Abstract
Amygdala D1 receptors have been implicated in the motivating effects of cocaine-conditioned cues and cocaine itself, but the specific nucleus involved is unclear. Thus, we infused the D1 antagonist, SCH-23390, into the rostral basolateral amygdala (rBLA), caudal basolateral amygdala (cBLA), or central amygdala (CEA), and tested its effects on self-administration of cocaine, as well as reinstatement of extinguished cocaine-seeking behavior by cocaine-conditioned cues or cocaine itself. Two anatomical controls, the posterior regions of basal ganglia (BG) and somatosensory/insular cortices (CTX), were also examined. Cocaine self-administration was increased and cue and cocaine reinstatement were decreased by SCH-23390 infusion into every region when examined across the hour test session, with the exception that cBLA infusion did not alter cocaine reinstatement. In the first 20 min of the session, when SCH-23390 was more localized in the target sites, self-administration was increased by infusion into the CEA, cBLA, BG, and CTX, with lesser increases in the rBLA. Cocaine reinstatement was attenuated during the first 20 min only by infusion into the CEA, rBLA, and CTX. Cue reinstatement was not reliably observed in the first 20 min, but there was a trend for attenuation by infusion into the cBLA, and surprisingly, significant attenuations in the BG and CTX. The findings suggest that D1 receptors in subregions of the amygdala play differential roles in the reinforcing/motivational effects of cocaine, while the cue reinstatement effects are less clear. Further research is needed to examine the novel findings that neighboring regions of the BG and CTX may play a role in motivation for cocaine.
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References
Alburges ME, Hunt ME, McQuade RD, Wamsley JK (1992). D1-receptor antagonists: comparison of [3H]SCH39166 to [3H]SCH23390. J Chem Neuroanat 5: 357–366.
Alleweireldt AT, Kirschner KF, Blake CB, Neisewander JL (2003). D1-receptor drugs and cocaine-seeking behavior: investigation of receptor mediation and behavioral disruption in rats. Psychopharmacology (Berl) 168: 109–117.
Alleweireldt AT, Weber SM, Kirschner KF, Bullock BL, Neisewander JL (2002). Blockade or stimulation of D1 dopamine receptors attenuates cue reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology (Berl) 159: 284–293.
Anderson SM, Bari AA, Pierce RC (2003). Administration of the D1-like dopamine receptor antagonist SCH-23390 into the medial nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug-seeking behavior in rats. Psychopharmacology (Berl) 168: 132–138.
Baker DA, Tran-Nguyen TL, Fuchs RA, Neisewander JL (2001). Influence of individual differences and chronic fluoxetine treatment on cocaine-seeking behavior in rats. Psychopharmacology (Berl) 155: 18–26.
Bonson KR, Grant SJ, Contoreggi CS, Links JM, Metcalf J, Weyl HL et al (2002). Neural systems and cue-induced cocaine craving. Neuropsychopharmacology 26: 376–386.
Burmeister JJ, Lungren EM, Kirschner KF, Neisewander JL (2004). Differential roles of 5-HT receptor subtypes in cue and cocaine reinstatement of cocaine-seeking behavior in rats. Neuropsychopharmacology 29: 660–668.
Burmeister JJ, Lungren EM, Neisewander JL (2003). Effects of fluoxetine and d-fenfluramine on cocaine-seeking behavior in rats. Psychopharmacology (Berl) 168: 146–154.
Burns LH, Robbins TW, Everitt BJ (1993). Differential effects of excitotoxic lesions of the basolateral amygdala, ventral subiculum and medial prefrontal cortex on responding with conditioned reinforcement and locomotor activity potentiated by intra-accumbens infusions of D-amphetamine. Behav Brain Res 55: 167–183.
Caine SB, Heinrichs SC, Coffin VL, Koob GF (1995). Effects of the dopamine D-1 antagonist SCH 23390 microinjected into the accumbens, amygdala or striatum on cocaine self-administration in the rat. Brain Res 692: 147–156.
Callahan PM, Cunningham KA (1995). Modulation of the discriminative stimulus properties of cocaine by 5-HT1B and 5-HT2C receptors. J Pharmacol Exp Ther 274: 1414–1424.
Capriles N, Rodaros D, Sorge RE, Stewart J (2003). A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 168: 66–74.
Carroll ME, France CP, Meisch RA (1981). Intravenous self-administration of etonitazene, cocaine and phencyclidine in rats during food deprivation and satiation. J Pharmacol Exp Ther 217: 241–247.
Childress A, Ehrman R, McLellan AT, O'Brien C (1988). Conditioned craving and arousal in cocaine addiction: a preliminary report. NIDA Res Monogr 81: 74–80.
Ciccocioppo R, Sanna PP, Weiss F (2001). Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence: reversal by D(1) antagonists. Proc Natl Acad Sci USA 98: 1976–1981.
de Wit H, Stewart J (1981). Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology (Berl) 75: 134–143.
Deroche V, Le Moal M, Piazza PV (1999). Cocaine self-administration increases the incentive motivational properties of the drug in rats. Eur J Neurosci 11: 2731–2736.
Di Chiara G (1999). Drug addiction as a dopamine-dependent associative learning disorder. Eur J Pharmacol 375: 13–30.
Di Ciano P, Everitt BJ (2004a). Contribution of the ventral tegmental area to cocaine-seeking maintained by a drug-paired conditioned stimulus in rats. Eur J Neurosci 19: 1661–1667.
Di Ciano P, Everitt BJ (2004b). Direct interactions between the basolateral amygdala and nucleus accumbens core underlie cocaine-seeking behavior by rats. J Neurosci 24: 7167–7173.
Drouin C, Waterhouse BD (2004). Cocaine-induced vs. behaviour-related alterations of spontaneous and evoked discharge of somatosensory cortical neurons. Eur J Neurosci 19: 1016–1026.
Duffy RA, Hunt MA, Wamsley JK, McQuade RD (2000). In vivo autoradiography of [3H]SCH 39166 in rat brain: selective displacement by D1/D5 antagonists. J Chem Neuroanat 19: 41–46.
Epping-Jordan MP, Markou A, Koob GF (1998). The dopamine D-1 receptor antagonist SCH 23390 injected into the dorsolateral bed nucleus of the stria terminalis decreased cocaine reinforcement in the rat. Brain Res 784: 105–115.
Filip M, Bubar MJ, Cunningham KA (2004). Contribution of serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor subtypes to the hyperlocomotor effects of cocaine: acute and chronic pharmacological analyses. J Pharmacol Exp Ther 310: 1246–1254.
Fletcher PJ, Chintoh AF, Sinyard J, Higgins GA (2004). Injection of the 5-HT2C receptor agonist Ro60-0175 into the ventral tegmental area reduces cocaine-induced locomotor activity and cocaine self-administration. Neuropsychopharmacology 29: 308–318.
Fletcher PJ, Grottick AJ, Higgins GA (2002). Differential effects of the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2C) receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding. Neuropsychopharmacology 27: 576–586.
Fuchs RA, See RE (2002). Basolateral amygdala inactivation abolishes conditioned stimulus- and heroin-induced reinstatement of extinguished heroin-seeking behavior in rats. Psychopharmacology (Berl) 160: 425–433.
Fuchs RA, Weber SM, Rice HJ, Neisewander JL (2002). Effects of excitotoxic lesions of the basolateral amygdala on cocaine-seeking behavior and cocaine conditioned place preference in rats. Brain Res 929: 15–25.
Garavan H, Pankiewicz J, Bloom A, Cho JK, Sperry L, Ross TJ et al (2000). Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli. Am J Psychiatry 157: 1789–1798.
Goeders NE, Smith JE (1993). Intracranial cocaine self-administration into the medial prefrontal cortex increases dopamine turnover in the nucleus accumbens. J Pharmacol Exp Ther 265: 592–600.
Grimm JW, Hope BT, Wise RA, Shaham Y (2001). Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature 412: 141–142.
Grimm JW, See RE (2000). Dissociation of primary and secondary reward-relevant limbic nuclei in an animal model of relapse. Neuropsychopharmacology 22: 473–479.
Groenewegen HJ, Berendse HW, Wolters JG, Lohman AH (1990). The anatomical relationship of the prefrontal cortex with the striatopallidal system, the thalamus and the amygdala: evidence for a parallel organization. Prog Brain Res 85: 95–116; discussion 116–118.
Grottick AJ, Fletcher PJ, Higgins GA (2000). Studies to investigate the role of 5-HT(2C) receptors on cocaine- and food-maintained behavior. J Pharmacol Exp Ther 295: 1183–1191.
Hiroi N, White NM (1991). The amphetamine conditioned place preference: differential involvement of dopamine receptor subtypes and two dopaminergic terminal areas. Brain Res 552: 141–152.
Hunt GE, McGregor IS (1998). Rewarding brain stimulation induces only sparse Fos-like immunoreactivity in dopaminergic neurons. Neuroscience 83: 501–515.
Hurd YL, McGregor A, Ponten M (1997). In vivo dopamine levels modulate cocaine self-administration behavior in the rat: D1 dopamine receptor involvement. Eur J Neurosci 9: 2541–2548.
Kantak KM, Black Y, Valencia E, Green-Jordan K, Eichenbaum HB (2002). Dissociable effects of lidocaine inactivation of the rostral and caudal basolateral amygdala on the maintenance and reinstatement of cocaine-seeking behavior in rats. J Neurosci 22: 1126–1136.
Khroyan TV, Barrett-Larimore RL, Rowlett JK, Spealman RD (2000). Dopamine D1- and D2-like receptor mechanisms in relapse to cocaine-seeking behavior: effects of selective antagonists and agonists. J Pharmacol Exp Ther 294: 680–687.
Khroyan TV, Platt DM, Rowlett JK, Spealman RD (2003). Attenuation of relapse to cocaine seeking by dopamine D1 receptor agonists and antagonists in non-human primates. Psychopharmacology (Berl) 168: 124–131.
Kita H, Kitai ST (1990). Amygdaloid projections to the frontal cortex and striatum in the rat. J Comp Neurol 298: 40–49.
Kruzich PJ, See RE (2001). Differential contributions of the basolateral and central amygdala in the acquisition and expression of conditioned relapse to cocaine-seeking behavior. J Neurosci 21: RC155.
Kuzhikandathil EV, Oxford GS (2002). Classic D1 dopamine receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pine hydrochloride (SCH23390) directly inhibits G protein-coupled inwardly rectifying potassium channels. Mol Pharmacol 62: 119–126.
Lu L, Hope BT, Dempsey J, Liu SY, Bossert JM, Shaham Y (2005). Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nat Neurosci 8: 212–219.
McDonald AJ (1991). Topographical organization of amygdaloid projections to the caudatoputamen, nucleus accumbens, and related striatal-like areas of the rat brain. Neuroscience 44: 15–33.
McFarland K, Kalivas PW (2001). The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 21: 8655–8663.
McFarland K, Lapish CC, Kalivas PW (2003). Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 23: 3531–3537.
McGregor A, Roberts DCS (1993). Dopaminergic antagonism within the nucleus accumbens or amygdala produces differential effects on intravenous cocaine self-administration under fixed and progressive ratio schedules of reinforcement. Brain Res 624: 245–252.
McLaughlin J, See RE (2003). Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology (Berl) 168: 57–65.
Meil WM, See RE (1997). Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine. Behav Brain Res 87: 139–148.
Millan MJ, Newman-Tancredi A, Quentric Y, Cussac D (2001). The ‘selective’ dopamine D1 receptor antagonist, SCH23390, is a potent and high efficacy agonist at cloned human serotonin2C receptors. Psychopharmacology (Berl) 156: 58–62.
Mowrer O, Jones H (1945). Habit strength as a function of the pattern of reinforcement. J Exp Psychiatry 35: 293–311.
Nader K, LeDoux JE (1999). Inhibition of the mesoamygdala dopaminergic pathway impairs the retrieval of conditioned fear associations. Behav Neurosci 113: 891–901.
National Research Council (1996). Guide for the Care and Use of Laboratory Animals. National Academy Press: Washington, DC.
Neisewander JL, Baker DA, Fuchs RA, Tran-Nguyen LT, Palmer A, Marshall JF (2000). Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment. J Neurosci 20: 798–805.
Neisewander JL, Fuchs RA, O'Dell LE, Khroyan TV (1998). Effects of SCH-23390 on dopamine D1 receptor occupancy and locomotion produced by intraaccumbens cocaine infusion. Synapse 30: 194–204.
Neisewander JL, O'Dell LE, Redmond JC (1995). Localization of dopamine receptor subtypes by intra-accumbens antagonists that reverse cocaine-induced locomotion. Brain Res 671: 201–212.
O'Dell LE, Sussman AN, Meyer KL, Neisewander JL (1999). Behavioral effects of psychomotor stimulant infusions into amygdaloid nuclei. Neuropsychopharmacology 20: 591–602.
Park WK, Bari AA, Jey AR, Anderson SM, Spealman RD, Rowlett JK et al (2002). Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by increasing AMPA receptor-mediated glutamate transmission in the nucleus accumbens. J Neurosci 22: 2916–2925.
Paxinos G, Watson C (1997). The Rat Brain in Stereotaxic Coordinates 3rd edn. Academic Press: San Diego.
Quinlan MG, Sharf R, Lee DY, Wise RA, Ranaldi R (2004). Blockade of substantia nigra dopamine D1 receptors reduces intravenous cocaine reward in rats. Psychopharmacology (Berl) 175: 53–59.
Ranaldi R, Wise RA (2001). Blockade of D1 dopamine receptors in the ventral tegmental area decreases cocaine reward: possible role for dendritically released dopamine. J Neurosci 21: 5841–5846.
Robledo P, Robbins TW, Everitt BJ (1996). Effects of excitotoxic lesions of the central amygdaloid nucleus on the potentiation of reward-related stimuli by intra-accumbens amphetamine. Behav Neurosci 110: 981–990.
See RE, Kruzich PJ, Grimm JW (2001). Dopamine, but not glutamate, receptor blockade in the basolateral amygdala attenuates conditioned reward in a rat model of relapse to cocaine-seeking behavior. Psychopharmacology (Berl) 154: 301–310.
Self DW, Barnhart WJ, Lehman DA, Nestler EJ (1996). Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists. Science 271: 1586–1589.
Self DW, Karanian DA, Spencer JJ (2000). Effects of the novel D1 dopamine receptor agonist ABT-431 on cocaine self-administration and reinstatement. Ann N Y Acad Sci 909: 133–144.
Shinonaga Y, Takada M, Mizuno N (1994). Topographic organization of collateral projections from the basolateral amygdaloid nucleus to both the prefrontal cortex and nucleus accumbens in the rat. Neuroscience 58: 389–397.
Shu SY (2003). Marginal division of the neostriatum: a subcortical memory center. J Biomed Sci 10: 14–29.
Shu SY, Bao XM, Ning Q, Wu YM, Wang J, Leonard BE (2003a). New component of the limbic system: marginal division of the neostriatum that links the limbic system to the basal nucleus of Meynert. J Neurosci Res 71: 751–757.
Shu SY, Bao XM, Wu YM, Wang J, Leonard B (2003b). Hippocampal long-term potentiation attenuated by lesions in the marginal division of neostriatum. Neurochem Res 28: 743–747.
Sun W, Rebec GV (2005). The role of prefrontal cortex D1-like and D2-like receptors in cocaine-seeking behavior in rats. Psychopharmacology (Berl) 177: 315–323.
Thomas KL, Arroyo M, Everitt BJ (2003). Induction of the learning and plasticity-associated gene Zif268 following exposure to a discrete cocaine-associated stimulus. Eur J Neurosci 17: 1964–1972.
Thomas KL, Everitt BJ (2001). Limbic-cortical-ventral striatal activation during retrieval of a discrete cocaine-associated stimulus: a cellular imaging study with gamma protein kinase C expression. J Neurosci 21: 2526–2535.
Tran-Nguyen LT, Fuchs RA, Coffey GP, Baker DA, O'Dell LE, Neisewander JL (1998). Time-dependent changes in cocaine-seeking behavior and extracellular dopamine levels in the amygdala during cocaine withdrawal. Neuropsychopharmacology 19: 48–59.
Wallace BC (1989). Psychological and environmental determinants of relapse in crack cocaine smokers. J Subst Abuse Treat 6: 95–106.
Wang GJ, Volkow ND, Fowler JS, Cervany P, Hitzemann RJ, Pappas NR et al (1999). Regional brain metabolic activation during craving elicited by recall of previous drug experiences. Life Sci 64: 775–784.
Weiss F, Martin-Fardon R, Ciccocioppo R, Kerr TM, Smith DL, Ben-Shahar O (2001). Enduring resistance to extinction of cocaine-seeking behavior induced by drug-related cues. Neuropsychopharmacology 25: 361–372.
Weissenborn R, Deroche V, Koob GF, Weiss F (1996). Effects of dopamine agonists and antagonists on cocaine-induced operant responding for a cocaine-associated stimulus. Psychopharmacology (Berl) 126: 311–322.
Whitelaw RB, Markou A, Robbins TW, Everitt BJ (1996). Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement. Psychopharmacology (Berl) 127: 213–224.
Yun IA, Fields HL (2003). Basolateral amygdala lesions impair both cue- and cocaine-induced reinstatement in animals trained on a discriminative stimulus task. Neuroscience 121: 747–757.
Acknowledgements
We thank Erin Lungren, Jessica Johnson, David Moritz, Laura Muhammad, and Thomas Shepherd for their expert technical assistance and Dr Cheryl Conrad, Dr Jeffrey Joyce, Dr Miles Orchinik, and Arturo Zavala for their helpful comments on an earlier version on this manuscript. This research was supported by NIDA grants DA11064 and DA06095, as well as by a grant from the Howard Hughes Medical Institute through the Biology Research Experience for Undergraduates program.
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Alleweireldt, A., Hobbs, R., Taylor, A. et al. Effects of SCH-23390 Infused into the Amygdala or Adjacent Cortex and Basal Ganglia on Cocaine Seeking and Self-Administration in Rats. Neuropsychopharmacol 31, 363–374 (2006). https://doi.org/10.1038/sj.npp.1300794
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DOI: https://doi.org/10.1038/sj.npp.1300794
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