Psychopharmacology

, Volume 233, Issue 14, pp 2841–2856 | Cite as

Lorcaserin and CP-809101 reduce motor impulsivity and reinstatement of food seeking behavior in male rats: Implications for understanding the anti-obesity property of 5-HT2C receptor agonists

  • Guy A. Higgins
  • Leo B. Silenieks
  • Everett B. Altherr
  • Cam MacMillan
  • Paul J. Fletcher
  • Wayne E. Pratt
Original Investigation

Abstract

Rationale

The 5-HT2C receptor agonist lorcaserin (Belviq®) has been approved by the FDA for the treatment of obesity. Impulsivity is a contributory feature of some eating disorders.

Objective

Experiments investigated the effect of lorcaserin and the highly selective 5-HT2C agonist CP-809101 on measures of impulsivity and on reinstatement of food-seeking behaviour, a model of dietary relapse. The effect of both drugs on 22-h deprivation-induced feeding was also examined, as was the effect of prefeeding in each impulsivity test.

Results

Lorcaserin (0.3–0.6 mg/kg SC) and CP-809101 (0.6–1 mg/kg SC) reduced premature responding in rats trained on the 5-CSRTT and improved accuracy in a Go-NoGo task by reducing false alarms. At equivalent doses, both drugs also reduced reinstatement for food-seeking behaviour. Neither drug altered impulsive choice measured in a delay-discounting task. Lorcaserin (1–3 mg/kg SC) and CP-809101 (3–6 mg/kg SC) reduced deprivation-induced feeding but only at higher doses.

Conclusions

These results suggest that in addition to previously reported effects on satiety and reward, altered impulse control may represent a contributory factor to the anti-obesity property of 5-HT2C receptor agonists. Lorcaserin may promote weight loss by improving adherence to dietary regimens in individuals otherwise prone to relapse and may be beneficial in cases where obesity is associated with eating disorders tied to impulsive traits, such as binge eating disorder.

Keywords

Impulsivity 5-HT2C receptor Lorcaserin CP-809101 Binge eating disorder Rat Food reinstatement Prefeeding 

References

  1. Aronne L, Shanahan W, Fain R, Glicklich A, Soliman W, Li Y, Smith S (2014) Safety and efficacy of lorcaserin: a combined analysis of the BLOOM and BLOSSOM trials. Postgrad Med 126:7–18CrossRefPubMedGoogle Scholar
  2. Avena NM (2010) The study of food addiction using animal models of binge eating. Appetite 55:734–737CrossRefPubMedPubMedCentralGoogle Scholar
  3. Baldo BA, Pratt WE, Will MJ, Hanlon EC, Bakshi VP, Cador M (2013) Principles of motivation revealed by the diverse functions of neuropharmacological and neuroanatomical substrates underlying feeding behavior. Neurosci Biobehav Rev 37:1985–1998CrossRefPubMedPubMedCentralGoogle Scholar
  4. Berg KA, Clarke WP, Cunningham KA, Spampinato U (2008) Fine-tuning serotonin2c receptor function in the brain: molecular and functional implications. Neuropharmacology 55:969–976CrossRefPubMedPubMedCentralGoogle Scholar
  5. Berridge KC (2007) The debate over dopamine’s role in reward: the case for incentive salience. Psychopharmacology (Berl) 191:391–431CrossRefGoogle Scholar
  6. Berthoud H-R (2011) Metabolic and hedonic drives in the neural control of appetite: who is the boss? Curr Opin Neurobiol 21:888–896CrossRefPubMedPubMedCentralGoogle Scholar
  7. Betley JN, Cao ZF, Ritola KD, Sternson SM (2013) Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell 155:1337–1150CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bizarro L, Stolerman IP (2003) Attentional effects of nicotine and amphetamine in rats at different levels of motivation. Psychopharmacology (Berl) 170:271–277CrossRefGoogle Scholar
  9. Bray GA, Ryan DH (2014) Update on obesity pharmacotherapy. Ann N Y Acad Sci 1311:1–13CrossRefPubMedGoogle Scholar
  10. Burke LK, Heisler LK (2015) 5-Hydroxytryptamine medications for the treatment of obesity. J Neuroendocrinol 27:389–398CrossRefPubMedGoogle Scholar
  11. Calu DJ, Chen YW, Kawa AB, Nair SG, Shaham Y (2014) The use of the reinstatement model to study relapse to palatable food seeking during dieting. Neuropharmacology 76:395–406CrossRefPubMedGoogle Scholar
  12. Cardinal RN, Robbins TW, Everitt BJ (2000) The effects of d-amphetamine, chlordiazepoxide, alpha-flupenthixol and behavioural manipulations on choice of signalled and unsignalled delayed reinforcement in rats. Psychopharmacology (Berl) 152:362–375CrossRefGoogle Scholar
  13. Carli M, Samanin R (1992) Serotonin2 receptor agonists and serotonergic anorectic drugs affect rats’ performance differently in a five-choice serial reaction time task. Psychopharmacology (Berl) 106:228–234CrossRefGoogle Scholar
  14. Carli M, Samanin R (2000) The 5-HT(1A) 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-HT(1A) receptors. Psychopharmacology (Berl) 149:259–268CrossRefGoogle Scholar
  15. Clifton PG, Lee MD, Dourish CT (2000) Similarities in the action of Ro 60-0175, a 5-HT2C receptor agonist and d-fenfluramine on feeding patterns in the rat. Psychopharmacology (Berl) 152:256–67CrossRefGoogle Scholar
  16. Corwin RL, Avena NM, Boggiano MM (2011) Feeding and reward: perspectives from three rat models of binge eating. Physiol Behav 104:87–97CrossRefPubMedGoogle Scholar
  17. Cunningham KA, Fox RG, Anastasio NC, Bubar MJ, Stutz SJ, Moeller FG, Gilbertson SR, Rosenzweig-Lipson S (2011) Selective serotonin 5-HT2C receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-associated cues. Neuropharmacology 61:513–523CrossRefPubMedPubMedCentralGoogle Scholar
  18. Dalley JW, Everitt BJ, Robbins TW (2011) Impulsivity, compulsivity, and top-down cognitive control. Neuron 69:680–694CrossRefPubMedGoogle Scholar
  19. Diergaarde L, Pattij T, Poortvliet I, Hogenboom F, de Vries W, Schoffelmeer AN, De Vries TJ (2008) Impulsive choice and impulsive action predict vulnerability to distinct stages of nicotine seeking in rats. Biol Psychiatry 63:301–308CrossRefPubMedGoogle Scholar
  20. Di Matteo V, Cacchio M, Di Giulio C, Esposito E (2002) Role of serotonin(2C) receptors in the control of brain dopaminergic function. Pharmacol Biochem Behav 71:727–734CrossRefPubMedGoogle Scholar
  21. Evenden JL (1999) Varieties of impulsivity. Psychopharmacology (Berl) 146:348–361CrossRefGoogle Scholar
  22. Evenden JL, Ryan CN (1996) The pharmacology of impulsive behaviour in rats: the effects of drugs on response choice with varying delays of reinforcement. Psychopharmacology (Berl) 128:161–170CrossRefGoogle Scholar
  23. Fidler MC, Sanchez M, Raether B, Weissman NJ, Smith SR, Shanahan WR, Anderson CM (2011) A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab 96:3067–3077CrossRefPubMedGoogle Scholar
  24. 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 (Berl) 195:223–234CrossRefGoogle Scholar
  25. Floresco SB, McLaughlin RJ, Haluk DM (2008) Opposing roles for the nucleus accumbens core and shell in cue-induced reinstatement of food-seeking behavior. Neuroscience 154:877–884CrossRefPubMedGoogle Scholar
  26. Grottick AJ, Higgins GA (2000) Effect of subtype selective nicotinic compounds on attention as assessed by the five-choice serial reaction time task. Behav Brain Res 117:197–208CrossRefPubMedGoogle Scholar
  27. Grottick AJ, Fletcher PJ, Higgins GA (2000) Studies to investigate the role of 5-HT2C receptors on cocaine- and food-maintained behavior. J Pharmacol Exp Ther 295:1183–1191PubMedGoogle Scholar
  28. Guy EG, Choi E, Pratt WE (2011) Nucleus accumbens dopamine and mu-opioid receptors modulate the reinstatement of food-seeking behavior by food-associated cues. Behav Brain Res 219:265–272CrossRefPubMedGoogle Scholar
  29. Hamilton KR, Mitchell MR, Wing VC, Balodis IM, Bickel WK, Fillmore M, Lane SD, Lejuez CW, Littlefield AK, Luijten M, Mathias CW, Mitchell SH, Napier TC, Reynolds B, Schütz CG, Setlow B, Sher KJ, Swann AC, Tedford SE, White MJ, Winstanley CA, Yi R, Potenza MN, Moeller FG (2015) Choice impulsivity: definitions, measurement issues, and clinical implications. Personal Disord 6:182–198CrossRefPubMedPubMedCentralGoogle Scholar
  30. Halford JC, Harrold JA, Lawton CL, Blundell JE (2005) Serotonin (5-HT) drugs: effects on appetite expression and use for the treatment of obesity. Curr Drug Targets 6:201–213CrossRefPubMedGoogle Scholar
  31. Hayes DJ, Clements R, Greenshaw AJ (2009) Effects of systemic and intra-nucleus accumbens 5-HT2C receptor compounds on ventral tegmental area self-stimulation thresholds in rats. Psychopharmacology (Berl) 203:579–588CrossRefGoogle Scholar
  32. 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 (Berl) 133:329–342CrossRefGoogle Scholar
  33. Harrison AA, Everitt BJ, Robbins TW (1999) Central serotonin depletion impairs both the acquisition and performance of a symmetrically reinforced go/no-go conditional visual discrimination. Behav Brain Res 100:99–112CrossRefPubMedGoogle Scholar
  34. Heal DJ, Gosden J, Smith S (2012) What is the prognosis for new centrally-acting anti-obesity drugs? Neuropharmacology 63:132–146CrossRefPubMedGoogle Scholar
  35. Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL, Rubinstein M, Tatro JB, Marcus JN (2002) Activation of central melanocortin pathways by fenfluramine. Science 297(5581):609–611CrossRefPubMedGoogle Scholar
  36. Hewitt KN, Lee MD, Dourish CT, Clifton PG (2002) Serotonin 2C receptor agonists and the behavioural satiety sequence in mice. Pharmacol Biochem Behav 71:691–700CrossRefPubMedGoogle Scholar
  37. Higgins GA, Desnoyer J, Van Niekerk A, Silenieks LB, Lau W, Thevarkunnel S, Izhakova J, De Lannoy IAM, Fletcher PJ, DeLay J, Dobson H (2015) Characterisation of the 5-HT2C receptor agonist lorcaserin on efficacy and safety measures in a rat model of diet-induced obesity. Pharmacol Res Perspect 3(1):e00084CrossRefPubMedGoogle Scholar
  38. Higgins GA, Enderlin M, Haman M, Fletcher PJ (2003) The 5-HT2A receptor antagonist M100,907 attenuates motor and ‘impulsive-type’ behaviours produced by NMDA receptor antagonism. Psychopharmacology (Berl) 170:309–319CrossRefGoogle Scholar
  39. Higgins GA, Fletcher PJ (2003) Serotonin and drug reward: focus on 5-HT2C receptors. Eur J Pharmacol 480:151–162CrossRefPubMedGoogle Scholar
  40. Higgins GA, Silenieks LB, Lau W, de Lannoy IA, Lee DK, Izhakova J, Coen K, Le AD, Fletcher PJ (2013) Evaluation of chemically diverse 5-HT2C receptor agonists on behaviours motivated by food and nicotine and on side effect profiles. Psychopharmacology (Berl) 226:475–490CrossRefGoogle Scholar
  41. Higgins GA, Silenieks LB, Roβmann A, Rizos Z, Noble K, Soko AD, Fletcher PJ (2012) The 5-HT2C receptor agonist lorcaserin reduces nicotine self-administration, discrimination and reinstatement: relationship to feeding behavior and impulse control. Neuropsychopharmacology 37:1177–1191CrossRefPubMedGoogle Scholar
  42. Higgs S, Cooper AJ, Barnes NM (2016) The 5-HT2C receptor agonist, lorcaserin, and the 5-HT6 receptor antagonist, SB-742457, promote satiety; a microstructural analysis of feeding behaviour. Psychopharmacology (Berl) 233:417–424CrossRefGoogle Scholar
  43. Katsidoni V, Apazoglou K, Panagis G (2011) Role of serotonin 5-HT2A and 5-HT2C receptors on brain stimulation reward and the reward-facilitating effect of cocaine. Psychopharmacology (Berl) 213:337–354CrossRefGoogle Scholar
  44. Kelley AE, Baldo BA, Pratt WE, Will MJ (2005) Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, reward, and action. Physiology and Behavior 86:773–795CrossRefPubMedGoogle Scholar
  45. Kennett GA, Clifton PG (2010) New approaches to the pharmacological treatment of obesity: can they break through the efficacy barrier? Pharmacol Biochem Behav 97:63–83CrossRefPubMedGoogle Scholar
  46. Kenny PJ (2011) Reward mechanisms in obesity: new insights and future directions. Neuron 69:644–679CrossRefGoogle Scholar
  47. Kolokotroni KZ, Rodgers RJ, Harrison AA (2011) Acute nicotine increases both impulsive choice and behavioural disinhibition in rats. Psychopharmacology (Berl) 217:455–473CrossRefGoogle Scholar
  48. Lam DD, Przydzial MJ, Ridley SH, Yeo GS, Rochford JJ, O’Rahilly S, Heisler LK (2008) Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors. Endocrinology 149:1323–1328CrossRefPubMedGoogle Scholar
  49. Levin ED, Johnson JE, Slade S, Wells C, Cauley M, Petro A, Rose JE (2011) Lorcaserin, a 5-HT2C agonist, decreases nicotine self-administration in female rats. J Pharmacol Exp Ther 338:890–896CrossRefPubMedPubMedCentralGoogle Scholar
  50. Lin W, Pratt WE (2014) Inactivation of the nucleus accumbens core or medial shell attenuates reinstatement of sugar-seeking behavior following sugar priming or exposure to food-associated cues. PLoS One 9(6):e99301CrossRefPubMedPubMedCentralGoogle Scholar
  51. Martin CK, Redman LM, Zhang J, Sanchez M, Anderson CM, Smith SR, Ravussin E (2011) Lorcaserin, a 5-HT(2C) receptor agonist, reduces body weight by decreasing energy intake without influencing energy expenditure. J Clin Endocrinol Metab 96:837–845CrossRefPubMedGoogle Scholar
  52. Mobbs O, Crépin C, Thiéry C, Golay A, Van der Linden M (2010) Obesity and the four facets of impulsivity. Patient Educ Couns 79:372–377CrossRefPubMedGoogle Scholar
  53. Mobini S, Chiang TJ, Ho MY, Bradshaw CM, Szabadi E (2000) Effects of central 5-hydroxytryptamine depletion on sensitivity to delayed and probabilistic reinforcement. Psychopharmacology (Berl) 152:390–397CrossRefGoogle Scholar
  54. Myerson J, Green L, Warusawitharana M (2001) Area under the curve as a measure of discounting. J Exp Anal Behav 76:235–243CrossRefPubMedPubMedCentralGoogle Scholar
  55. Nair SG, Adams-Deutsch T, Epstein DH, Shaham Y (2009) The neuropharmacology of relapse to food seeking: methodology, main findings, and comparison with relapse to drug seeking. Prog Neurobiol 89:18–45CrossRefPubMedPubMedCentralGoogle Scholar
  56. Navarra R, Comery TA, Graf R, Rosenzweig-Lipson S, Day M (2008) The 5-HT(2C) receptor agonist WAY-163909 decreases impulsivity in the 5-choice serial reaction time test. Behav Brain Res 188:412–415CrossRefPubMedGoogle Scholar
  57. Pattij T, De Vries TJ (2013) The role of impulsivity in relapse vulnerability. Curr Opin Neurobiol 23:700–705CrossRefPubMedGoogle Scholar
  58. Pickens CL, Cifani C, Navarre BM, Eichenbaum H, Theberge FR, Baumann MH, Calu DJ, Shaham Y (2012) Effect of fenfluramine on reinstatement of food seeking in female and male rats: implications for the predictive validity of the reinstatement model. Psychopharmacology (Berl) 221:341–353CrossRefGoogle Scholar
  59. Powell AG, Apovian CM, Aronne LJ (2011) New drug targets for the treatment of obesity. Clin Pharmacol Ther 90:40–51CrossRefPubMedGoogle Scholar
  60. Pratt WE, Ford RT (2013) Systemic treatment with D-fenfluramine, but not sibutramine, blocks cue-induced reinstatement of food-seeking behavior in the rat. Neurosci Lett 556:232–237CrossRefPubMedGoogle Scholar
  61. Quarta D, Naylor CG, Stolerman IP (2007) The serotonin2C receptor agonist Ro-60-0175 attenuates effects of nicotine in the five-choice serial reaction time task and in drug discrimination. Psychopharmacology (Berl) 193:391–402CrossRefGoogle Scholar
  62. Richards JB, Mitchell SH, de Wit H, Seiden LS (1997) Determination of discount functions in rats with an adjusting-amount procedure. J Exp Anal Behav 67:353–366CrossRefPubMedPubMedCentralGoogle Scholar
  63. Robbins TW (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology (Berl) 163:362–380CrossRefGoogle Scholar
  64. Salamone JD, Correa M (2012) The mysterious motivational functions of mesolimbic dopamine. Neuron 76(3):470–485CrossRefPubMedPubMedCentralGoogle Scholar
  65. Schag K, Schönleber J, Teufel M, Zipfel S, Giel KE (2013) Food-related impulsivity in obesity and binge eating disorder–a systematic review. Obes Rev 14:477–495CrossRefPubMedGoogle Scholar
  66. Serafine KM, Rice KC, France CP (2015) Directly observable behavioral effects of lorcaserin in rats. J Pharmacol Exp Ther 355:381–385CrossRefPubMedPubMedCentralGoogle Scholar
  67. Siuciak JA, Chapin DS, McCarthy SA, Guanowsky V, Brown J, Chiang P, Marala R, Patterson T, Seymour PA, Swick A, Iredale PA (2007) CP-809,101, a selective 5-HT2C agonist, shows activity in animal models of antipsychotic activity. Neuropharmacology 52:279–290CrossRefPubMedGoogle Scholar
  68. Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Dosa PI, Covel JA, Ren A, Webb RR, Beeley NR, Martin M, Morgan M, Espitia S, Saldana HR, Bjenning C, Whelan KT, Grottick AJ, Menzaghi F, Thomsen WJ (2008) Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity. J Med Chem 51:305–313CrossRefPubMedGoogle Scholar
  69. Smith DG, Robbins TW (2013) The neurobiological underpinnings of obesity and binge eating: a rationale for adopting the food addiction model. Biol Psychiatry 73:804–810CrossRefPubMedGoogle Scholar
  70. Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, Bays H, Shanahan WR, Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group (2010) Multicentre, placebo-controlled trial of lorcaserin for weight management. N Eng J Med 263:245–256CrossRefGoogle Scholar
  71. Sohn JW, Xu Y, Jones JE, Wickman K, Williams KW, Elmquist JK (2011) Serotonin 2C receptor activates a distinct population of arcuate pro-opiomelanocortin neurons via TRPC channels. Neuron 71:488–497CrossRefPubMedPubMedCentralGoogle Scholar
  72. St Onge JR, Chiu YC, Floresco SB (2010) Differential effects of dopaminergic manipulations on risky choice. Psychopharmacology (Berl) 211:209–221CrossRefGoogle Scholar
  73. Tanno T, Maguire DR, Henson C, France CP (2014) Effects of amphetamine and methylphenidate on delay discounting in rats: interactions with order of delay presentation. Psychopharmacology (Berl) 231:85–95CrossRefGoogle Scholar
  74. Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espita S, Yuskin D, Whelan K, Martin M, Morgan M, Chen W, Al-Shamma H, Smith B, Chalmers D, Behan D (2008) Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. J Pharmacol Exp Ther 325:577–587CrossRefPubMedGoogle Scholar
  75. Velázquez-Sánchez C, Ferragud A, Moore CF, Everitt BJ, Sabino V, Cottone P (2014) High trait impulsivity predicts food addiction-like behavior in the rat. Neuropsychopharmacology 39:2463–2472CrossRefPubMedPubMedCentralGoogle Scholar
  76. Vickers SP, Clifton PG, Dourish CT, Tecott LH (1999) Reduced satiating effect of d-fenfluramine in serotonin 5-HT2C receptor mutant mice. Psychopharmacology (Berl) 143:309–314CrossRefGoogle Scholar
  77. Vickers SP, Dourish CT, Kennett GA (2001) Evidence that hypophagia induced by d-fenfluramine and d-norfenfluramine in the rat is mediated by 5-HT2C receptors. Neuropharmacology 41:200–209CrossRefPubMedGoogle Scholar
  78. Vickers SP, Hackett D, Murray F, Hutson PH, Heal DJ (2015) Effects of lisdexamfetamine in a rat model of binge-eating. J Psychopharmacol 29:1290–1307CrossRefPubMedGoogle Scholar
  79. Volkow ND, Wang GJ, Tomasi D, Baler RD (2013) Obesity and addiction: neurobiological overlaps. Obes Rev 14:2–18CrossRefPubMedGoogle Scholar
  80. Volkow ND, Wise RA (2005) How can drug addiction help us understand obesity? Nat Neurosci 8:555–560CrossRefPubMedGoogle Scholar
  81. Winstanley CA (2011) The utility of rat models of impulsivity in developing pharmacotherapies for impulse control disorders. Br J Pharmacol 164:1301–1321CrossRefPubMedPubMedCentralGoogle Scholar
  82. Winstanley CA, Dalley JW, Theobald DE, Robbins TW (2004a) Fractionating impulsivity: contrasting effects of central 5-HT depletion on different measures of impulsive behavior. Neuropsychopharmacology 29:1331–1343CrossRefPubMedGoogle Scholar
  83. Winstanley CA, Theobald DE, Dalley JW, Glennon JC, Robbins TW (2004b) 5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion. Psychopharmacology (Berl) 176:376–385CrossRefGoogle Scholar
  84. Wogar MA, Bradshaw CM, Szabadi E (1993) Effect of lesions of the ascending 5-hydroxytryptaminergic pathways on choice between delayed reinforcers. Psychopharmacology (Berl) 111:239–243CrossRefGoogle Scholar
  85. Zeeb FD, Higgins GA, Fletcher PJ (2015) The serotonin 2C receptor agonist lorcaserin attenuates intracranial self-stimulation and blocks the reward-enhancing effects of nicotine. ACS Chem Neurosci 6:1231–1240CrossRefPubMedGoogle Scholar
  86. Zlebnik NE, Carroll ME (2015) Effects of the combination of wheel running and atomoxetine on cue- and cocaine-primed reinstatement in rats selected for high or low impulsivity. Psychopharmacology (Berl) 232:1049–1059CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Guy A. Higgins
    • 1
    • 4
  • Leo B. Silenieks
    • 1
  • Everett B. Altherr
    • 3
  • Cam MacMillan
    • 2
  • Paul J. Fletcher
    • 5
    • 6
    • 7
  • Wayne E. Pratt
    • 3
  1. 1.InterVivo Solutions Inc.TorontoCanada
  2. 2.VivocoreTorontoCanada
  3. 3.Department of PsychologyWake Forest UniversityWinston-SalemUSA
  4. 4.Department of Pharmacology and ToxicologyUniversity of TorontoTorontoCanada
  5. 5.Department of PsychiatryUniversity of TorontoTorontoCanada
  6. 6.Department of PsychologyUniversity of TorontoTorontoCanada
  7. 7.Centre for Addiction and Mental HealthTorontoCanada

Personalised recommendations