Abstract
Rationale
Endocannabinoids are involved in a variety of behavioral and physiological processes that are just beginning to be understood. In the five-choice serial reaction-time task, exogenous cannabinoids have been found to alter attention, but endocannabinoids such as anandamide have not been studied.
Objectives
We used this task to evaluate the effects of anandamide in rats. Since anandamide is a ligand for not only cannabinoid receptors but also transient receptor potential vanilloid 1 (TRPV1) receptors, and as recently suggested, peroxisome proliferator-activated nuclear receptor-α (PPARα), we also determined whether anandamide’s effects in this task were mediated by each of these receptors.
Materials and methods
Whenever one of five holes was illuminated for 2 s, a food pellet was delivered if a response occurred in that hole during the light or within 2 s after the light.
Results
Anandamide increased omission errors and decreased responding during inter-trial intervals. These effects were blocked by the TRPV1 antagonist capsazepine, but not by the cannabinoid-receptor antagonist rimonabant or the PPARα antagonist MK886. Testing with open-field activity and food-consumption procedures in the same rats suggested that the disruption of operant responding observed in the attention task was not due to motor depression, anxiety, decreased appetite, or an inability to find and consume food pellets.
Conclusions
The vanilloid-dependent behavioral disruption induced by anandamide was specific to the operant attention task. These effects of anandamide resemble effects of systemically administered dopamine antagonists and might reflect changes in vanilloid-mediated dopamine transmission.
References
Arguello PA, Jentsch JD (2004) Cannabinoid CB1 receptor-mediated impairment of visuospatial attention in the rat. Psychopharmacology 177:141–150
Arizzi MN, Cervone KM, Aberman JE, Betz A, Liu Q, Lin S, Makriyannis A, Salamone JD (2004) Behavioral effects of inhibition of cannabinoid metabolism: the amidase inhibitor AM374 enhances the suppression of lever pressing produced by exogenously administered anandamide. Life Sci 74:1001–1011
Berridge KC (1996) Food reward: brain substrates of wanting and liking. Neurosci Biobehav Rev 20:1–25
Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949
Di Marzo V, Maccarrone M (2008) FAAH and anandamide: is 2-AG really the odd one out? Trends Pharmacol Sci 29:229–233
Di Marzo V, Lastres-Becker I, Bisogno T, De Petrocellis L, Milone A, Davis JB, Fernandez-Ruiz JJ (2001) Hypolocomotor effects in rats of capsaicin and two long chain capsaicin homologues. Eur J Pharmacol 420:123–131
Fegley D, Kathuria S, Mercier R, Li C, Goutopoulos A, Makriyannis A, Piomelli D (2004) Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172. Proc Natl Acad Sci USA 101:8756–8761
Hahn B, Shoaib M, Stolerman IP (2002) Effects of dopamine receptor antagonists on nicotine-induced attentional enhancement. Behav Pharmacol 13:621–632
Harrison AA, Everitt BJ, Robbins TW (1997) Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms. Psychopharmacology 133:329–342
Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ, Jung J, Cho S, Min KH, Suh YG, Kim D, Oh U (2000) Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci USA 97:6155–6160
Koskinen T, Sirviö J (2001) Studies on the involvement of the dopaminergic system in the 5-HT2 agonist (DOI)-induced premature responding in a five-choice serial reaction time task. Brain Res Bull 54:65–75
de Lago E, de Miguel R, Lastres-Becker I, Ramos JA, Fernández-Ruiz J (2004) Involvement of vanilloid-like receptors in the effects of anandamide on motor behavior and nigrostriatal dopaminergic activity: in vivo and in vitro evidence. Brain Res 1007:152–159
Lee J, Di Marzo V, Brotchie JM (2006) A role for vanilloid receptor 1 (TRPV1) and endocannabinoid signalling in the regulation of spontaneous and L-DOPA induced locomotion in normal and reserpine-treated rats. Neuropharmacology 51:557–565
Maccarrone M, Rossi S, Bari M, De Chiara V, Fezza F, Musella A, Gasperi V, Prosperetti C, Bernardi G, Finazzi-Agrò A, Cravatt BF, Centonze D (2008) Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum. Nat Neurosci 11:152–159
Mor M, Rivara S, Lodola A, Plazzi PV, Tarzia G, Duranti A, Tontini A, Piersanti G, Kathuria S, Piomelli D (2004) Cyclohexylcarbamic acid 3′- or 4′-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: synthesis, quantitative structure–activity relationships, and molecular modeling studies. J Med Chem 47:4998–5008
O’Sullivan SE (2007) Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol 152:576–582
Palmer SL, Thakur GA, Makriyannis A (2002) Cannabinergic ligands. Chem Phys Lipids 121:3–19
Passetti F, Levita L, Robbins TW (2003) Sulpiride alleviates the attentional impairments of rats with medial prefrontal cortex lesions. Behav Brain Res 138:59–69
Pattij T, Vanderschuren LJ (2008) The neuropharmacology of impulsive behaviour. Trends Pharmacol Sci 29:192–199
Pattij T, Janssen MC, Schepers I, González-Cuevas G, de Vries TJ, Schoffelmeer AN (2007) Effects of the cannabinoid CB1 receptor antagonist rimonabant on distinct measures of impulsive behavior in rats. Psychopharmacology 193:85–96
Piomelli D (2001) The ligand that came from within. Trends Pharmacol Sci 22:17–19
Presburger G, Robinson JK (1999) Spatial signal detection in rats is differentially disrupted by delta-9-tetrahydrocannabinol, scopolamine, and MK-801. Behav Brain Res 99:27–34
Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33
Robbins TW (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology 163:362–380
Rubino T, Realini N, Castiglioni C, Guidali C, Viganó D, Marras E, Petrosino S, Perletti G, Maccarrone M, Di Marzo V, Parolaro D (2008) Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex. Cereb Cortex 18:1292–1301
Salamone JD, Correa M (2002) Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine. Behav Brain Res 137:3–25
Scherma M, Medalie J, Fratta W, Vadivel SK, Makriyannis A, Piomelli D, Mikics E, Haller J, Yasar S, Tanda G, Goldberg SR (2008) The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition. Neuropharmacology 54:129–140
Starowicz K, Nigam S, Di Marzo V (2007) Biochemistry and pharmacology of endovanilloids. Pharmacol Ther 114:13–33
Sun Y, Alexander SP, Kendall DA, Bennett AJ (2006) Cannabinoids and PPARalpha signalling. Biochem Soc Trans 34:1095–1097
Tzavara ET, Li DL, Moutsimilli L, Bisogno T, Di Marzo V, Phebus LA, Nomikos GG, Giros B (2006) Endocannabinoids activate transient receptor potential vanilloid 1 receptors to reduce hyperdopaminergia-related hyperactivity: therapeutic implications. Biol Psychiatry 59:508–515
Valenzano KJ, Sun Q (2004) Current perspectives on the therapeutic utility of VR1 antagonists. Curr Med Chem 11:3185–3202
van Gaalen MM, van Koten R, Schoffelmeer AN, Vanderschuren LJ (2006) Critical involvement of dopaminergic neurotransmission in impulsive decision making. Biol Psychiatry 60:66–73
Veldhuis WB, van der Stelt M, Wadman MW, van Zadelhoff G, Maccarrone M, Fezza F, Veldink GA, Vliegenthart JF, Bär PR, Nicolay K, Di Marzo V (2003) Neuroprotection by the endogenous cannabinoid anandamide and arvanil against in vivo excitotoxicity in the rat: role of vanilloid receptors and lipoxygenases. J Neurosci 23:4127–4133
Verrico CD, Jentsch JD, Roth RH, Taylor JR (2004) Repeated, intermittent delta(9)-tetrahydrocannabinol administration to rats impairs acquisition and performance of a test of visuospatial divided attention. Neuropsychopharmacology 29:522–529
Wise RA, Raptis L (1986) Effects of naloxone and pimozide on initiation and maintenance measures of free feeding. Brain Res 368:62–68
Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sørgård M, Di Marzo V, Julius D, Högestätt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:452–457
Acknowledgments
This research was supported by the Intramural Research Program of the NIH, National Institute on Drug Abuse. We thank John E. Warner and Chanel Barnes for technical assistance.
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Panlilio, L.V., Mazzola, C., Medalie, J. et al. Anandamide-induced behavioral disruption through a vanilloid-dependent mechanism in rats. Psychopharmacology 203, 529–538 (2009). https://doi.org/10.1007/s00213-008-1399-x
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DOI: https://doi.org/10.1007/s00213-008-1399-x