Endocannabinoids (eCBs) are critical gatekeepers of dopaminergic signaling, and disrupting cannabinoid receptor-1 (CB1) signaling alters DA dynamics to attenuate cue-motivated behaviors. Prior studies suggest that dopamine (DA) release plays a critical role in driving sign-tracking.
Here, we determine whether systemic injections of rimonabant, a CB1 receptor inverse agonist, during Pavlovian lever autoshaping impair the expression of sign-tracking. We next examine whether rimonabant blocks the reinforcing properties of the Pavlovian lever cue in a conditioned reinforcement test.
In Exp. 1, we trained rats in Pavlovian lever autoshaping prior to systemic rimonabant injections (0, 1, 3 mg/kg) during early and late Pavlovian lever autoshaping sessions. In Exp. 2, we trained rats in Pavlovian lever autoshaping prior to systemic rimonabant injections (0, 1 mg/kg) during a conditioned reinforcement test.
Rimonabant dose-dependently decreased lever contact and probability, and increased sign-tracker’s latency to approach the lever cue early in Pavlovian training. With extended training, many previously goal-tracking and intermediate rats shifted to lever approach, which remained dose-dependently sensitive to rimonabant. Rimonabant attenuated cue-evoked food cup approach early, but not late, in conditioning, and did not affect pellet retrieval or consumption. The inserted lever cue served as a robust conditioned reinforcer after Pavlovian lever autoshaping, and 1 mg/kg rimonabant blocked conditioned reinforcement.
Together, our results suggest that CB1 signaling mediates two critical properties of incentive stimuli; their ability to attract (Exp. 1) and their ability to reinforce (Exp. 2) behavior.
This is a preview of subscription content, log in to check access.
Buy single article
Instant unlimited access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Ahmad T, Laviolette SR (2017) Cannabinoid reward and aversion effects in the posterior ventral tegmental area are mediated through dissociable opiate receptor subtypes and separate amygdalar and accumbal dopamine receptor substrates. Psychopharmacology 234(15):2325–2336
Ahmad T, Lauzon NM, de Jaeger X, Laviolette SR (2013) Cannabinoid transmission in the prelimbic cortex bidirectionally controls opiate reward and aversion signaling through dissociable kappa versus mu-opiate receptor dependent mechanisms. J Neurosci 33(39):15642–15651
Ahmad T, Sun N, Lyons D, Laviolette SR (2017) Bi-directional cannabinoid signalling in the basolateral amygdala controls rewarding and aversive emotional processing via functional regulation of the nucleus accumbens. Addict Biol 22(5):1218–1231
Ahrens AM, Singer BF, Fitzpatrick CJ, Morrow JD, Robinson TE (2015) Rats that sign-track are resistant to Pavlovian but not instrumental extinction. Behav Brain Res 296:418–430
Anselme P, Robinson MJ, Berridge KC (2013) Reward uncertainty enhances incentive salience attribution as sign-tracking. Behav Brain Res 238:53–61
Beckmann JS, Chow JJ (2015) Isolating the incentive salience of reward-associated stimuli: value, choice, and persistence. Learn Mem 22(2):116–127
Blasio A, Rice KC, Sabino V, Cottone P (2014) Characterization of a shortened model of diet alternation in female rats: effects of the CB1 receptor antagonist rimonabant on food intake and anxiety-like behavior. Behav Pharmacol 25(7):609–617
Boakes R (1977) Operant pavlovian interactions. Erlbaum, Hillsdale
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(1):33–41
Campolongo P, Roozendaal B, Trezza V, Hauer D, Schelling G, McGaugh JL, Cuomo V (2009) Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory. Proc Natl Acad Sci U S A 106(12):4888–4893
Cheer JF, Wassum KM, Heien ML, Phillips PE, Wightman RM (2004) Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats. J Neurosci 24(18):4393–4400
Cheer JF, Wassum KM, Sombers LA, Heien ML, Ariansen JL, Aragona BJ, Phillips PE, Wightman RM (2007) Phasic dopamine release evoked by abused substances requires cannabinoid receptor activation. J Neurosci 27(4):791–795
Chow JJ, Nickell JR, Darna M, Beckmann JS (2016) Toward isolating the role of dopamine in the acquisition of incentive salience attribution. Neuropharmacology 109:320–331
Clark JJ, Collins AL, Sanford CA, Phillips PE (2013) Dopamine encoding of Pavlovian incentive stimuli diminishes with extended training. J Neurosci 33(8):3526–3532
Cohen J (1988) Statistical power analysis for the behavioral sciences. Lawrence Erlbaum Associates, Hillsdale
Collins AL, Aitken TJ, Greenfield VY, Ostlund SB, Wassum KM (2016) Nucleus Accumbens acetylcholine receptors modulate dopamine and motivation. Neuropsychopharmacology 41(12):2830–2838
Covey DP, Mateo Y, Sulzer D, Cheer JF, Lovinger DM (2017) Endocannabinoid modulation of dopamine neurotransmission. Neuropharmacology 124:52–61
Day JJ, Roitman MF, Wightman RM, Carelli RM (2007) Associative learning mediates dynamic shifts in dopamine signaling in the nucleus accumbens. Nat Neurosci 10(8):1020–1028
Di S, Itoga CA, Fisher MO, Solomonow J, Roltsch EA, Gilpin NW, Tasker JG (2016) Acute stress suppresses synaptic inhibition and increases anxiety via endocannabinoid release in the basolateral amygdala. J Neurosci 36(32):8461–8470
Everitt BJ, Robbins TW (2016) Drug addiction: updating actions to habits to compulsions ten years on. Annu Rev Psychol 67:23–50
Exley R, Clements MA, Hartung H, McIntosh JM, Cragg SJ (2008) Alpha6-containing nicotinic acetylcholine receptors dominate the nicotine control of dopamine neurotransmission in nucleus accumbens. Neuropsychopharmacology 33(9):2158–2166
Flagel SB, Watson SJ, Robinson TE, Akil H (2007) Individual differences in the propensity to approach signals vs goals promote different adaptations in the dopamine system of rats. Psychopharmacology 191(3):599–607
Flagel SB, Akil H, Robinson TE (2009) Individual differences in the attribution of incentive salience to reward-related cues: implications for addiction. Neuropharmacology 56(Suppl 1):139–148
Flagel SB, Clark JJ, Robinson TE, Mayo L, Czuj A, Willuhn I, Akers CA, Clinton SM, Phillips PE, Akil H (2011) A selective role for dopamine in stimulus-reward learning. Nature 469(7328):53–57
Fraser KM, Janak PH (2017) Long-lasting contribution of dopamine in the nucleus accumbens core, but not dorsal lateral striatum, to sign-tracking. Eur J Neurosci 46(4):2047–2055
Fraser KM, Haight JL, Gardner EL, Flagel SB (2016) Examining the role of dopamine D2 and D3 receptors in Pavlovian conditioned approach behaviors. Behav Brain Res 305:87–99
Gremel CM, Chancey JH, Atwood BK, Luo G, Neve R, Ramakrishnan C, Deisseroth K, Lovinger DM, Costa RM (2016) Endocannabinoid modulation of Orbitostriatal circuits gates habit formation. Neuron 90(6):1312–1324
Hearst E, Jenkins H (1974) Sign-tracking: the stimulus–reinforcer relation and directed action. Monograph of the Psychonomic Society, Austin
Hernandez G, Cheer JF (2012) Effect of CB1 receptor blockade on food-reinforced responding and associated nucleus accumbens neuronal activity in rats. J Neurosci 32(33):11467–11477
Lau BK, Cota D, Cristino L, Borgland SL (2017) Endocannabinoid modulation of homeostatic and non-homeostatic feeding circuits. Neuropharmacology 124:38–51
Lopez JC, Karlsson RM, O'Donnell P (2015) Dopamine D2 modulation of sign and goal tracking in rats. Neuropsychopharmacology 40(9):2096–2102
Lupica CR, Riegel AC (2005) Endocannabinoid release from midbrain dopamine neurons: a potential substrate for cannabinoid receptor antagonist treatment of addiction. Neuropharmacology 48(8):1105–1116
Madayag AC, Stringfield SJ, Reissner KJ, Boettiger CA, Robinson DL (2017) Sex and adolescent ethanol exposure influence Pavlovian conditioned approach. Alcohol Clin Exp Res 41:846–856
Mahler SV, Smith KS, Berridge KC (2007) Endocannabinoid hedonic hotspot for sensory pleasure: anandamide in nucleus accumbens shell enhances 'liking' of a sweet reward. Neuropsychopharmacology 32(11):2267–2278
Mateo Y, Johnson KA, Covey DP, Atwood BK, Wang HL, Zhang S, Gildish I, Cachope R, Bellocchio L, Guzman M, Morales M, Cheer JF, Lovinger DM (2017) Endocannabinoid actions on cortical terminals orchestrate local modulation of dopamine release in the nucleus Accumbens. Neuron 96(5):1112–1126 e1115
McCarthy MM, Woolley CS, Arnold AP (2017) Incorporating sex as a biological variable in neuroscience: what do we gain? Nat Rev Neurosci 18(12):707–708
Melis M, Pistis M, Perra S, Muntoni AL, Pillolla G, Gessa GL (2004) Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. J Neurosci 24(1):53–62
Meyer PJ, Lovic V, Saunders BT, Yager LM, Flagel SB, Morrow JD, Robinson TE (2012) Quantifying individual variation in the propensity to attribute incentive salience to reward cues. PLoS One 7(6):e38987
Miller LR, Marks C, Becker JB, Hurn PD, Chen WJ, Woodruff T, McCarthy MM, Sohrabji F, Schiebinger L, Wetherington CL, Makris S, Arnold AP, Einstein G, Miller VM, Sandberg K, Maier S, Cornelison TL, Clayton JA (2017) Considering sex as a biological variable in preclinical research. FASEB J 31(1):29–34
Morrison SE, Bamkole MA, Nicola SM (2015) Sign tracking, but not goal tracking, is resistant to outcome devaluation. Front Neurosci 9:468
Nasser HM, Chen YW, Fiscella K, Calu DJ (2015) Individual variability in behavioral flexibility predicts sign-tracking tendency. Front Behav Neurosci 9:289
Oleson EB, Beckert MV, Morra JT, Lansink CS, Cachope R, Abdullah RA, Loriaux AL, Schetters D, Pattij T, Roitman MF, Lichtman AH, Cheer JF (2012) Endocannabinoids shape accumbal encoding of cue-motivated behavior via CB1 receptor activation in the ventral tegmentum. Neuron 73(2):360–373
Pitchers KK, Flagel SB, O'Donnell EG, Woods LC, Sarter M, Robinson TE (2015) Individual variation in the propensity to attribute incentive salience to a food cue: influence of sex. Behav Brain Res 278:462–469
Riegel AC, Lupica CR (2004) Independent presynaptic and postsynaptic mechanisms regulate endocannabinoid signaling at multiple synapses in the ventral tegmental area. J Neurosci 24(49):11070–11078
Robinson TE, Flagel SB (2009) Dissociating the predictive and incentive motivational properties of reward-related cues through the study of individual differences. Biol Psychiatry 65(10):869–873
Saddoris MP, Wang X, Sugam JA, Carelli RM (2016) Cocaine self-administration experience induces pathological phasic Accumbens dopamine signals and abnormal incentive behaviors in drug-abstinent rats. J Neurosci 36(1):235–250
Saunders BT, Robinson TE (2012) The role of dopamine in the accumbens core in the expression of Pavlovian-conditioned responses. Eur J Neurosci 36(4):2521–2532
Smedley EB, Smith KS (2018) Evidence of structure and persistence in motivational attraction to serial Pavlovian cues. Learn Mem 25(2):78–89
Solinas M, Goldberg SR (2005) Motivational effects of cannabinoids and opioids on food reinforcement depend on simultaneous activation of cannabinoid and opioid systems. Neuropsychopharmacology 30(11):2035–2045
Solinas M, Goldberg SR, Piomelli D (2008) The endocannabinoid system in brain reward processes. Br J Pharmacol 154(2):369–383
Soria-Gomez E, Bellocchio L, Reguero L, Lepousez G, Martin C, Bendahmane M, Ruehle S, Remmers F, Desprez T, Matias I, Wiesner T, Cannich A, Nissant A, Wadleigh A, Pape HC, Chiarlone AP, Quarta C, Verrier D, Vincent P, Massa F, Lutz B, Guzman M, Gurden H, Ferreira G, Lledo PM, Grandes P, Marsicano G (2014) The endocannabinoid system controls food intake via olfactory processes. Nat Neurosci 17(3):407–415
Szabo B, Siemes S, Wallmichrath I (2002) Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids. Eur J Neurosci 15(12):2057–2061
Tallett AJ, Blundell JE, Rodgers RJ (2007) Grooming, scratching and feeding: role of response competition in acute anorectic response to rimonabant in male rats. Psychopharmacology 195(1):27–39
Tan H, Lauzon NM, Bishop SF, Chi N, Bechard M, Laviolette SR (2011) Cannabinoid transmission in the basolateral amygdala modulates fear memory formation via functional inputs to the prelimbic cortex. J Neurosci 31(14):5300–5312
Taylor JR, Robbins TW (1984) Enhanced behavioural control by conditioned reinforcers following microinjections of d-amphetamine into the nucleus accumbens. Psychopharmacology 84(3):405–412
Thornton-Jones ZD, Vickers SP, Clifton PG (2005) The cannabinoid CB1 receptor antagonist SR141716A reduces appetitive and consummatory responses for food. Psychopharmacology 179(2):452–460
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(1):58–64
Tomie A (1996) Locating reward cue at response manipulandum (CAM) induces symptoms of drug abuse. Neurosci Biobehav Rev 20(3):505–535
Trezza V, Damsteegt R, Manduca A, Petrosino S, Van Kerkhof LW, Pasterkamp RJ, Zhou Y, Campolongo P, Cuomo V, Di Marzo V, Vanderschuren LJ (2012) Endocannabinoids in amygdala and nucleus accumbens mediate social play reward in adolescent rats. J Neurosci 32(43):14899–14908
Villaruel FR, Chaudhri N (2016) Individual differences in the attribution of incentive salience to a Pavlovian alcohol cue. Front Behav Neurosci 10:238
Wagner EJ (2016) Sex differences in cannabinoid-regulated biology: a focus on energy homeostasis. Front Neuroendocrinol 40:101–109
Wenzel JM, Oleson EB, Gove WN, Cole AB, Gyawali U, Dantrassy HM, Bluett RJ, Dryanovski DI, Stuber GD, Deisseroth K, Mathur BN, Patel S, Lupica CR, Cheer JF (2018) Phasic dopamine signals in the nucleus Accumbens that cause active avoidance require endocannabinoid mobilization in the midbrain. Curr Biol 28(9):1392–1404 e1395
Wolterink G, Phillips G, Cador M, Donselaar-Wolterink I, Robbins TW, Everitt BJ (1993) Relative roles of ventral striatal D1 and D2 dopamine receptors in responding with conditioned reinforcement. Psychopharmacology 110(3):355–364
Zador F, Lenart N, Csibrany B, Santha M, Molnar M, Tuka B, Samavati R, Klivenyi P, Vecsei L, Marton A, Vizler C, Nagy GM, Borsodi A, Benyhe S, Paldy E (2015) Low dosage of rimonabant leads to anxiolytic-like behavior via inhibiting expression levels and G-protein activity of kappa opioid receptors in a cannabinoid receptor independent manner. Neuropharmacology 89:298–307
All procedures were performed in accordance with the “Guide for the care and use of laboratory animals” (8th edition, 2011, US National Research Council) and were approved by the University of Maryland, School of Medicine Institutional Animal Care and Use Committee (IACUC).
Conflict of interest
The authors declare that they have no conflict of interest.
About this article
Cite this article
Bacharach, S.Z., Nasser, H.M., Zlebnik, N.E. et al. Cannabinoid receptor-1 signaling contributions to sign-tracking and conditioned reinforcement in rats. Psychopharmacology 235, 3031–3043 (2018) doi:10.1007/s00213-018-4993-6
- CB1 receptor
- Conditioned reinforcement