Glutamate receptor in the lateral habenula and place conditioning

制約性場地作業為一種廣泛地被使用於測試環境與藥物連結學習的制約行為作業，藉此制約的學習檢測藥物引發的場地偏好或厭惡的效果。該作業探討常見於具有上癮性的藥物，其神經作用機制證實與多巴胺傳導系統有關。近年來在神經解剖證據與功能性研究上，發現外側疆核藉由麩胺酸將神經訊息投射到腹側頂蓋區，對中腦多巴胺神經元扮演抑制效果，進而影響個體對酬賞動機行為表現。外側疆核本身是否具有影響酬賞動機行為或相關的制約行為仍然不清楚。本研究探討外側疆核的麩胺酸受體是否對於場地制約作業行為之形成有所影響，以麩胺酸的AMPA與NMDA之致效劑與拮抗劑直接微量注射於大鼠的外側疆核測試之。實驗一的結果顯示AMPA注入外側疆核無法產生場地制約作業偏好或是厭惡表現；而麩胺酸AMPA受體的拮抗劑CNQX會有制約的效果，唯在中劑量與高劑量有不同的行為表現；在中劑量 (0.4 μg)的CNQX注入外側疆核時會形成制約性場地偏好效果的趨勢；而在高劑量則出現制約性場地嫌惡效果。實驗二的結果顯示NMDA與其拮抗劑AP5注入外側疆核時，皆無法產生制約性場地偏好或嫌惡效果。實驗三的結果顯示腹腔注腔1mg/kg的安非他命可有效形成制約性場地偏好，而注入CNQX (0.4 μg) 於外側疆核並未形成任何制約性場地反應；當這項CNQX操弄結合安非他命處理，安非他命的制約場地偏好行為未受影響。實驗四結果顯示AP5注入外側疆核會抑制安非他命引發的制約性場地偏好行為。綜合以上的實驗結果，麩胺酸藥物單獨注入到外側疆核對大白鼠習得場地制約的影響有限，麩胺酸受體拮抗劑對安非他命引發的制約場地偏好行為習得歷程，不如預期設想的單純。外側疆核上麩胺酸受體與中腦多巴胺系統之間，可能還有其他不同的神經傳導物質調控酬賞動機相關的制約行為。The place conditioning task is an animal model that tests the formation and performance of conditioning association between the environment or contextual cues with drug effect. It is commonly used to measure the rewarding and aversive effects of psychoactive drugs. The neuronal circuit underlying this animal behavior has been confirmed to be related to the dopamine (DA) system. As shown by recent neurophysiological and anatomical studies, the lateral habenula (LHb) may inhibit the DA reward system via its glutamatergic efferents projected to the midbrain dopaminergic neurons. However, at the behavioral level, whether the LHb could regulate the DA related reward motivation and its learning are still unknown. The present study was then designed to examine the role of LHb in the place conditioning task via the local infusions of drugs that activate or block glutamatergic AMPA or NMDA receptors. The results of Experiment 1 showed that the intra-LHb infusion of AMPA did not produce any significant effects on place conditioning. In contrast to AMPA, CNQX showed dose-related effects. CNQX (0.4 μg) nearly produced an effect of conditioned placed preference (CPP), whereas CNQX (1.6 μg) caused an effect of conditioned place aversion (CPA). In Experiment 2, neither NMDA nor AP5 infused into the LHb had produced place conditioning. The following two experiments investigated the effects of CNQX and AP5 on the CPP induced by systemic amphetamine. Experiment 3 showed that amphetamine (1 mg/kg) significantly induced CPP, and such an effect was not affected by the intra-LHb CNQX (0.4 μg). In Experiment 4, intra-LHb infusion of AP5 (1.5 μg) attenuated the amphetamine induced CPP. In summary of the above results, the intra-LHb injections of the glutamatergic drugs had a limited effect on place conditioning. The glutamatergic AMPA and NMDA receptor blockade in LHb had mixed results. V These results indicate that the proposal regarding to inhibitory regulation of LHb on the DA reward system may be more complicated than it was initially thought, at least dependent on what being measured