Abstract
Rationale
Pavlovian conditioned approach paradigms are used to characterize the nature of motivational behaviors in response to stimuli as either directed toward the cue (i.e., sign-tracking) or the site of reward delivery (i.e., goal-tracking). Recent evidence has shown that activity of the endocannabinoid system increases dopaminergic activity in the mesocorticolimbic system, and other studies have shown that sign-tracking behaviors are dependent on dopamine.
Objectives
Therefore, we hypothesized that administration of a cannabinoid agonist would increase sign-tracking and decrease goal-tracking behaviors.
Methods
Forty-seven adult male Sprague-Dawley rats were given a low, medium, or high dose of the cannabinoid agonist CP-55,940 (N = 12 per group) or saline (N = 11) before Pavlovian conditioned approach training. A separate group of rats (N = 32) were sacrificed after PCA training for measurement of cannabinoid receptor type 1 (CB1) and fatty acid amide hydrolase (FAAH) using in situ hybridization.
Results
Contrary to our initial hypothesis, CP-55,940 dose-dependently decreased sign-tracking and increased goal-tracking behavior. CB1 expression was higher in sign-trackers compared with that in goal-trackers in the prelimbic cortex, but there were no significant differences in CB1 or FAAH expression in the infralimbic cortex, dorsal or ventral CA1, dorsal or ventral CA3, dorsal or ventral dentate gyrus, or amygdala.
Conclusions
These results demonstrate that cannabinoid signaling can specifically influence behavioral biases toward sign- or goal-tracking. Pre-existing differences in CB1 expression patterns, particularly in the prelimbic cortex, could contribute to individual differences in the tendency to attribute incentive salience to reward cues.
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References
Adamczyk P, McCreary AC, Przegalinski E, Mierzejewski P, Bienkowski P, Filip M (2009) The effects of fatty acid amide hydrolase inhibitors on maintenance of cocaine and food self-administration and on reinstatement of cocaine-seeking and food-taking behavior in rats. J Physiol Pharmacol 60:119–125
Bacharach SZ, Nasser HM, Zlebnik NE, Dantrassy HM, Kochli DE, Gyawali U, Cheer JF, Calu DJ (2018) Cannabinoid receptor-1 signaling contributions to sign-tracking and conditioned reinforcement in rats. Psychopharmacology 235:3031–3043. https://doi.org/10.1007/s00213-018-4993-6
Batten SR, Pomerleau F, Quintero J, Gerhardt GA, Beckmann JS (2018) The role of glutamate signaling in incentive salience: second-by-second glutamate recordings in awake Sprague-Dawley rats. J Neurochem 145:276–286. https://doi.org/10.1111/jnc.14298
Beckmann JS, Marusich JA, Gipson CD, Bardo MT (2011) Novelty seeking, incentive salience and acquisition of cocaine self-administration in the rat. Behav Brain Res 216:159–165. https://doi.org/10.1016/j.bbr.2010.07.022
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
Cheer JF, Wassum KM, Heien MLAV, Phillips PE, Wightman RM (2004) Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats. J Neurosci 24:4393–4400. https://doi.org/10.1523/JNEUROSCI.0529-04.2004
Chen J, Paredes W, Li J, Smith D, Lowinson J, Gardner EL (1990) Δ9-Tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacology 102:156–162. https://doi.org/10.1007/BF02245916
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. https://doi.org/10.1016/j.neuropharm.2016.06.028
Coria SM, Roura-Martínez D, Ucha M, Assis MA, Miguéns M, García-Lecumberri C, Higuera-Matas A, Ambrosio E (2014) Strain differences in the expression of endocannabinoid genes and in cannabinoid receptor binding in the brain of Lewis and Fischer 344 rats. Prog Neuro-Psychopharmacol Biol Psychiatry 53:15–22. https://doi.org/10.1016/j.pnpbp.2014.02.012
De Vries TJ, Shaham Y, Homberg JR et al (2001) A cannabinoid mechanism in relapse to cocaine seeking. Nat Med 7:1151–1154. https://doi.org/10.1038/nm1001-1151
De Vries TJ, Homberg JR, Binnekade R et al (2003) Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats. Psychopharmacology 168:164–169. https://doi.org/10.1007/s00213-003-1422-1
DiFeliceantonio AG, Berridge KC (2016) Dorsolateral neostriatum contribution to incentive salience: opioid or dopamine stimulation makes one reward cue more motivationally attractive than another. Eur J Neurosci 43:1203–1218. https://doi.org/10.1111/ejn.13220
Fattore L, Martellotta MC, Cossu G, Mascia MS, Fratta W (1999) CB1 cannabinoid receptor agonist WIN 55, 212-2 decreases intravenous cocaine self-administration in rats. Behav Brain Res 104:141–146. https://doi.org/10.1016/S0166-4328(99)00059-5
Fattore L, Spano MS, Cossu G, Deiana S, Fratta W (2003) Cannabinoid mechanism in reinstatement of heroin-seeking after a long period of abstinence in rats. Eur J Neurosci 17:1723–1726. https://doi.org/10.1046/j.1460-9568.2003.02607.x
Filbey FM, Schacht JP, Myers US, Chavez RS, Hutchison KE (2010) Individual and additive effects of the CNR1 and FAAH genes on brain response to marijuana cues. Neuropsychopharmacology 35:967–975. https://doi.org/10.1038/npp.2009.200
Fitzgerald ML, Shobin E, Pickel VM (2012) Cannabinoid modulation of the dopaminergic circuitry: implications for limbic and striatal output. Prog Neuro-Psychopharmacol Biol Psychiatry 38:21–29. https://doi.org/10.1016/j.pnpbp.2011.12.004
Fitzpatrick CJ, Morrow JD (2016) Pavlovian conditioned approach training in rats. JoVE (Journal of Visualized Experiments) e53580. https://doi.org/10.3791/53580,
Flagel SB, Cameron CM, Pickup KN, Watson SJ, Akil H, Robinson TE (2011a) A food predictive cue must be attributed with incentive salience for it to induce c-fos mRNA expression in cortico-striatal-thalamic brain regions. Neuroscience 196:80–96. https://doi.org/10.1016/j.neuroscience.2011.09.004
Flagel SB, Clark JJ, Robinson TE, Mayo L, Czuj A, Willuhn I, Akers CA, Clinton SM, Phillips PEM, Akil H (2011b) A selective role for dopamine in stimulus–reward learning. Nature 469:53–57. https://doi.org/10.1038/nature09588
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 46:2047–2055. https://doi.org/10.1111/ejn.13642
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. https://doi.org/10.1016/j.bbr.2016.02.022
Gamaleddin I, Wertheim C, Zhu AZX, Coen KM, Vemuri K, Makryannis A, Goldberg SR, le Foll B (2012) Cannabinoid receptor stimulation increases motivation for nicotine and nicotine seeking. Addict Biol 17:47–61. https://doi.org/10.1111/j.1369-1600.2011.00314.x
Gillis ZS, Morrison SE (2019) Sign tracking and goal tracking are characterized by distinct patterns of nucleus accumbens activity. eNeuro 6. https://doi.org/10.1523/ENEURO.0414-18.2019
Hansson AC, Bermúdez-Silva FJ, Malinen H, Hyytiä P, Sanchez-Vera I, Rimondini R, Rodriguez de Fonseca F, Kunos G, Sommer WH, Heilig M (2007) Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference. Neuropsychopharmacology 32:117–126. https://doi.org/10.1038/sj.npp.1301034
Hillard CJ, Weinlander KM, Stuhr KL (2012) Contributions of endocannabinoid signaling to psychiatric disorders in humans: genetic and biochemical evidence. Neuroscience 204:207–229. https://doi.org/10.1016/j.neuroscience.2011.11.020
López-Moreno JA, González-Cuevas G, de Fonseca FR, Navarro M (2004) Long-lasting increase of alcohol relapse by the cannabinoid receptor agonist WIN 55,212-2 during alcohol deprivation. J Neurosci 24:8245–8252. https://doi.org/10.1523/JNEUROSCI.2179-04.2004
López-Moreno JA, Echeverry-Alzate V, Bühler K-M (2012) The genetic basis of the endocannabinoid system and drug addiction in humans. J Psychopharmacol 26:133–143. https://doi.org/10.1177/0269881111416689
Mansouri E, Nobrega JN, Hill MN, Tyndale RF, Lee FS, Hendershot CS, Best LM, di Ciano P, Balsevich G, Sloan ME, Kish SJ, Tong J, le Foll B, Boileau I (2020) D3 dopamine receptors and a missense mutation of fatty acid amide hydrolase linked in mouse and men: implication for addiction. Neuropsychopharmacology 45:745–752. https://doi.org/10.1038/s41386-019-0580-8
McGregor IS, Dam KDB, Mallet PE, Gallate JE (2005) Δ9-THC reinstates beer- and sucrose-seeking behaviour in abstinent rats: comparison with midazolam, food deprivation and predator odour. Alcohol Alcohol 40:35–45. https://doi.org/10.1093/alcalc/agh113
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:e38987. https://doi.org/10.1371/journal.pone.0038987
Nawata Y, Yamaguchi T, Fukumori R, Yamamoto T (2019) Inhibition of monoacylglycerol lipase reduces the reinstatement of methamphetamine-seeking and anxiety-like behaviors in methamphetamine self-administered rats. Int J Neuropsychopharmacol 22:165–172. https://doi.org/10.1093/ijnp/pyy086
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
Robinson TE, Berridge KC (2000) The psychology and neurobiology of addiction: an incentive–sensitization view. Addiction 95:91–117. https://doi.org/10.1046/j.1360-0443.95.8s2.19.x
Rubino T, Massi P, Patrini G, Venier I, Giagnoni G, Parolaro D (1994) Chronic CP-55,940 alters cannabinoid receptor mRNA in the rat brain: an in situ hybridization study. Neuroreport 5:2493–2496. https://doi.org/10.1097/00001756-199412000-00022
Saunders BT, Robinson TE (2010) A cocaine cue acts as an incentive stimulus in some but not others: implications for addiction. Biol Psychiatry 67:730–736. https://doi.org/10.1016/j.biopsych.2009.11.015
Saunders BT, Robinson TE (2011) Individual variation in the motivational properties of cocaine. Neuropsychopharmacology 36:1668–1676. https://doi.org/10.1038/npp.2011.48
Saunders BT, Robinson TE (2012) The role of dopamine in the accumbens core in the expression of Pavlovian-conditioned responses. Eur J Neurosci 36:2521–2532. https://doi.org/10.1111/j.1460-9568.2012.08217.x
Scherma M, Panlilio LV, Fadda P, Fattore L, Gamaleddin I, le Foll B, Justinová Z, Mikics E, Haller J, Medalie J, Stroik J, Barnes C, Yasar S, Tanda G, Piomelli D, Fratta W, Goldberg SR (2008) Inhibition of anandamide hydrolysis by cyclohexyl carbamic acid 3′-carbamoyl-3-yl ester (URB597) reverses abuse-related behavioral and neurochemical effects of nicotine in rats. J Pharmacol Exp Ther 327:482–490. https://doi.org/10.1124/jpet.108.142224
Sloan ME, Gowin JL, Ramchandani VA, Hurd YL, le Foll B (2017) The endocannabinoid system as a target for addiction treatment: trials and tribulations. Neuropharmacology 124:73–83. https://doi.org/10.1016/j.neuropharm.2017.05.031
Solinas M, Justinova Z, Goldberg SR, Tanda G (2006) Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats. J Neurochem 98:408–419. https://doi.org/10.1111/j.1471-4159.2006.03880.x
Tanda G, Pontieri FE, Chiara GD (1997) Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common μ1 opioid receptor mechanism. Science 276:2048–2050. https://doi.org/10.1126/science.276.5321.2048
Tunstall BJ, Kearns DN (2015) Sign-tracking predicts increased choice of cocaine over food in rats. Behav Brain Res 281:222–228. https://doi.org/10.1016/j.bbr.2014.12.034
Versaggi CL, King CP, Meyer PJ (2016) The tendency to sign-track predicts cue-induced reinstatement during nicotine self-administration, and is enhanced by nicotine but not ethanol. Psychopharmacology 233:2985–2997. https://doi.org/10.1007/s00213-016-4341-7
Vlachou S, Nomikos GG, Panagis G (2003) WIN 55,212-2 decreases the reinforcing actions of cocaine through CB1 cannabinoid receptor stimulation. Behav Brain Res 141:215–222. https://doi.org/10.1016/S0166-4328(02)00370-4
Volkow ND, Fowler JS, Wang G-J, Goldstein RZ (2002) Role of dopamine, the frontal cortex and memory circuits in drug addiction: insight from imaging studies. Neurobiol Learn Mem 78:610–624. https://doi.org/10.1006/nlme.2002.4099
Yager LM, Robinson TE (2010) Cue-induced reinstatement of food seeking in rats that differ in their propensity to attribute incentive salience to food cues. Behav Brain Res 214:30–34. https://doi.org/10.1016/j.bbr.2010.04.021
Zhou Y, Schwartz BI, Giza J, Gross SS, Lee FS, Kreek MJ (2017) Blockade of alcohol escalation and “relapse” drinking by pharmacological FAAH inhibition in male and female C57BL/6J mice. Psychopharmacology 234:2955–2970. https://doi.org/10.1007/s00213-017-4691-9
Acknowledgments
The authors would like to thank Dr. Ken Mackie at the University of Indiana for his helpful advice and for providing the plasmids used for in situ hybridization experiments. We would also like to thank Dr. Stanley Watson and Ms. Jennifer Fitzpatrick at the University of Michigan for providing some material support for the in situ hybridization experiments. All experiments in this study comply with the current laws of the USA and were conducted in accordance with the Principles of laboratory animal care as set out by the Institutional Animal Care and Use Committee of the University of Michigan.
Funding
Funding for these studies was provided by the Brain & Behavior Research Foundation (NARSAD 20829 [JDM]), and the National Institute on Drug Abuse (NIDA; K08 DA037912 [JDM]; K01 DA044270 [LMC]; R01 DA044961 [JDM]; T32 DA007281 [CJF]; T32 DA07268 [AG]).
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Gheidi, A., Cope, L.M., Fitzpatrick, C.J. et al. Effects of the cannabinoid receptor agonist CP-55,940 on incentive salience attribution. Psychopharmacology 237, 2767–2776 (2020). https://doi.org/10.1007/s00213-020-05571-3
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DOI: https://doi.org/10.1007/s00213-020-05571-3