Approach and avoidance decisions are made when an animal experiences a state of motivational conflict inflicted by stimuli imbued with both positive and negative valences. The nucleus accumbens (NAc), a site where valenced information and action selection converge, has recently been found to be critically involved in the resolution of approach-avoidance conflict. However, the individual roles of the region’s dopamine receptor D1 (D1R)- and D2 (D2R)-expressing medium spiny neurons (MSNs) in regulating conflict resolution have not been well established.
Here, we examined the roles of NAc D1R and D2R in cue-elicited approach-avoidance decision-making.
Using a conditioned mixed-valence conflict paradigm, rats were initially trained in a radial maze to associate separate visuotactile cues with sucrose reward, foot shock punishment, and no outcome. Following acquisition of the cue-outcome associations, rats were subjected to a conditioned approach-avoidance conflict scenario, in which they were presented with a maze arm containing a superimposition of the reward and punishment cues, and another arm containing neutral cues.
Post-training intra-NAc D1R antagonism (SCH23390) led to an avoidance of the arm containing the mixed-valence cue over the neutral arm, whereas intra-NAc D2R antagonism (sulpiride) resulted in rats exhibiting a preference for the mixed-valence arm.
Our results suggest that NAc D1R and D2R exert differential control over decision-making involving cue-elicited approach-avoidance conflict resolution.
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Anderson SM, Schmidt HD, Pierce CR (2006) Administration of the D2 dopamine receptor antagonist sulpiride into the shell, but not the core, of the nucleus accumbens attenuates cocaine priming-induced reinstatement of drug seeking. Neuropsychopharmacology 31:1452-1461. https://doi.org/10.1038/sj.npp.1300922
Albin RL, Young AB, Penney JB (1989) Functional anatomy of basal ganglia disorders. Perspect Dis 12:366–375. https://doi.org/10.1146/annurev.ne.06.030183.000445
Alexander G (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9:357–381. https://doi.org/10.1146/annurev.neuro.9.1.357
Baker D, Fuchs R, Specio S et al (1998) Effects of intraaccumbens administration of SCH-23390 on cocaine-induced locomotion and conditioned place preference. Synapse 193:181–193
Balleine BW, Dickinson A (1998) Goal-directed instrumental action: contingency and incentive learning and their cortical substrates. Neuropharmacology 37:407–419. https://doi.org/10.1016/S0028-3908(98)00033-1
Beninger RJ, Miller R (1998) Dopamine D1-like receptors and reward-related incentive learning. Neurosci Biobehav Rev 22:335–345. https://doi.org/10.1016/S0149-7634(97)00019-5
Beninger RJ, Mason ST, Phillips AG, Fibiger HC (1980) The use of conditioned suppression to evaluate the nature of neuroleptic-induced avoidance deficits. J Pharmacol Exp Ther 213:623–627
Beninger RJ, Phillips AG, Fibiger HC (1983) Prior training and intermittent retraining attenuate pimozide-induced avoidance deficits. Pharmacol Biochem Behav 18:619–624. https://doi.org/10.1016/0091-3057(83)90290-3
Bock R, Shin JH, Kaplan AR, Dobi A, Markey E, Kramer PF, Gremel CM, Christensen CH, Adrover MF, Alvarez VA (2013) Strengthening the accumbal indirect pathway promotes resililence to compulsive cocaine use. Nat Neurosci 16:632–638
Boschen SL, Wietzikoski EC, Winn P, Da Cunha C (2011) The role of nucleus accumbens and dorsolateral striatal D2 receptors in active avoidance conditioning. Neurobiol Learn Mem 96:254–262. https://doi.org/10.1016/j.nlm.2011.05.002
Cachope R, Mateo Y, Mathur BN, Irving J, Wang HL, Morales M, Lovinger DM, Cheer JF (2012) Selective activation of cholinergic interneurons enhances accumbal phasic dopamine release: setting the tone for reward processing. Cell Rep 2:33–41. https://doi.org/10.1016/j.celrep.2012.05.011
Caine SB, Negus SS, Mello NK, Patel S, Bristow L, Kulagowski J, Vallone D, Saiardi A, Borrelli E (2002) Role of dopamine D2-like receptors in cocaine self-administration: studies with D2 receptor mutant mice and novel D2 receptor antagonists. J Neurosci 22:2977–2988
Cardinal RN, Parkinson JA, Hall J, Everitt BJ (2002) Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci Biobehav Rev 26:321–352. https://doi.org/10.1016/s0149-7634(02)00007-6
Charara A, Grace AA (2003) Dopamine receptor subtypes selectively modulate excitatory afferents from the hippocampus and amygdala to rat nucleus accumbens neurons. Neuropsychopharmacology 28:1412–1421. https://doi.org/10.1038/sj.npp.1300220
Farrar AM, Segovia KN, Randall PA, Nunes EJ, Collins LE, Stopper CM, Port RG, Hockemeyer J, Müller CE, Correa M, Salamone JD (2010) Nucleus accumbens and effort-related functions: behavioral and neural markers of the interactions between adenosine A2A and dopamine D2 receptors. Neuroscience 166:1056–1067. https://doi.org/10.1016/j.neuroscience.2009.12.056
Friedman A, Homma D, Gibb LG, Amemori KI, Rubin SJ, Hood AS, Riad MH, Graybiel AM (2015) A corticostriatal path targeting striosomes controls decision-making under conflict. Cell 161:1320–1333. https://doi.org/10.1016/j.cell.2015.04.049
Gagnon D, Petryszyn S, Sanchez MG, Bories C, Beaulieu JM, de Koninck Y, Parent A, Parent M (2017) Striatal neurons expressing D1 and D2 receptors are morphologically distinct and differently affected by dopamine denervation in mice. Sci Rep 7:41432. https://doi.org/10.1038/srep41432
Gerfen C, Surmeier D (2011) Modulation of striatal projection systems by dopamine. Annu Rev Neurosci 34:441–466. https://doi.org/10.1038/jid.2014.371
Goto Y, Grace AA (2005) Dopaminergic modulation of limbic and cortical drive of nucleus accumbens in goal-directed behavior. Nat Neurosci 8:805–812. https://doi.org/10.1038/nn1471
Grace AA (1991) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41:1–24. https://doi.org/10.1016/0306-4522(91)90196-U
Graybiel AM (2000) The Basal ganglia. Curr Biol 10:509–511. https://doi.org/10.1016/S0960-9822(00)00593-5
Hamel L, Thangarasa T, Samadi O, Ito R (2017) Caudal nucleus accumbens core is critical in the regulation of cue-elicited approach-avoidance decisions. Eneuro 4. https://doi.org/10.1523/ENEURO.0330-16.2017
Heimer L, Zahm DS, Churchill L, Kalivas PW, Wohltmann C (1991) Specificity in the projection patterns of accumbal core and shell in the rat. Neuroscience 41:89–125. https://doi.org/10.1016/0306-4522(91)90202-Y
Ito R, Lee ACH (2016) The role of the hippocampus in approach-avoidance conflict decision-making: evidence from rodent and human studies. Behav Brain Res 313:345–357. https://doi.org/10.1016/j.bbr.2016.07.039
Kalivas PW, Stewart J (1991) Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Rev 16:223–244. https://doi.org/10.1016/0165-0173(91)90007-U
Kravitz AV, Freeze BS, Parker PRL et al (2010) Regulation of parkinsonian motor behaviors by optogenetic control of basal ganglia circuitry. Nature 466:N28–N29. https://doi.org/10.1227/01.neu.0000389744.90809.e8
Kravitz AV, Tye LD, Kreitzer AC (2012) Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nat Neurosci 15:816–818. https://doi.org/10.1038/nn.3100
Kravitz AV, Tomasi D, Leblanc KH et al (2015) Cortico-striatal circuits: novel therapeutic targets for substance use disorders. Brain Res 1628:186–198. https://doi.org/10.1016/j.brainres.2015.03.048
Kupchik YM, Brown RM, Heinsbroek JA, Lobo MK, Schwartz DJ, Kalivas PW (2015) Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections. Nat Neurosci 18:1230–1232. https://doi.org/10.1038/nn.4068
Lammel S, Lim BK, Malenka RC (2014) Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacology 76:351–359. https://doi.org/10.1016/j.neuropharm.2013.03.019
Lobo MK, Nestler EJ (2011) The striatal balancing act in drug addiction: distinct roles of direct and indirect pathway medium spiny neurons. Front Neuroanat 5:1–11. https://doi.org/10.3389/fnana.2011.00041
Lobo MK, Covington HE, Chaudhury D et al (2010) Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science 330:385–390. https://doi.org/10.1126/science.1188472
Manago F, Castellano C, Oliverio A, Mele A, de Leonibus E (2008) Role of dopamine receptors subtypes, D1-like and D2-like, within the nucleus accumbens subregions, core and shell, on memory consolidation in the one-trial inhibitory avoidance task. Learn Mem 16:46–52. https://doi.org/10.1101/lm.1177509
Maurice N, Mercer J, Chan C, Hernandez-Lopez S, Held J, Tkatch T, Surmeier DJ (2004) D2 dopamine receptor-mediated modulation of voltage-dependent Na+ channels reduces autonomous activity in striatal cholinergic interneurons. J Neurosci 24:10289–10301. https://doi.org/10.1523/JNEUROSCI.2155-04.2004
McCullough LD, Sokolowski JD, Salamone JD (1993) A neurochemical and behavioral investigation of the involvement of nucleus accumbens dopamine in instrumental avoidance. Neuroscience 52:919–925. https://doi.org/10.1016/0306-4522(93)90538-Q
Mogenson GJ, Jones DL, Yim CY (1980) From motivation to action: functional interface between the limbic system and the motor system. Prog Neurobiol 14:69–97. https://doi.org/10.1016/0301-0082(80)90018-0
Nguyen D, Schumacher A, Erb S, Ito R (2015) Aberrant approach-avoidance conflict resolution following repeated cocaine pre-exposure. Psychopharmacology 232:3573–3583. https://doi.org/10.1007/s00213-015-4006-y
Nicola SM (2010) The flexible approach hypothesis: unification of effort and cue-responding hypotheses for the role of nucleus accumbens dopamine in the activation of reward-seeking behavior. J Neurosci 30:16585–16600. https://doi.org/10.1523/JNEUROSCI.3958-10.2010
Nieh EH, Kim SY, Namburi P, Tye KM (2013) Optogenetic dissection of neural circuits underlying emotional valence and motivated behaviors. Brain Res 1511:73–92. https://doi.org/10.1016/j.brainres.2012.11.001
Nowend KL, Arizzi M, Carlson BB, Salamone JD (2001) D1 or D2 antagonism in nucleus accumbens core or dorsomedial shell suppresses lever pressing for food but leads to compensatory increases in chow consumption. Pharmacol Biochem Behav 69:373–382. https://doi.org/10.1016/S0091-3057(01)00524-X
Nunes EJ, Randall PA, Santerre JL, Given AB, Sager TN, Correa M, Salamone JD (2010) Differential effects of selective adenosine antagonists on the effort-related impairments induced by dopamine D1 and D2 antagonism. Neuroscience 170:268–280. https://doi.org/10.1016/j.neuroscience.2010.05.068
Nunes EJ, Randall PA, Podurgiel S, Correa M, Salamone JD (2013) Nucleus accumbens neurotransmission and effort-related choice behavior in food motivation: effects of drugs acting on dopamine, adenosine, and muscarinic acetylcholine receptors. Neurosci Biobehav Rev 37:2015–2025. https://doi.org/10.1016/j.neubiorev.2013.04.002
Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Acad Press 1–474. https://doi.org/10.1007/s13398-014-0173-7.2
Pennartz CMA, Ito R, Verschure PFMJ, Battaglia FP, Robbins TW (2011) The hippocampal-striatal axis in learning, prediction and goal-directed behavior. Trends Neurosci 34:548–559. https://doi.org/10.1016/j.tins.2011.08.001
Pina MM, Cunningham CL (2014) Effects of dopamine receptor antagonists on the acquisition of ethanol-induced conditioned place preference in mice. Psychopharmacology 231:459–468. https://doi.org/10.1007/s00213-013-3252-0
Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247–291. https://doi.org/10.1016/0165-0173(93)90013-P
Santerre JL, Nunes EJ, Kovner R, Leser CE, Randall PA, Collins-Praino LE, Lopez Cruz L, Correa M, Baqi Y, Müller CE, Salamone JD (2012) The novel adenosine A2A antagonist prodrug MSX-4 is effective in animal models related to motivational and motor functions. Pharmacol Biochem Behav 102:477–487. https://doi.org/10.1016/j.pbb.2012.06.009
Schumacher A, Vlassov E, Ito R (2016) The ventral hippocampus, but not the dorsal hippocampus is critical for learned approach-avoidance decision making. Hippocampus 26:530–542. https://doi.org/10.1002/hipo.22542
Schumacher A, Villaruel FR, Ussling A, Riaz S, Lee ACH, Ito R (2018) Ventral hippocampal CA1 and CA3 differentially mediate learned approach-avoidance conflict processing. Curr Biol 28:1318–1324.e4
Serra G, Forgione A, D’Aquila PS et al (1990) Possible mechanism of antidepressant effect of l-sulpiride. Clin Neuropharmacol 13:S76–S83
Sigala S, Rizzonelli P, Zanelli E, Forgione A, Missale C, Spano PF (1991) Low doese of l-sulpiride down-regulate striatal and cortical dopamine receptors and B-adrenoceptors. Eur J Pharmacol 199:247–253
Smith RJ, Lobo MK, Spencer S, Kalivas PW (2013) Cocaine-induced adaptations in D1 and D2 accumbens projection neurons (a dichotomy not necessarily synonymous with direct and indirect pathways). Curr Opin Neurobiol 23:546–552. https://doi.org/10.1016/j.conb.2013.01.026
Soares-Cunha C, Coimbra B, David-Pereira A, Borges S, Pinto L, Costa P, Sousa N, Rodrigues AJ (2016a) Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation. Nat Commun 7:11829. https://doi.org/10.1038/ncomms11829
Soares-Cunha C, Coimbra B, Sousa N, Rodrigues AJ (2016b) Reappraising striatal D1- and D2-neurons in reward and aversion. Neurosci Biobehav Rev 68:370–386. https://doi.org/10.1016/j.neubiorev.2016.05.021
Threlfell S, Lalic T, Platt NJ, Jennings KA, Deisseroth K, Cragg SJ (2012) Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Neuron 75:58–64. https://doi.org/10.1016/j.neuron.2012.04.038
Volkow ND, Baler RD (2014) Addiction science: uncovering neurobiological complexity. Neuropharmacology 76:235–249. https://doi.org/10.1016/j.neuropharm.2013.05.007
Wakabayashi KT, Fields HL, Nicola SM (2004) Dissociation of the role of nucleus accumbens dopamine in responding to reward-predictive cues and waiting for reward. Behav Brain Res 154:19–30. https://doi.org/10.1016/j.bbr.2004.01.013
Wietzikoski EC, Boschen SL, Miyoshi E, Bortolanza M, dos Santos LM, Frank M, Brandão ML, Winn P, da Cunha C (2012) Roles of D1-like dopamine receptors in the nucleus accumbens and dorsolateral striatum in conditioned avoidance responses. Psychopharmacology 219:159–169. https://doi.org/10.1007/s00213-011-2384-3
Wolf ME (2016) Synaptic mechanisms underlying persistent cocaine craving. Nat Rev Neurosci 17:351–365. https://doi.org/10.1038/nrn.2016.39
Young EA, Dreumont SE, Cunningham CL (2014) Role of nucleus accumbens dopamine receptor subtypes in the learning and expression of alcohol-seeking behavior. Neurobiol Learn Mem 108:28–37. https://doi.org/10.1016/j.nlm.2013.05.004
Zahm DS, Heimer L (1990) Two transpallidal pathways originating in the rat nucleus accumbens. J Comp Neurol 302:437–446. https://doi.org/10.1002/cne.903020302
This work was supported by NSERC Discovery Grants 402642 and 240790 awarded to RI and SE.
The study was carried out in accordance with the regulations of the Canadian Council of Animal Care and the approval of the University of Toronto Animal Care Committee.
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Nguyen, D., Fugariu, V., Erb, S. et al. Dissociable roles of the nucleus accumbens D1 and D2 receptors in regulating cue-elicited approach-avoidance conflict decision-making. Psychopharmacology 235, 2233–2244 (2018). https://doi.org/10.1007/s00213-018-4919-3
- Ventral striatum