afin de caractériser le rôle de la dopamine, la sérotonine, l’adénosine et le glutamate dans la régulation génique contrôlée par les antagonistes D2. En premier lieu, nous avons examiné l’impact de la co-administration d’agents sérotonergiques et adrénergiques sur l’expression de l’ARNm de Nur77 induite par l’halopéridol, un antipsychotique de première génération. Nous avons observé que le 8-OH-DPAT et le MDL11939 préviennent partiellement l’induction de Nur77 dans le striatum. Au contraire, l’idazoxan potentialise l’effet de l’halopéridol sur l’expression de Nur77 alors que le prazosin reste sans effet. Ces résultats démontrent que l’expression striatale de Nur77 induite par l’halopéridol peut être modulée à la baisse avec un agoniste 5-HT1A ou un antagoniste 5-HT2A. Par la suite, nous avons évalué dans divers paradigmes expérimentaux l’effet de l’éticlopride, un antagoniste spécifique D2, afin d’explorer davantage le mécanisme de l’effet transcriptionnel des antagonistes D2. Étonnamment, la suppression de l’isoforme D2L chez la souris D2L KO ne réduit pas la réponse de l’éticlopride dans le striatum. Par contre, une lésion corticale avec l’acide iboténique bloque l’effet de l’éticlopride sur la transcription de Nur77, suggérant un rôle du glutamate. La combinaison d’un antagoniste des récepteurs métabotropes du glutamate de types 5 (mGluR5) et d’un antagoniste des récepteurs de l’adénosine A2A abolit complètement l’augmentation de la transcription de Nur77 induit par l’éticlopride dans le striatum. La modulation directe de l’expression striatale de Nur77 par les récepteurs mGluR5 et A2A a été confirmée dans un modèle de cultures organotypiques de tranches cérébrales. Ces résultats démontrent clairement que la modulation de l’expression génique dans le striatum, à la suite d’un traitement avec un antagoniste D2 pourrait être indépendante d’une interaction directe avec les récepteurs D2 post-synaptiques, et reposerait plutôt sur son interaction avec les récepteurs D2 hétérosynaptiques des afférences corticostriées et l’activation subséquente des récepteurs post-synaptiques du glutamate et de l’adénosine. En résumé, nos résultats suggèrent que l’interaction des antipsychotiques atypiques avec les récepteurs 5-HT2A et 5-HT1A pourrait expliquer la différence dans le patron d’expression génique induit par ces drogues en comparaison avec les antipsychotiques typiques. De plus, nos résultats révèlent un nouveau mécanisme d’action des antagonistes D2 et supportent un rôle primordial du glutamate et de l’adénosine dans les effets des antipsychotiques de première génération. / Antipsychotic drugs have been used to alleviate schizophrenia symptoms for more than 50 years. Despite extensive research, little is known about the molecular and cellular mechanism responsible for their clinical outcome. These drugs are usually recognized as dopamine D2 antagonists and are known to modulate gene expression in the striatum. In the present thesis, we used the expression of Nur77, a transcription factor of the orphan nuclear receptor family, to explore the role of dopamine, serotonin, glutamate and adenosine receptors in the effect of a dopamine D2 antagonist in the striatum. First, we examined the abilities of serotoninergic and adrenergic receptor drugs to modify the pattern of Nur77 mRNA expression induced by haloperidol, a first generation antipsychotic drug. We observed that 8-OH-DPAT and MDL11939 partially prevent haloperidol-induced Nur77 upregulation. On the contrary, idazoxan consistently potentiated haloperidol-induced Nur77 mRNA levels in the striatum whereas prazosin remained without effect. Taken together, these results show the ability of a 5-HT1A agonist or a 5-HT2A antagonist to reduce haloperidol-induced Nur77 striatal expression. Subsequently, we evaluated in different experimental designs the effect of eticlopride, a specific D2 antagonist, to provide additional information on the mechanism by which D2 antagonist controls transcriptional activity in the striatum. Surprisingly, deletion of the D2L receptor isoform did not reduce eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. However, cortical lesions with ibotenic acid strongly reduced eticlopride-induced upregulation of Nur77 mRNA, suggesting a role for glutamate neurotransmission. A combination of a metabotropic glutamate type 5 (mGluR5) antagonist with an antagonist of its synergistic partner adenosine A2A receptor abolished eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Direct modulation of striatal Nur77 expression by glutamate and adenosine receptors was confirmed using corticostriatal organotypic cultures. Taken together, these results indicate that modulation of gene expression in the striatum, following a D2 antagonist, might not involve a direct interaction of the drug at postsynaptic D2 receptors, but rather relies on its interaction with corticostriatal presynaptic D2 receptors and subsequent activation of postsynaptic glutamate and adenosine receptors in the striatum. In summary, our results suggest that interaction of atypical antipsychotic drugs with 5-HT2A and 5-HT1A receptors participate in the differential pattern of gene expression induced by these drugs when compared with typical antipsychotic drugs. Moreover, our results uncover a new mechanism of action of D2 antagonists and support a prominent role of glutamate and adenosine in the effect of classic antipsychotic drugs.