Impulsive choice refers to the inability to delay gratification and is associated with increased drug abuse vulnerability. Understanding the underlying neural mechanisms linking impulsive choice and drug abuse can contribute to improved treatment options for individuals with substance use disorders. Evidence suggests a major role for nucleus accumbens core (NAcc) in impulsive choice and the reinforcing effects of drugs of abuse. The neurotransmitters glutamate (Glu) and dopamine (DA) are implicated in the neural adaptations observed in drug addiction; however, the role of intra-NAcc Glu and DA in impulsive choice is unclear. Rats were trained in a delay discounting task, in which animals chose between a small, immediate reinforcer and large, delayed reinforcer. Consistently choosing the small, immediate reinforcer was considered to reflect increased impulsivity. Following delay discounting, in vitro receptor autoradiography was performed to quantify the number of N-methyl-D-aspartate (NMDA) receptors and dopamine transporters (DAT) in NAcc and nucleus accumbens shell (NAcSh). In a separate experiment, rats were trained in delay discounting and were implanted with guide cannulae into NAcc. Following surgery, rats received microinfusions of either a) the Glu-selective ligands MK-801 (noncompetitive NMDA receptor channel blocker; 0, 0.3, and 1.0 μg), AP-5 (competitive NMDA receptor antagonist; 0, 0.3, and 1.0 μg), ifenprodil (NMDA NR2B subunit antagonist; 0, 0.3, and 1.0 μg), and CNQX (AMPA receptor antagonist; 0, 0.2, and 0.5 μg) or b) the DA-selective ligands SKF 38393 (D1-like receptor agonist; 0, 0.03, and 0.1 μg), SCH 23390 (D1-like receptor antagonist; 0, 0.3, and 1.0 μg), quinpirole (D2-like receptor agonist; 0, 0.3, and 1.0 μg), and eticlopride (D2-like receptor antagonist; 0, 0.3, and 1.0 μg). In NAcc and NAcSh, NMDA receptor and DAT expression did not differ between high and low impulsive rats. Furthermore, intra-NAcc administration of NDMA and DA receptor ligands did not significantly alter impulsive choice. These results suggest that Glu and DA systems within NAcc do not directly mediate impulsive decision making. Future work is needed to determine the precise role of NAcc in mediating impulsive choice.

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L'impulsivité, un trait multidimensionnel, détermine la sévérité d'affections comportant des désordres compulsifs (syndrome de Gilles de la Tourette, maladie de Parkinson, troubles obsessionnels compulsifs), mais la nature de la relation impulsivité / compulsivité reste méconnue. L'intérêt du présent travail est d'identifier les substrats neurobiologiques de la balance impulsivité / compulsivité, dans une approche transnosographique, en s'aidant au plan préclinique, de manipulations causales et au plan clinique, d'une approche corrélationnelle. Ainsi, nous démontrons pour la première fois en dehors du champ de l'addiction, non seulement que l'impulsivité motrice, endophénotype de vulnérabilité à la compulsivité, prédit, sous l'influence de la transmission noradrénergique, la transition vers la compulsivité, mais aussi que (dans le modèle de la maladie de Parkinson) la dénervation de la voie nigrostriée et les traitements substitutifs dopaminergiques amplifient l'état impulsif. D'où l'interaction complexe entre le trait impulsif, les traitements et le processus dégénératif. Enfin, nous démontrons le bénéfice thérapeutique de la stimulation de la portion antérieure du pallidum interne dans les formes sévères de tics et suggérons dans un modèle préclinique d'une grande valeur heuristique, que le trait impulsif prédit l'efficacité de la stimulation du core du noyau accumbens. Nos résultats démontrent l'intérêt de mieux caractériser le trait impulsif des patients présentant des désordres compulsifs (syndrome de Gilles de la Tourette, maladie de Parkinson) et ouvrent ainsi de nouvelles perspectives thérapeutiques, tant pour la prévention de la transition de l'impulsivité à la compulsivité, que dans le traitement de ceux-ci. / Impulsivity, a multidimensional trait, determines the severity of compulsive disorders (Tourette's syndrome, Parkinson's disease, obsessive compulsive disorders), but the impulsive / compulsive relation remains unclear. The aim of this work is to identify the neurobiological substrates of impulsive / compulsive balance, using causal manipulations in rats and correlational studies in patients. The results demonstrate - for the first time beside the field of addiction - that, not only high impulsive trait is a transnosological endophenotype of increased vulnerability to develop compulsive disorders, but also that the transition from impulsivity toward compulsivity depends upon the noradrenergic transmission. Furthermore, we also show that, in a Parkinson's disease preclinical model, both the nigrostriatal denervation and dopaminergic treatments increase impulsive state, thereby indicating the contribution of a complex interaction between impulsive trait, medications and neurodegenerative process to the impulsive/compulsive balance. Finally, we show the therapeutic benefit of anterior globus pallidus interna in severe forms of tics and suggest in a preclinical model, with great heuristic value, that impulsive trait predicts the efficacy of nucleus accumbens core stimulation. Together, our results demonstrate the need to address the impulsive/compulsive balance in compulsive disorders and show promise for developing new pathophysiological-based therapeutic strategies that will treat both impulsivity and compulsivity.

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.