Please use this identifier to cite or link to this item:

Title: 外側疆核的麩胺酸受器與場地制約行為
Glutamate receptor in the lateral habenula and place conditioning
Authors: 張綺紋
Contributors: 廖瑞銘
Keywords: 外側疆核
lateral habenula
place conditioning
Date: 2013
Issue Date: 2014-11-03 10:12:10 (UTC+8)
Abstract: 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.
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.
Reference: 張雅惠 (1998) 麩胺酸對心理興奮劑引發場地偏好行為之探討。未發表之碩士學位論文,國立政治大學心理學研究所。

林禧岳 (2012) 電刺激大鼠側疆核對區辨性低頻操作式制約行為的影響。未發表之碩士學位論文,國立政治大學神經科學研究所。

Aizawa H, Kobayashi M, Tanaka S, Fukai T, Okamoto H (2012) Molecular characterization of the subnuclei in rat habenula. J Comp Neurol 520:4051–4066.

Bardo MT, Valone JM, Bevins RA (1999) Locomotion and conditioned place preference produced by acute intravenous amphetamine: role of dopamine receptors and individual differences in amphetamine self-administration. Psychopharmacology (Berl) 143:39-46.

Bardo MT, Bevins RA (2000) Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology (Berl) 153:31-43.

Björklund A, Dunnett SB (2007) Dopamine neuron systems in the brain: an update. Trends Neurosci 30:194-202.

Brinschwitz K, Dittgen A, Madai VI, Lommel R, Geisler S, Veh RW (2010) Glutamatergic axons from the lateral habenula mainly terminate on GABAergic neurons of the ventral midbrain. Neuroscience 168:463-76.

Bianco IH, Wilson SW (2009) The habenular nuclei: a conserved asymmetric relay station in the vertebrate brain. Philos Trans R Soc Lond B Biol Sci 364:1005-20.

Caine SB, Koob GF (1994) Effects of mesolimbic dopamine depletion on responding maintained by cocaine and food. J Exp Anal Behav 61:213-21.

Carr GD, White NM (1983) Conditioned place preference from intra-accumbens but not intra-caudate amphetamine injections. Life Sci 33:2551-7.

Carvey PM, Kao LC, Klawans HL (1987) The effect of bilateral kainic acid-induced
lateral habenula lesions on dopamine-mediated behaviors. Brain Res 409:193-6.

Christoph GR, Leonzio RJ, Wilcox KS (1986) Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmental area of the rat. J Neurosci 6:613–619.

Cornish JL, Nakamura M, Kalivas PW (2001) Dopamine-independent locomotion following blockade of N-methyl-D-aspartate receptors in the ventral tegmental area J Pharmacol Exp Ther 298:226-33.

Cunningham CL, Gremel CM, Groblewski PA (2006) Drug-induced conditioned place preference and aversion in mice. Nat Protoc 4:1662-70.

David HN, Sissaoui K, Abraini JH (2004) Modulation of the locomotor responses induced by D1-like and D2-like dopamine receptor agonists and D-amphetamine by NMDA and non-NMDA glutamate receptor agonists and antagonists in the core of the rat nucleus accumbens. Neuropharmacology 46:179-91.

Duchesne V, Boye SM (2013) Differential contribution of mesoaccumbens and mesohabenular dopamine to intracranial self-stimulation. Neuropharmacology 70:43-50.

Ellison G (1994) Stimulant-induced psychosis, the dopamine theory of schizophrenia, and the habenula. Brain Res Brain Res Rev 19:223-39.

Everitt BJ, Wolf ME (2002) Psychomotor stimulant addiction: a neural systems perspective. J Neurosci 22:3312-20.

Friedman A, Lax E, Dikshtein Y, Abraham L, Flaumenhaft Y, Sudai E, Ben-Tzion M, Ami-Ad L, Yaka R, Yadid G (2010) Electrical stimulation of the lateral habenula produces enduring inhibitory effect on cocaine seeking behavior. Neuropharmacology 59:452-9.

Friedman A, Lax E, Dikshtein Y, Abraham L, Flaumenhaft Y, Sudai E, Ben-Tzion M, Yadid G (2011) Electrical stimulation of the lateral habenula produces an inhibitory
effect on sucrose self-administration. Neuropharmacology 60:381-7.

Geisler S, Derst C, Veh RW, Zahm DS (2007) Glutamatergic afferents of the ventral tegmental area in the rat. J Neurosci 27:5730-43.

Geisler S, Trimble M (2008) The lateral habenula: no longer neglected. CNS Spectr, 13, 484-489.
Gerrits MA, Van Ree JM (1996) Effect of nucleus accumbens dopamine depletion on motivational aspects involved in initiation of cocaine and heroin self-administration in rats. Brain Res 713:114-24.

Ghalandari-Shamami M, Hassanpour-Ezatti M, Haghparast A (2011) Intra-accumbal NMDA but not AMPA/kainate receptor antagonist attenuates WIN55,212-2 cannabinoid receptor agonist-induced antinociception in the basolateral amygdala in a rat model of acute pain. Pharmacol Biochem Behav 100:213-9.

Gifuni AJ, Jozaghi S, Gauthier-Lamer AC, Boye SM (2012) Lesions of the lateral habenula dissociate the reward-enhancing and locomotor-stimulant effects of amphetamine. Neuropharmacology 63:945-57.

Gonçalves L, Sego C, Metzger M (2012) Differential projections from the lateral habenula to the rostromedial tegmental nucleus and ventral tegmental area in the rat. J Comp Neurol 520:1278-300.

Good CH, Wang H, Chen YH, Mejias-Aponte CA, Hoffman AF, Lupica CR (2013) Dopamine D4 receptor excitation of lateral habenula neurons via multiple cellular mechanisms. J Neurosci 33:16853-64.

Gray A, Allison C, Pratt JA (1999) A role for AMPA/kainate receptors in conditioned place preference induced by diazepam in the rat. Neurosci Lett 1999 268:127-30.

Gruber C, Kahl A, Lebenheim L, Kowski A, Dittgen A, Veh RW (2007) Dopaminergic projections from the VTA substantially contribute to the mesohabenular pathway in the rat. Neurosci Lett 427:165-70.

Heldt SA, Ressler KJ (2006) Lesions of the habenula produce stress- and dopamine-dependent alterations in prepulse inhibition and locomotion. Brain Res 1073-1074: 229-39.

Herkenham M, Nauta WJ (1977) Afferent connections of the habenular nuclei in the rat. A horseradish peroxidase study, with a note on the fiber-of-passage problem. J Comp Neurol 173: 123-46.

Herkenham M, Nauta WJ (1979) Efferent connections of the habenular nuclei in the rat. J Comp Neurol 187:19-47.
Hernandez G, Hamdani S, Rajabi H, Conover K, Stewart J, Arvanitogiannis A, Shizgal P (2006) Prolonged rewarding stimulation of the rat medial forebrain bundle: neurochemical and behavioral consequences. Behav Neurosci 120:888-904.

Ilango A, Shumake J, Wetzel W, Scheich H, Ohl FW (2013) Electrical stimulation of lateral habenula during learning: frequency-dependent effects on acquisition but not retrieval of a two-way active avoidance response. PLoS One 8:e65684.

Ikemoto S (2010) Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory. Neurosci Biobehav Rev 35:129-50.

Ji H, Shepard PD (2007) Lateral habenula stimulation inhibits rat midbrain dopamine neurons through a GABA(A) receptor-mediated mechanism. J Neurosci 27:6923-30.

Kawasaki Y, Jin C, Suemaru K, Kawasaki H, Shibata K, Choshi T, Hibino S, Gomita Y, Araki H (2005) Effect of glutamate receptor antagonists on place aversion induced by naloxone in single-dose morphine-treated rats. Br J Pharmacol 145:751-7.

Kim U, Chang SY (2005) Dendritic morphology, local circuitry, and intrinsic electrophysiology of neurons in the rat medial and lateral habenular nuclei of the epithalamus. J Comp Neurol 483:236-50.

Kowski AB, Geisler S, Krauss M, Veh RW (2008) Differential projections from subfields in the lateral preoptic area to the lateral habenular complex of the rat. J Comp Neurol 507:1465-78.

Kotlińska J, Biała G (1999) Effects of the NMDA/ glycine receptor antagonist, L-701,324, on morphine- and cocaine-induced place preference. Pol J Pharmacol 51:323-30.

Lecca S, Meye FJ, Mameli M (2014) The lateral habenula in addiction and depression: an anatomical, synaptic and behavioral overview. Eur J Neurosci 39:1170-8.

Lammel S, Lim BK, Ran C, Huang KW, Betley MJ, Tye KM, Deisseroth K, Malenka RC (2012) Input-specific control of reward and aversion in the ventral tegmental area. Nature 491:212-7.

Lecourtier L, Neijt HC, Kelly PH (2004) Habenula lesions cause impaired cognitive performance in rats: implications for schizophrenia. Eur J Neurosci 19:2551-60.

Lecourtier L, Kelly PH (2005) Bilateral lesions of the habenula induce attentional disturbances in rats. Neuropsychopharmacology 30:484-96.

Lecourtier L, Kelly PH (2007) A conductor hidden in the orchestra? Role of the habenular complex in monoamine transmission and cognition. Neurosci Biobehav Rev 31:658-72.

Lecourtier L, Defrancesco A, Moghaddam B (2008) Differential tonic influence of lateral habenula on prefrontal cortex and nucleus accumbens dopamine release. Eur J Neurosci 27:1755-62.

Liao RM (2008) Development of conditioned place preference induced by intra-accumbens infusion of amphetamine is attenuated by co-infusion of dopamine D1 and D2 receptor antagonists. Pharmacol Biochem Behav 89:367-73.

Li B, Piriz J, Mirrione M, Chung C, Proulx CD, Schulz D, Henn F, Malinow R (2011)
Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature 470:535-9.

Mahieux G, Benabid AL (1987) Naloxone-reversible analgesia induced by electrical
stimulation of the habenula in the rat. Brain Res 406:118-29.

Matsumoto M, Hikosaka O (2007) Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 447:1111-5.

Matsumoto M, Hikosaka O (2009) Representation of negative motivational value in the primate lateral habenula. Nat Neurosci 12:77-84.

Mead AN, Stephens DN (1999) CNQX but not NBQX prevents expression of amphetamine-induced place preference conditioning: a role for the glycine site of the NMDA receptor, but not AMPA receptors. J Pharmacol Exp Ther 290:9-15.

Meye FJ, Lecca S, Valentinova K, Mameli M (2013) Synaptic and cellular profile of neurons in the lateral habenula. Front Hum Neurosci 860:1-7.

Morissette MC, Boye SM (2008) Electrolytic lesions of the habenula attenuate brain stimulation reward. Behav Brain Res 187:17-26.

Nestler EJ (2005) Is there a common molecular pathway for addiction? Nat Neurosci 8:1445-9.

Omelchenko N, Bell R, Sesack SR (2009) Lateral habenula projections to dopamine and GABA neurons in the rat ventral tegmental area. Eur J Neurosci 30:1239-50.

Olds J, Milner P (1954) Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J Comp Physiol Psychol 47:419-27.

Panos JJ, Rademacher DJ, Renner SL, Steinpreis RE (1999) The rewarding properties of NMDA and MK-801 (dizocilpine) as indexed by the conditioned place preference paradigm. Pharmacol Biochem Behav 64:591-5.

Paul MJ, Indic P, Schwartz WJ (2011) A role for the habenula in the regulation of locomotor activity cycles. Eur J Neurosci 34:478-88.

Pierce RC, Kumaresan V (2006) The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev 30:215-38.

Pobbe RL, Zangrossi H Jr (2008) Involvement of the lateral habenula in the regulation of generalized anxiety- and panic-related defensive responses in rats. Life Sci 82:1256-61.

Poller WC, Madai VI, Bernard R, Laube G, Veh RW (2013) A glutamatergic projection from the lateral hypothalamus targets VTA-projecting neurons in the lateral habenula of the rat. Brain Res 1507:45-60.

Pulvirenti L, Berrier R, Kreifeldt M, Koob GF (1994) Modulation of locomotor activity by NMDA receptors in the nucleus accumbens core and shell regions of the rat.
Brain Res 664:231-6.

Sanchis-Segura C, Spanagel R (2006) Behavioural assessment of drug reinforcement and addictive features in rodents: an overview. Addict Biol 11:2-38.

Sandyk R (1991) Relevance of the habenular complex to neuropsychiatry: a review and hypothesis. Int J Neurosci 61:189-219.

Schenk S, Partridge B (1997) Effects of acute and repeated administration of N-methyl-D-aspartate (NMDA) into the ventral tegmental area: locomotor activating effects of NMDA and cocaine. Brain Res 769:225-32.

Shabel Steven J, Proulx Christophe D, Trias A, Murphy Ryan T, Malinow R (2012) Input to the Lateral Habenula from the Basal Ganglia Is Excitatory, Aversive, and Suppressed by Serotonin. Neuron 74:475-81.

Shen YL, Chang TY, Chang YC, Tien HH, Yang FC, Wang PY, Liao RM. (2014) Elevated BDNF mRNA expression in the medial prefrontal cortex after d-amphetamine reinstated conditioned place preference in rats. Neuroscience 263:88-95.

Shinohara F, Kihara Y, Ide S, Minami M, Kaneda K (2014) Critical role of cholinergic transmission from the laterodorsal tegmental nucleus to the ventral tegmental area in cocaine-induced place preference. Neuropharmacology 79:573-9.

Shelton L, Becerra L, Borsook D (2012) Unmasking the mysteries of the habenula in pain and analgesia. Prog Neurobiol 96:208-19.

Shumake J, Ilango A, Scheich H, Wetzel W, Ohl FW (2010) Differential neuromodulation of acquisition and retrieval of avoidance learning by the lateral habenula and ventral tegmental area. J Neurosci 30:5876-83.

Sourani D, Eitan R, Gordon N, Goelman G (2012) The habenula couples the dopaminergic and the serotonergic systems: application to depression in Parkinson's disease. Eur J Neurosci 36:2822-9.

Stamatakis AM, Stuber GD (2012) Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. Nat Neurosci 15:1105-07.

Stamatakis AM, Jennings JH, Ung RL, Blair GA, Weinberg RJ, Neve RL, Boyce F, Mattis J, Ramakrishnan C, Deisseroth K, Stuber GD (2013) A unique population of ventral tegmental area neurons inhibits the lateral habenula to promote reward. Neuron 80:1039-53.

Sutherland RJ. (1982) The dorsal diencephalic conduction system: a review of the anatomy and functions of the habenular complex. Neurosci Biobehav Rev 6:1-13.

Svensson L, Zhang J, Johannessen K, Engel JA (1994) Effect of local infusion of glutamate analogues into the nucleus accumbens of rats: an electrochemical and behavioural study. Brain Res 643:155-61.

Tzschentke TM (1998) Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol 56:613-72.

Tzschentke TM (2007) Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol 12:227-462.

Wang Y, Zhang F, Tang S, Lai M, Hao W, Zhang Y, Yang J, Zhou W (2009) Lack of effect of habenula lesion on heroin self-administration in rats. Neurosci Lett 461:167-71.

Winter C, Vollmayr B, Djodari-Irani A, Klein J, Sartorius A (2011) Pharmacological inhibition of the lateral habenula improves depressive-like behavior in an animal model of treatment resistant depression. Behav Brain Res 216:463-5.

Wirtshafter D, Asin KE, Pitzer MR (1994) Dopamine agonists and stress produce different patterns of Fos-like immunoreactivity in the lateral habenula. Brain Res 633:21-6.

Wise RA, Rompre PP (1989) Brain dopamine and reward. Annu Rev Psychol 40:191-225.

Wise RA (2004) Dopamine, learning and motivation. Nat Rev Neurosci 5:483-94.

Yang LM, Hu B, Xia YH, Zhang BL, Zhao H (2008) Lateral habenula lesions improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus. Behav Brain Res 188:84-90.

Zahm DS (1999) Functional-anatomical implications of the nucleus accumbens core and shell subterritories. Ann N Y Acad Sci 877:113-28.

Zuo, Chen L, Wang L, Ye JH (2013) Cocaine facilitates glutamatergic transmission and activates lateral habenular neurons. Neuropharmacology 70:180-9.
Description: 碩士
Source URI:
Data Type: thesis
Appears in Collections:[神經科學研究所 ] 學位論文

Files in This Item:

File Description SizeFormat
400301.pdf1579KbAdobe PDF740View/Open

All items in 學術集成 are protected by copyright, with all rights reserved.

社群 sharing