Hypocretin/orexin in addiction: a mediator of stress-induced reinstatement of cocaine-seeking behaviour

The importance of the lateral hypothalamus in the pursuit of reward has long been recognized. However, the hypothalamic neuronal network involved in the regulation of reward still remains partially unknown. Hypocretins (aka orexins) are neuropeptides synthesized by a few thousand neurons restricted to the lateral hypothalamus and the perifornical area. Compelling evidence indicates that hypocretin neurons receive inputs from sensory and limbic systems and drive hyper-arousal possibly through modulation of stress responses. Major advances have been made in the elucidation of the hypocretin involvement in the regulation of arousal, stress, motivation, and reward seeking, without clearly defining the role of hypocretins in addictionrelated behaviors. We have recently gathered substantial evidence that points to a previously unidentified role for hypocretin-1 in driving relapse for cocaine seeking through activation of brain stress pathways. Meanwhile, several authors published concordant observations rather suggesting a direct activation of the mesolimbic dopamine system. In particular, hypocretin-1 has been shown to be critically involved in cocaine sensitization through the recruitment of NMDA receptors in the ventral tegmental area. Overall, on can conclude from recent findings that activation of hypocretin/orexin neurons plays a critical role in the development of the addiction process, either by contributing to brain sensitization (which is thought to lead to the unmanageable desire for drug intake) or by modulating the brain reward system that, in coordination with brain stress systems, leads to a vulnerable state that may facilitate relapse for drug seeking behavior.

GLUT8 subcellular localization and absence of translocation to the plasma membrane in PC12 cells and hippocampal neurons.

GLUT8 is a high-affinity glucose transporter present mostly in testes and a subset of brain neurons. At the cellular level, it is found in a poorly defined intracellular compartment in which it is retained by an N-terminal dileucine motif. Here we assessed GLUT8 colocalization with markers for different cellular compartments and searched for signals, which could trigger its cell surface expression. We showed that when expressed in PC12 cells, GLUT8 was located in a perinuclear compartment in which it showed partial colocalization with markers for the endoplasmic reticulum but not with markers for the trans-Golgi network, early endosomes, lysosomes, and synaptic-like vesicles. To evaluate its presence at the plasma membrane, we generated a recombinant adenovirus for the expression of GLUT8 containing an extracellular myc epitope. Cell surface expression was evaluated by immunofluorescence microscopy of transduced PC12 cells or primary hippocampal neurons exposed to different stimuli. Those included substances inducing depolarization, activation of protein kinase A and C, activation or inhibition of tyrosine kinase-linked signaling pathways, glucose deprivation, AMP-activated protein kinase stimulation, and osmotic shock. None of these stimuli-induced GLUT8 cell surface translocation. Furthermore, when GLUT8myc was cotransduced with a dominant-negative form of dynamin or GLUT8myc-expressing PC-12 cells or neurons were incubated with an anti-myc antibody, no evidence for constitutive recycling of the transporter through the cell surface could be obtained. Thus, in cells normally expressing it, GLUT8 was associated with a specific intracellular compartment in which it may play an as-yet-uncharacterized role.

Glut2-dependent glucose-sensing controls thermoregulation by enhancing the leptin sensitivity of NPY and POMC neurons.

The physiological contribution of glucose in thermoregulation is not completely established nor whether this control may involve a regulation of the melanocortin pathway. Here, we assessed thermoregulation and leptin sensitivity of hypothalamic arcuate neurons in mice with inactivation of glucose transporter type 2 (Glut2)-dependent glucose sensing. Mice with inactivation of Glut2-dependent glucose sensors are cold intolerant and show increased susceptibility to food deprivation-induced torpor and abnormal hypothermic response to intracerebroventricular administration of 2-deoxy-d-glucose compared to control mice. This is associated with a defect in regulated expression of brown adipose tissue uncoupling protein I and iodothyronine deiodinase II and with a decreased leptin sensitivity of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons, as observed during the unfed-to-refed transition or following i.p. leptin injection. Sites of central Glut-2 expression were identified by a genetic tagging approach and revealed that glucose-sensitive neurons were present in the lateral hypothalamus, the dorsal vagal complex, and the basal medulla but not in the arcuate nucleus. NPY and POMC neurons were, however, connected to nerve terminals from Glut2-expressing neurons. Thus, our data suggest that glucose controls thermoregulation and the leptin sensitivity of NPY and POMC neurons through activation of Glut2-dependent glucose-sensing neurons located outside of the arcuate nucleus.

Mouse Grueneberg ganglion neurons share molecular and functional features with C. elegans amphid neurons.

The mouse Grueneberg ganglion (GG) is an olfactory subsystem located at the tip of the nose close to the entry of the naris. It comprises neurons that are both sensitive to cold temperature and play an important role in the detection of alarm pheromones (APs). This chemical modality may be essential for species survival. Interestingly, GG neurons display an atypical mammalian olfactory morphology with neurons bearing deeply invaginated cilia mostly covered by ensheathing glial cells. We had previously noticed their morphological resemblance with the chemosensory amphid neurons found in the anterior region of the head of Caenorhabditis elegans (C. elegans). We demonstrate here further molecular and functional similarities. Thus, we found an orthologous expression of molecular signaling elements that was furthermore restricted to similar specific subcellular localizations. Calcium imaging also revealed a ligand selectivity for the methylated thiazole odorants that amphid neurons are known to detect. Cellular responses from GG neurons evoked by chemical or temperature stimuli were also partially cGMP-dependent. In addition, we found that, although behaviors depending on temperature sensing in the mouse, such as huddling and thermotaxis did not implicate the GG, the thermosensitivity modulated the chemosensitivity at the level of single GG neurons. Thus, the striking similarities with the chemosensory amphid neurons of C. elegans conferred to the mouse GG neurons unique multimodal sensory properties.

Ligands for pheromone-sensing neurons are not conformationally activated odorant binding proteins.

Pheromones form an essential chemical language of intraspecific communication in many animals. How olfactory systems recognize pheromonal signals with both sensitivity and specificity is not well understood. An important in vivo paradigm for this process is the detection mechanism of the sex pheromone (Z)-11-octadecenyl acetate (cis-vaccenyl acetate [cVA]) in Drosophila melanogaster. cVA-evoked neuronal activation requires a secreted odorant binding protein, LUSH, the CD36-related transmembrane protein SNMP, and the odorant receptor OR67d. Crystallographic analysis has revealed that cVA-bound LUSH is conformationally distinct from apo (unliganded) LUSH. Recombinantly expressed mutant versions of LUSH predicted to enhance or diminish these structural changes produce corresponding alterations in spontaneous and/or cVA-evoked activity when infused into olfactory sensilla, leading to a model in which the ligand for pheromone receptors is not free cVA, but LUSH that is "conformationally activated" upon cVA binding. Here we present evidence that contradicts this model. First, we demonstrate that the same LUSH mutants expressed transgenically affect neither basal nor pheromone-evoked activity. Second, we compare the structures of apo LUSH, cVA/LUSH, and complexes of LUSH with non-pheromonal ligands and find no conformational property of cVA/LUSH that can explain its proposed unique activated state. Finally, we show that high concentrations of cVA can induce neuronal activity in the absence of LUSH, but not SNMP or OR67d. Our findings are not consistent with the model that the cVA/LUSH complex acts as the pheromone ligand, and suggest that pheromone molecules alone directly activate neuronal receptors.

Glutamate reduces glucose utilization while concomitantly enhancing AQP9 and MCT2 expression in cultured rat hippocampal neurons.

The excitatory neurotransmitter glutamate has been reported to have a major impact on brain energy metabolism. Using primary cultures of rat hippocampal neurons, we observed that glutamate reduces glucose utilization in this cell type, suggesting alteration in mitochondrial oxidative metabolism. The aquaglyceroporin AQP9 and the monocarboxylate transporter MCT2, two transporters for oxidative energy substrates, appear to be present in mitochondria of these neurons. Moreover, they not only co-localize but they interact with each other as they were found to co-immunoprecipitate from hippocampal neuron homogenates. Exposure of cultured hippocampal neurons to glutamate 100 μM for 1 h led to enhanced expression of both AQP9 and MCT2 at the protein level without any significant change at the mRNA level. In parallel, a similar increase in the protein expression of LDHA was evidenced without an effect on the mRNA level. These data suggest that glutamate exerts an influence on neuronal energy metabolism likely through a regulation of the expression of some key mitochondrial proteins.

Alterations in neurofilament protein immunoreactivity in human hippocampal neurons related to normal aging and Alzheimer's disease.

The distribution of immunoreactivity for the neurofilament triplet class of intermediate filament proteins was examined in the hippocampus of young, adult and elderly control cases and compared to that of Alzheimer's disease cases. In a similar fashion to non-human mammalian species, pyramidal neurons in the CA1 region showed a very low degree of neurofilament triplet immunoreactivity in the three younger control cases examined. However, in the other control cases of 49 years of age and older, many CA1 pyramidal neurons showed elevated neurofilament immunoreactivity. In the Alzheimer's disease cases, most of the surviving CA1 neurons showed intense labeling for the neurofilament triplet proteins, with many of these neurons giving off abnormal "sprouting" processes. Double labeling demonstrated that many of these neurons contained tangle-like or granular material that was immunoreactive for abnormal forms of tau and stained with thioflavine S, indicating that these neurons are in a transitional degenerative stage. An antibody to phosphorylated neurofilament proteins labeled a subset of neurofibrillary tangles in the Alzheimer's disease cases. However, following formic acid pre-treatment, the number of neurofibrillary tangles showing phosphorylated neurofilament protein immunoreactivity increased, with double labeling confirming that all of the tau-immunoreactive neurofibrillary tangles were also immunoreactive for phosphorylated neurofilament proteins. Immunoblotting demonstrated that there was a proportionately greater amount of the neurofilament triplet subunit proteins in hippocampal tissue from Alzheimer's disease cases as compared to controls. These results indicate that there are changes in the cytoskeleton of CA1 neurons associated with age which are likely to involve an increase in the level of neurofilament proteins and may be a predisposing factor contributing towards their high degree of vulnerability in degenerative conditions such as Alzheimer's disease. The cellular factors affecting hippocampal neurons during aging may be potentiated in Alzheimer's disease to result in even higher levels of intracellular neurofilament proteins and the progressive alterations of neurofilaments and other cytoskeletal proteins that finally results in neurofibrillary tangle formation and cellular degeneration.

Neurobiology of addiction: the role of transcription factors CREB and C/EBP as well as that of their coactivators

Résumé Le présent travail de thèse a fait face au défi de lier les changements transcriptionnels dans les neurones du système nerveux central au développement de l'addiction aux drogues. I1 est connu que l'apprentissage induit des modifications au niveau de la structure du cerveau, principalement en changeant la manière dont les neurones sont interconnectés par des synapses. De plus en plus d'évidences soutiennent un scénario selon lequel l'activité neuronale déclenche des cascades de signalisation intracellulaire qui ciblent des facteurs de transcription. Ces derniers peuvent activer la transcription de gènes spécifiques qui codent pour des protéines nécessaires au renforcement des synapses mémorisant ainsi la nouvelle information. Puisque l'addiction peut être considérée comme une forme aberrante d'apprentissage, et que les modifications synaptiques sont connues pour être impliquées dans le processus d'addiction, nous essayons de décrire des mécanismes transcriptionels étant à la base des changements synaptiques induits par les drogues. Comme modèle nous utilisons des cultures primaires des neurones de striatum, d'hippocampe et de cortex de souris ainsi que des tranches de cerveau de rat. Une des caractéristiques communes de quasiment toutes les substances addictives est de pouvoir activer le système mésolimbique dopaminergique provoquant la libération de dopamine sur les neurones du striatum (du noyau accumbens). Dans ce travail de thèse nous démontrons que dans des cultures du striatum, la dopamine induit le facteur de transcription C/EBPβ qui, à son tour, provoque l'expression du gène codant pour la substance P. Ce mécanisme pourrait potentiellement contribuer à la tolérance envers les drogues puisqu'il fait partie d'une rétroaction (feed-back) sur les cellules produisant la dopamine. Etant donné que ces résultats montrent l'importance de C/EBPβ dans la psychopathologie de l'addiction, nous avons également décidé d'étudier les mécanismes fondamentaux de l'activation de la transcription par C/EBPβ. Nos expériences démontrent que trois isoformes activatrices de la famille C/EBP recrutent le coactivateur CBP et provoquent en même temps sa phosphorylation. Enfin, nous montrons que les coactivateurs nommés TORC, nouvellement découverts et clonés, sont capables de détecter la coïncidence d'un signal cAMP et d'une entrée de calcium dans des neurones. Par conséquent les TORCs pourraient contribuer à détecter la coïncidence d'un signal glutamate et d'un signal dopamine dans les neurones de striatum, ce qui pourrait être important pour associer les effets hédonistes de la drogue à l'information contextuelle (par exemple à l'environnement où la drogue a été consommée). Nous sommes les premiers à observer que les TORCs sont nécessaires pour la potentiation à long terme dans l'hippocampe. Summary The present thesis work faced the challenge to link the development of drug addiction to transcriptional changes in the neurons of the central nervous system. Experience and learning are known to induce structural modifications in the brain, and these changes are thought to occur mainly in the way neurons are interconnected by synapses. More and more evidences point to a scenario in which neuronal activity would activate signalization cascades that impinge on transcription factors, which, in turn, would activate genes necessary for the reinforcement of synapses coding for new informations. Given that drug addiction can be considered as an aberrant form of learning and is thought to involve synaptic modifications, we try to elucidate some of the transcriptional mechanisms that could underlie drug-induced synaptic changes. As a model system, we use primary cultures of striatal, cortical and hippocampal neurons dissected from mouse embryos as well as brain slices from rats. One of the common features of virtually all drugs of abuse is to activate the mesocorticolimbic dopaminergic system that results in the release of dopamine onto the neurons of the striatum (nucleus accumbens). In this thesis work we show that in striatal cultures, dopamine induces the transcription factor C/EBPβ that in turn drives the expression of the gene coding for substance P. This mechanism is likely to be important for the drug-induced tolerance in the brain since it might be a part of a feedback acting on dopaminergic neurons. Given the suspected importance of C/EBPβ in drug addiction, we also try to elucidate some aspects of the basic mechanisms by which the C/EBP family activates transcription. We show that three activating members of the C/EBP family recruit the coactivator CBP and trigger its phosphorylation. Finally, we demonstrate that the newly discovered and cloned transcriptional coactivators, named TORCs (transducers of regulated CREB activity) are able to detect the coincidence of a calcium and a cAMP signal in the central nervous system. This way, TORCs could contribute to the detection of a coincidence between a glutamate and a dopamine signal in striatal neurons - a process that is suggested to be important for an association between the rewarding effect of a drug and contextual information (such as the environment where the drug had been taken). We demonstrate that TORCs are required for hippocampal LTP.

Glutathione deficit in schizophrenia: strategies to increase glutathione levels in " in vitro " and clinical studies

Summary: Decrease in glutathione (GSH) levels was observed in cerebrospinal fluid, prefrontal cortex and post-mortem striatum of schizophrenia patients. Evidences suggest a defect in GSH synthesis at the levels of the rate-limiting synthesizing enzyme, glutamate cysteine ligase (GCL). Indeed, polymorphisms in the gene of the modifier subunit of GCL (GCLM) was shown to be associated with the disease in three different populations, GCLM gene expression is decreaséd in fibroblasts from patients and the increase in GCL activity induced by an oxidative stress is lower in patients' fibroblasts compared to controls. GSH being a major antioxydant and redox regulator, its presence is of high importance for protecting cells against oxidative stress. The aim of the present work was to use various substances to increase GSH levels by diverse strategies. Since the synthesizing enzyme GCL is defective, bypassing this enzyme was the first strategy we used. GSH ethyl ester (GSHEE), a membrane permeable analog of GSH, succeeded in replenishing GSH levels in cultured neurons and astrocytes previously depleted in GSH by L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of GCL. GSHEE also abolished dopamine-induced decrease of NMDA-mediated calcium response observed in BSO-treated neurons. y-Glutamylcysteine ethyl ester (GCSE), a membrane permeable analog of the product of GCL, increased GSH levels only in astrocytes. The second strategy was to boost the defective enzyme GCL. While quercetin (flavonoid) could increase GSH levels only in astrocytes, curcumin (polyphenol) and tertbutylhydroquinone (quinone) were successful in both neurons and astrocytes, via an increase in the gene expression of the two subunits of GCL and, consequently, an increase in the activity of the enzyme. However, FK506, an immunosupressant, was unefficient. Treating astrocytes from GCLM KO mice showed that the modulatory subunit is necessary for the action of the substances. Finally, since cysteine is the limiting precursor in the synthesis of GSH, we hypothesized that we could increase GSH levels by providing more of this precursor. N-acetyl-cysteine (NAC), a cysteine donor, was administered to schizophrenia patients, using adouble-blind and cross-over protocol. NAC significantly improved the mismatch negativity (MMN), a component of the auditory evoked potentials, thought to reflect selective current flowing through open, unblocked NMDA channels. Considering that NMDA function is reduced when GSH levels are low, increasing these levels with NAC could improve NMDA function as reflected by the improvement in the generation of the MMN. Résumé: Les taux de glutathion (GSH) dans le liquide céphalo-rachidien, le cortex préfrontal ainsi que le striatum post-mortem de patients schizophrènes, sont diminués. L'enzyme limitante dans la synthèse du GSH, la glutamyl-cysteine ligase (GCL), est défectueuse. En effet, des polymorphismes dans le gène de la sous-unité modulatrice de GCL (GCLM) sont associés à la maladie, l'expression du gène GCLM est diminuée dans les fibroblastes de patients et, lors d'un stress oxidative, l'augmentation de l'activité de GCL est plus faible chez les patients que chez les contrôles. Le GSH étant un important antioxydant et régulateur du status redox, sa présence est primordiale afin de protéger les cellules contre les stress oxydatifs. Au cours du présent travail, une variété de substances ont été utilisées dans le but d'augmenter les taux de GSH. Passer outre l'enzyme de synthèse GCL qui est défectueuse fut la première stratégie utilisée. L'éthylester de GSH (GSHEE), un analogue du GSH qui pénètre la membrane cellulaire, a augmenté les taux de GSH dans des neurones et des astrocytes déficitaires en GSH dû au L-buthionine-(S,R)-sulfoximine (BSO), un inhibiteur du GCL. Dans ces neurones, le GSHEE a aussi aboli la diminution de la réponse NMDA, induite parla dopamine. L'éthyl-ester de y-glutamylcysteine (GCEE), un analogue du produit de la GCL qui pénètre la membrane cellulaire, a augmenté les taux de GSH seulement dans les astrocytes. La seconde stratégie était d'augmenter l'activité de l'enzyme GCL. Tandis que la quercétine (flavonoïde) n'a pu augmenter les taux de GSH que dans les astrocytes, la curcumin (polyphénol) et le tert-butylhydroquinone (quinone) furent efficaces dans les deux types de cellules, via une augmentation de l'expression des gènes des deux sous-unités de GCL et de l'activité de l'enzyme. Le FK506 (immunosupresseur) n' a démontré aucune efficacité. Traiter des astrocytes provenant de souris GCLM KO a permis d'observer que la sous-unité modulatoire est nécessaire à l'action des substances. Enfin, puisque la cysteine est le substrat limitant dans la synthèse du GSH, fournir plus de ce présurseur pourrait augmenter les taux de GSH. Nacétyl-cystéine (NAC), un donneur de cystéine, a été administrée à des schizophrènes, lors d'une étude en double-aveugle et cross-over. NAC a amélioré le mismatch negativity (MMN), un composant des potentials évoqués auditifs, qui reflète le courant circulant via les canaux NMDA. Puisque la fonctionnalité des R-NMDA est diminuée lorsque les taux de GSH sont bas, augmenter ces taux avec NAC pourrait améliorer la fonction des R-NMDA, réflété par une augmentation de l'amplitude du MMN.

Dyrk1A is dynamically expressed on subsets of motor neurons and in the neuromuscular junction: possible role in Down syndrome

Individuals with Down syndrome (DS) present important motor deficits that derive from altered motor development of infants and young children. DYRK1A, a candidate gene for DS abnormalities has been implicated in motor function due to its expression in motor nuclei in the adult brain, and its overexpression in DS mouse models leads to hyperactivity and altered motor learning. However, its precise role in the adult motor system, or its possible involvement in postnatal locomotor development has not yet been clarified. During the postnatal period we observed time-specific expression of Dyrk1A in discrete subsets of brainstem nuclei and spinal cord motor neurons. Interestingly, we describe for the first time the presence of Dyrk1A in the presynaptic terminal of the neuromuscular junctions and its axonal transport from the facial nucleus, suggesting a function for Dyrk1A in these structures. Relevant to DS, Dyrk1A overexpression in transgenic mice (TgDyrk1A) produces motor developmental alterations possibly contributing to DS motor phenotypes and modifies the numbers of motor cholinergic neurons, suggesting that the kinase may have a role in the development of the brainstem and spinal cord motor system.

Lipid rafts act as specialised domains for tetanus toxin binding and internalisation in neurons

Tetanus (TeNT) is a zinc protease that blocks neurotransmission by cleaving the synaptic protein vesicle-associated membrane protein/synaptobrevin. Although its intracellular catalytic activity is well established, the mechanism by which this neurotoxin interacts with the neuronal surface is not known. In this study, we characterize p15s, the first plasma membrane TeNT binding proteins and we show that they are glycosylphosphatidylinositol-anchored glycoproteins in nerve growth factor (NGF)-differentiated PC12 cells, spinal cord cells, and purified motor neurons. We identify p15 as neuronal Thy-1 in NGF-differentiated PC12 cells. Fluorescence lifetime imaging microscopy measurements confirm the close association of the binding domain of TeNT and Thy-1 at the plasma membrane. We find that TeNT is recruited to detergent-insoluble lipid microdomains on the surface of neuronal cells. Finally, we show that cholesterol depletion affects a raft subpool and blocks the internalization and intracellular activity of the toxin. Our results indicate that TeNT interacts with target cells by binding to lipid rafts and that cholesterol is required for TeNT internalization and/or trafficking in neurons.

Dose and time-dependent selective neurotoxicity induced by mephedrone in mice.

Mephedrone is a drug of abuse marketed as 'bath salts'. There are discrepancies concerning its long-term effects. We have investigated the neurotoxicity of mephedrone in mice following different exposition schedules. Schedule 1: four doses of 50 mg/kg. Schedule 2: four doses of 25 mg/kg. Schedule 3: three daily doses of 25 mg/kg, for two consecutive days. All schedules induced, in some animals, an aggressive behavior and hyperthermia as well as a decrease in weight gain. Mephedrone (schedule 1) induced dopaminergic and serotoninergic neurotoxicity that persisted 7 days after exposition. At a lower dose (schedule 2) only a transient dopaminergic injury was found. In the weekend consumption pattern (schedule 3), mephedrone induced dopamine and serotonin transporter loss that was accompanied by a decrease in tyrosine hydroxylase and tryptophan hydroxylase 2 expression one week after exposition. Also, mephedrone induced a depressive-like behavior, as well as a reduction in striatal D2 density, suggesting higher susceptibility to addictive drugs. In cultured cortical neurons, mephedrone induced a concentration-dependent cytotoxic effect. Using repeated doses for 2 days in an elevated ambient temperature we evidenced a loss of frontal cortex dopaminergic and hippocampal serotoninergic neuronal markers that suggest injuries at nerve endings.

The Impact of Catechol-O-Methyltransferase and Dopamine D4 Receptor Genotypes on Neurophysiological Markers of Performance Monitoring

Dynamic adaptations of one"s behavior by means of performance monitoring are a central function of the human executive system, that underlies considerable interindividual variation. Converging evidence from electrophysiological and neuroimaging studies in both animals and humans hints atthe importance ofthe dopaminergic system forthe regulation of performance monitoring. Here, we studied the impact of two polymorphisms affecting dopaminergic functioning in the prefrontal cortex [catechol-O-methyltransferase (COMT) Val108/158Met and dopamine D4 receptor (DRD4) single-nucleotide polymorphism (SNP)-521] on neurophysiological correlates of performance monitoring. We applied a modified version of a standard flanker task with an embedded stop-signal task to tap into the different functions involved, particularly error monitoring, conflict detection and inhibitory processes. Participants homozygous for the DRD4 T allele produced an increased error-related negativity after both choice errors and failed inhibitions compared with C-homozygotes. This was associated with pronounced compensatory behavior reflected in higher post-error slowing. No group differences were seen in the incompatibility N2, suggesting distinct effects of the DRD4 polymorphism on error monitoring processes. Additionally, participants homozygous for the COMTVal allele, with a thereby diminished prefrontal dopaminergic level, revealed increased prefrontal processing related to inhibitory functions, reflected in the enhanced stop-signal-related components N2 and P3a. The results extend previous findings from mainly behavioral and neuroimaging data on the relationship between dopaminergic genes and executive functions and present possible underlying mechanisms for the previously suggested association between these dopaminergic polymorphisms and psychiatric disorders as schizophrenia or attention deficit hyperactivity disorder.