Abstract
Rationale
Cannabinoid CB1 inverse agonists hold therapeutic promise as appetite suppressants but have produced suicidal behaviors among a small subpopulation in clinical trials. Anatomical and pharmacological evidence implicate the 5HT1A serotonin receptor in suicide in humans and impulsivity in humans and animals.
Objective
The objective of the study is to assess whether 5HT1A blockade is necessary for CB1 ligands to produce impulsivity.
Methods
Sprague Dawley rats were administered the CB1 inverse agonist AM 251, the CB1 antagonist AM 6527, or the peripherally restricted antagonist AM 6545, with or without pretreatment with the 5HT1A antagonist WAY 100,635 (WAY) on the paced fixed consecutive number (FCN) task, which measures choice to terminate a chain of responses prematurely. As FCN is sensitive to changes in time perception, which have been demonstrated with CB1 blockade, a novel variable consecutive number task with discriminative stimulus (VCN-S D ) was also performed and proposed to be less sensitive to changes in timing.
Results
Pretreatment with WAY enabled mild but significant reductions in FCN accuracy for AM 251 and AM 6527. No effects were found for AM 6545. On the VCN-S D task, substantial impairments were found for the combination of WAY and AM 251.
Conclusions
AM 251, but not the antagonists AM 6527 or AM 6545, produced impulsivity only following systemic 5HT1A blockade. Although preliminary, the results may indicate that disrupted serotonin signaling produces a vulnerability to undesirable effects of CB1 inverse agonists, which is not evident in the general population. Furthermore, neutral CB1 antagonists do not produce this effect and therefore may have greater safety.
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References
Arango V, Underwood MD, Boldrini M et al (2001) Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology 25:892–903. doi:10.1016/S0893-133X(01)00310-4
Aso E, Renoir T, Mengod G et al (2009) Lack of CB1 receptor activity impairs serotonergic negative feedback. J Neurochem 109:935–944. doi:10.1111/j.1471-4159.2009.06025.x
Bagdy G, Juhasz G, Gonda X (2012) A new clinical evidence-based gene-environment interaction model of depression. Neuropsychopharmacol Hungarica 14:213–220. doi:10.5706/nph201212001
Bambico FR, Katz N, Debonnel G, Gobbi G (2007) Cannabinoids elicit antidepressant-like behavior and activate serotonergic neurons through the medial prefrontal cortex. J Neurosci 27:11700–11711. doi:10.1523/JNEUROSCI.1636-07.2007
Bambico FR, Duranti A, Tontini A et al (2009) Endocannabinoids in the treatment of mood disorders: evidence from animal models. Curr Pharm Des 15:1623–1646
Beyer CE, Dwyer JM, Piesla MJ et al (2010) Depression-like phenotype following chronic CB1 receptor antagonism. Neurobiol Dis 39:148–155. doi:10.1016/j.nbd.2010.03.020
Bhagwagar Z, Rabiner E, Sargent P et al (2004) Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635. Mol Psychiatry 9:386–392. doi:10.1038/sj.mp.4001401
Blasio A, Narayan AR, Kaminski BJ et al (2012) A modified adjusting delay task to assess impulsive choice between isocaloric reinforcers in non-deprived male rats: effects of 5-HT2A/C and 5-HT1A receptor agonists. Psychopharmacology 219:377–386. doi:10.1007/s00213-011-2517-8
Blier P, de Montigny C (1994) Current advances and trends in the treatment of depression. Trends Pharmacol Sci 15:220–226
Boggs DL, Kelly DL, McMahon RP et al (2012) Rimonabant for neurocognition in schizophrenia: a 16-week double blind randomized placebo controlled trial. Schizophr Res 134:207–210. doi:10.1016/j.schres.2011.11.009
Boomhower SR, Rasmussen EB, Doherty TS (2013) Impulsive-choice patterns for food in genetically lean and obese Zucker rats. Behav Brain Res 241:214–221. doi:10.1016/j.bbr.2012.12.013
Breukelaar JW, Dalrymple-Alford JC (1998) Timing ability and numerical competence in rats. J Exp Psychol Anim Behav Process 24:84–97. doi:10.1037/0097-7403.24.1.84
Brezo J, Paris J, Turecki G (2006) Personality traits as correlates of suicidal ideation, suicide attempts, and suicide completions: a systematic review. Acta Psychiatr Scand 113:180–206. doi:10.1111/j.1600-0447.2005.00702.x
Carli M, Samanin R (2000) The 5-HT1(A) receptor agonist 8-OH-DPAT reduces rats’ accuracy of attentional performance and enhances impulsive responding in a five-choice serial reaction time task: role of presynaptic 5-HT1(A) receptors. Psychopharmacology 149:259–268. doi:10.1007/s002139900368
Celada P, Bortolozzi A, Artigas F (2013) Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research. CNS Drugs 27:703–716. doi:10.1007/s40263-013-0071-0
Christensen R, Kristensen PK, Bartels EM et al (2007) Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 370:1706–1713. doi:10.1016/S0140-6736(07)61721-8
Cluny NL, Vemuri VK, Chambers AP et al (2010) A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents. Br J Pharmacol 161:629–642. doi:10.1111/j.1476-5381.2010.00908.x
Courtet P, Baud P, Abbar M et al (2001) Association between violent suicidal behavior and the low activity allele of the serotonin transporter gene. Mol Psychiatry 6:338–341. doi:10.1038/sj.mp.4000856
Dalley JW, Roiser JP (2012) Dopamine, serotonin and impulsivity. Neuroscience 215:42–58. doi:10.1016/j.neuroscience.2012.03.065
Dalley JW, Everitt BJ, Robbins TW (2011) Impulsivity, compulsivity, and top-down cognitive control. Neuron 69:680–694. doi:10.1016/j.neuron.2011.01.020
Davis H, Memmott J (1983) Autocontingencies: rats count to three to predict safety from shock. Anim Learn Behav 11:95–100. doi:10.3758/BF03212314
Dellu-Hagedorn F (2006) Relationship between impulsivity, hyperactivity and working memory: a differential analysis in the rat. Behav Brain Funct 2:10. doi:10.1186/1744-9081-2-10
Deroche-Gamonet V, Le Moal M, Piazza P, Soubrié P (2001) SR141716, a CB1 receptor antagonist, decreases the sensitivity to the reinforcing effects of electrical brain stimulation in rats. Psychopharmacology 157:254–259. doi:10.1007/s002130100804
Di Narzo AF, Kozlenkov A, Roussos P et al (2014) A unique gene expression signature associated with serotonin 2C receptor RNA editing in the prefrontal cortex and altered in suicide. Hum Mol Genet 23:4801–4813. doi:10.1093/hmg/ddu195
Dillon GM, Lubbers LS, Ferguson MT et al (2011) MK-7128, a novel CB1 receptor inverse agonist, improves scopolamine-induced learning and memory deficits in mice. Behav Pharmacol 22:91–100. doi:10.1097/FBP.0b013e3283423d7e
Dougherty DM, Mathias CW, Marsh DM et al (2004) Laboratory measured behavioral impulsivity relates to suicide attempt history. Suicide Life Threat Behav 34:374–385. doi:10.1521/suli.34.4.374.53738
Dvorak RD, Lamis DA, Malone PS (2013) Alcohol use, depressive symptoms, and impulsivity as risk factors for suicide proneness among college students. J Affect Disord 149:326–334. doi:10.1016/j.jad.2013.01.046
Evenden JL (1998) The pharmacology of impulsive behaviour in rats IV: the effects of selective serotonergic agents on a paced fixed consecutive number schedule. Psychopharmacology 140:319–330. doi:10.1007/s002130050773
Evenden JL (1999) Varieties of impulsivity. Psychopharmacology 146:348–361. doi:10.1007/PL00005481
Evenden J, Meyerson B (1999) The behavior of spontaneously hypertensive and Wistar Kyoto rats under a paced fixed consecutive number schedule of reinforcement. Pharmacol Biochem Behav 63:71–82. doi:10.1016/S0091-3057(98)00222-6
Fink LH, Anastasio NC, Fox RG et al (2015) Individual differences in impulsive action reflect variation in the cortical serotonin 5-HT2A receptor system. Neuropsychopharmacology 40:1–45. doi:10.1038/npp.2015.46
Fletcher PJ, Tampakeras M, Sinyard J, Higgins GA (2007) Opposing effects of 5-HT2A and 5-HT2C receptor antagonists in the rat and mouse on premature responding in the five-choice serial reaction time test. Psychopharmacology 195:223–234. doi:10.1007/s00213-007-0891-z
Gvion Y, Horresh N, Levi-Belz Y et al (2014) Aggression-impulsivity, mental pain, and communication difficulties in medically serious and medically non-serious suicide attempters. Compr Psychiatry 55:40–50. doi:10.1016/j.comppsych.2013.09.003
Halcomb ME, Gould TD, Grahame NJ (2013) Lithium, but not valproate, reduces impulsive choice in the delay-discounting task in mice. Neuropsychopharmacology 38:1937–1944. doi:10.1038/npp.2013.89
Han CJ, Robinson JK (2001) Cannabinoid modulation of time estimation in the rat. Behav Neurosci 115:243–246. doi:10.1037/0735-7044.115.1.243
Hill MN, Ho WSV, Hillard CJ, Gorzalka BB (2008) Differential effects of the antidepressants tranylcypromine and fluoxetine on limbic cannabinoid receptor binding and endocannabinoid contents. J Neural Transm 115:1673–1679. doi:10.1007/s00702-008-0131-7
Hodge J, Bow JP, Plyler KS et al (2008) The cannabinoid CB1 receptor inverse agonist AM 251 and antagonist AM 4113 produce similar effects on the behavioral satiety sequence in rats. Behav Brain Res 193:298–305. doi:10.1016/j.bbr.2008.06.010
Hsiung SC, Adlersberg M, Arango V et al (2003) Attenuated 5-HT1A receptor signaling in brains of suicide victims: involvement of adenylyl cyclase, phosphatidylinositol 3-kinase, Akt and mitogen-activated protein kinase. J Neurochem 87:182–194. doi:10.1046/j.1471-4159.2003.01987.x
Institute of Laboratory Animal Resources (2011) Guide for the care and use of laboratory animals, 8th edn. National Academy Press, Washington DC
Ito H, Halldin C, Farde L (1999) Localization of 5-HT1A receptors in the living human brain using [carbonyl-11C]WAY-100635: PET with anatomic standardization technique. J Nucl Med 40:102–109
Johansson K, Neovius K, Desantis SM et al (2009) Discontinuation due to adverse events in randomized trials of orlistat, sibutramine and rimonabant: a meta-analysis. Obes Rev 10:564–575. doi:10.1111/j.1467-789X.2009.00581.x
Keppel G, Wickens TD (2004) Design and analysis: a researcher’s handbook, 4th edn. Prentice-Hall, Englewood Cliffs
Kirilly E, Hunyady L, Bagdy G (2013) Opposing local effects of endocannabinoids on the activity of noradrenergic neurons and release of noradrenaline: relevance for their role in depression and in the actions of CB1 receptor antagonists. J Neural Transm 120:177–186. doi:10.1007/s00702-012-0900-1
Klonsky ED, May AM (2010) Rethinking impulsivity in suicide. Suicide Life Threat Behav 40:612–619. doi:10.1521/suli.2010.40.6.612
Laties VG (1972) The modification of drug effects on behavior by external discriminative stimuli. J Pharmacol Exp Ther 183:1–13
Lazary J, Juhasz G, Hunyady L, Bagdy G (2011) Personalized medicine can pave the way for the safe use of CB1 receptor antagonists. Trends Pharmacol Sci 32:270–280. doi:10.1016/j.tips.2011.02.013
Le Foll B, Forget B, Aubin HJ, Goldberg SR (2008) Blocking cannabinoid CB1 receptors for the treatment of nicotine dependence: insights from pre-clinical and clinical studies. Addict Biol 13:239–252. doi:10.1111/j.1369-1600.2008.00113.x
Lemonde S, Turecki G, Bakish D et al (2003) Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 23:8788–8799
Limebeer CL, Vemuri VK, Bedard H et al (2010) Inverse agonism of cannabinoid CB 1 receptors potentiates LiCl-induced nausea in the conditioned gaping model in rats. Br J Pharmacol 161:336–349. doi:10.1111/j.1476-5381.2010.00885.x
Lindström MB, Ryding E, Bosson P et al (2004) Impulsivity related to brain serotonin transporter binding capacity in suicide attempters. Eur Neuropsychopharmacol 14:295–300. doi:10.1016/j.euroneuro.2003.11.001
Malkesman O, Pine DS, Tragon T et al (2009) Animal models of suicide-trait-related behaviors. Trends Pharmacol Sci 30:165–173. doi:10.1016/j.tips.2009.01.004
Malone DT, Taylor DA (1998) Modulation of delta9-tetrahydrocannabinol-induced hypothermia by fluoxetine in the rat. Br J Pharmacol 124:1419–1424. doi:10.1038/sj.bjp.0701980
Malone DT, Taylor DA (1999) Modulation by fluoxetine of striatal dopamine release following Delta9-tetrahydrocannabinol: a microdialysis study in conscious rats. Br J Pharmacol 128:21–26. doi:10.1038/sj.bjp.0702753
Mansbach RS, Rovetti CC, Winston EN, Lowe JA (1996) Effects of the cannabinoid CB1 receptor antagonist SR141716A on the behavior of pigeons and rats. Psychopharmacology 124:315–322. doi:10.1007/BF02247436
Mathew RJ, Wilson WH, Turkington TG, Coleman RE (1998) Cerebellar activity and disturbed time sense after THC. Brain Res 797:183–189
Mato S, Vidal R, Castro E et al (2010) Long-term fluoxetine treatment modulates cannabinoid type 1 receptor-mediated inhibition of adenylyl cyclase in the rat prefrontal cortex through 5-hydroxytryptamine 1A receptor-dependent mechanisms. Mol Pharmacol 77:424–434. doi:10.1124/mol.109.060079
McLaughlin PJ (2012) Reports of the death of CB1 antagonists have been greatly exaggerated: recent preclinical findings predict improved safety in the treatment of obesity. Behav Pharmacol 23:537–550. doi:10.1097/FBP.0b013e3283566a8c
McLaughlin PJ, Winston K, Swezey L et al (2003) The cannabinoid CB1 antagonists SR 141716A and AM 251 suppress food intake and food-reinforced behavior in a variety of tasks in rats. Behav Pharmacol 14:583–588. doi:10.1097/00008877-200312000-00002
McLaughlin PJ, Brown CM, Winston KM et al (2005) The novel cannabinoid agonist AM 411 produces a biphasic effect on accuracy in a visual target detection task in rats. Behav Pharmacol 16:477–486
McLaughlin PJ, Winston KM, Swezey LA et al (2010) Detailed analysis of food-reinforced operant lever pressing distinguishes effects of a cannabinoid CB1 inverse agonist and dopamine D1 and D2 antagonists. Pharmacol Biochem Behav 96:75–81. doi:10.1016/j.pbb.2010.04.009
Mechner F, Guevrekian L (1962) Effects of deprivation upon counting and timing in rats. J Exp Anal Behav 5:463–466. doi:10.1901/jeab.1962.5-463
Minzenberg MJ, Grossman R, New AS et al (2005) Blunted hormone responses to ipsapirone are associated with trait impulsivity in personality disorder patients. Neuropsychopharmacology 2:197–203. doi:10.1038/sj.npp.1300853
Moreira FA, Crippa JAS (2009) The psychiatric side-effects of rimonabant. Rev Bras Psiquiatr 31:145–153. doi:10.1590/S1516-44462009000200012
Nissen SE, Nicholls SJ, Wolski K et al (2008) Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA 299:1547–1560. doi:10.1001/jama.299.13.1547
Pattij T, Janssen MCW, Schepers I et al (2007) Effects of the cannabinoid CB1 receptor antagonist rimonabant on distinct measures of impulsive behavior in rats. Psychopharmacology 193:85–96. doi:10.1007/s00213-007-0773-4
Randall PA, Vemuri VK, Segovia KN et al (2010) The novel cannabinoid CB1 antagonist AM6545 suppresses food intake and food-reinforced behavior. Pharmacol Biochem Behav 97:179–184. doi:10.1016/j.pbb.2010.07.021
Reynolds B, Ortengren A, Richards JB, de Wit H (2006) Dimensions of impulsive behavior: personality and behavioral measures. Pers Individ Dif 40:305–315. doi:10.1016/j.paid.2005.03.024
Rivalan M, Grégoire S, Dellu-Hagedorn F (2007) Reduction of impulsivity with amphetamine in an appetitive fixed consecutive number schedule with cue for optimal performance in rats. Psychopharmacology 192:171–182. doi:10.1007/s00213-007-0702-6
Sagredo O, Ramos JA, Fernández-Ruiz J et al (2006) Chronic Δ9-tetrahydrocannabinol administration affects serotonin levels in the rat frontal cortex. Naunyn Schmiedeberg's Arch Pharmacol 372:313–317. doi:10.1007/s00210-005-0026-1
Samadi Rad B, Ghasemi A, Seifi M et al (2012) Serotonin 1A receptor genetic variations, suicide, and life events in the Iranian population. Psychiatry Clin Neurosci 66:337–343. doi:10.1111/j.1440-1819.2012.02333.x
Sartim AG, Guimarães FS, Joca SRL (2016) Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex-possible involvement of 5-HT1A and CB1 receptors. Behav Brain Res 303:218–227. doi:10.1016/j.bbr.2016.01.033
Scheen AJ, Finer N, Hollander P et al (2006) Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 368:1660–1672. doi:10.1016/S0140-6736(06)69571-8
Seo D, Patrick CJ, Kennealy PJ (2008) Role of serotonin and dopamine system interactions in the neurobiology of impulsive aggression and its comorbidity with other clinical disorders. Aggress Violent Behav 13:383–395. doi:10.1016/j.avb.2008.06.003
Sewell RA, Schnakenberg A, Elander J et al (2013) Acute effects of THC on time perception in frequent and infrequent cannabis users. Psychopharmacology 226:401–413. doi:10.1007/s00213-012-2915-6
Sink KS, Vemuri VK, Wood J et al (2009) Oral bioavailability of the novel cannabinoid CB1 antagonist AM6527: effects on food-reinforced behavior and comparisons with AM4113. Pharmacol Biochem Behav 91:303–306. doi:10.1016/j.pbb.2008.07.013
Soubrié P (1986) Reconciling the role of central serotonin neurons in human and animal behavior. Behav Brain Sci 9:319. doi:10.1017/S0140525X00022871
Stockmeier CA, Shapiro LA, Dilley GE et al (1998) Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression: postmortem evidence for decreased serotonin activity. J Neurosci 18:7394–7401
Sullivan GM, Oquendo MA, Milak M et al (2015) Positron emission tomography quantification of serotonin(1A) receptor binding in suicide attempters with major depressive disorder. JAMA Psychiatry 72:169. doi:10.1001/jamapsychiatry.2014.2406
Szabo B, Nordheim U, Niederhoffer N (2001) Effects of cannabinoids on sympathetic and parasympathetic neuroeffector transmission in the rabbit heart. J Pharmacol Exp Ther 297:819–826
Takahashi T, Ikeda K, Fukushima H, Hasegawa T (2007) Salivary alpha-amylase levels and hyperbolic discounting in male humans. Neuro Endocrinol Lett 28:17–20
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 195:27–39. doi:10.1007/s00213-007-0880-2
Thompson PM, Cruz DA, Olukotun DY, Delgado PL (2012) Serotonin receptor, SERT mRNA and correlations with symptoms in males with alcohol dependence and suicide. Acta Psychiatr Scand 126:165–174. doi:10.1111/j.1600-0447.2011.01816.x
Thompson EE, Jagielo-Miller JE, Vemuri VK et al (2016) CB1 antagonism produces behaviors more consistent with satiety than reduced reward value in food-maintained responding in rats. J Psychopharmacol 30:482–491. doi:10.1177/0269881116639287
Topol EJ, Bousser M-G, Fox KAA et al (2010) Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet 376:517–523. doi:10.1016/S0140-6736(10)60935-X
Underwood MD, Kassir SA, Bakalian MJ et al (2012) Neuron density and serotonin receptor binding in prefrontal cortex in suicide. Int J Neuropsychopharmacol 15:435–447. doi:10.1017/S1461145711000691
Van Gaal LF, Rissanen AM, Scheen AJ et al (2005) Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365:1389–1397. doi:10.1016/S0140-6736(05)66374-X
van Heeringen C, Audenaert K, Van Laere K et al (2003) Prefrontal 5-HT2a receptor binding index, hopelessness and personality characteristics in attempted suicide. J Affect Disord 74:149–158
Wang TS, Huang WL, Kuo TBJ et al (2013) Inattentive and hyperactive preschool-age boys have lower sympathetic and higher parasympathetic activity. J Physiol Sci 63:87–94. doi:10.1007/s12576-012-0238-3
Winstanley CA, Theobald DEH, Dalley JW, Robbins TW (2005) Interactions between serotonin and dopamine in the control of impulsive choice in rats: therapeutic implications for impulse control disorders. Neuropsychopharmacology 30:669–682. doi:10.1038/sj.npp.1300610
Wiskerke J, Stoop N, Schetters D et al (2011) Cannabinoid CB1 receptor activation mediates the opposing effects of amphetamine on impulsive action and impulsive choice. PLoS One. doi:10.1371/journal.pone.0025856
Acknowledgements
The authors are grateful to Rachel E. Drozdowski, Rachel M. Hardy, Caitlin M. Luskin, Felicia M. Myers, Marigny C. Normann, Taylor M. Proper, and Emily E. Thompson for assistance in conducting this project.
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McLaughlin, P.J., Jagielo-Miller, J.E., Plyler, E.S. et al. Differential effects of cannabinoid CB1 inverse agonists and antagonists on impulsivity in male Sprague Dawley rats: identification of a possibly clinically relevant vulnerability involving the serotonin 5HT1A receptor. Psychopharmacology 234, 1029–1043 (2017). https://doi.org/10.1007/s00213-017-4548-2
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DOI: https://doi.org/10.1007/s00213-017-4548-2