, Volume 235, Issue 2, pp 419–432 | Cite as

Do psychoactive drugs have a therapeutic role in compulsivity? Studies on schedule-induced polydipsia

  • Elena Martín-González
  • Ángeles Prados-Pardo
  • Santiago Mora
  • Pilar Flores
  • Margarita Moreno
Original Investigation



Clinical studies have shown that some psychoactive recreational drugs have therapeutic applications in anxiety, depression, and schizophrenia. However, to date, there are few studies on the therapeutic potential efficacy of recreational drugs in compulsive neuropsychiatric disorders.


We explored the therapeutic potential of different psychoactive and psychedelic drugs in a preclinical model of compulsive behavior.


Outbred male Wistar rats were selected as either high (HD) or low (LD) drinkers according to their behavior in schedule-induced polydipsia (SIP). Subsequently, we assessed the effects of acute administration of scopolamine (0.125, 0.25, and 0.5 mg/kg), methamphetamine (0.25, 0.5, 1.25, and 2.5 mg/kg), ketamine (1.25, 2.5, 5, and 10 mg/kg), cannabidiol (1 and 3 mg/kg), WIN21255–2 (0.5, 075, and 1 mg/kg), and AM404 (0.25 and 0.5 mg/kg) on compulsive drinking in SIP.


Scopolamine reduced dose-dependent compulsive drinking in HD compared with LD rats in SIP. Methamphetamine induced a dose-dependent inverted U-curve effect in both groups, in which lower doses increased and higher doses reduced compulsive drinking in SIP. Ketamine, cannabidiol, WIN21255-2, and AM404 did not have any relevant effects in SIP.


These data provide new evidence that low doses of scopolamine and intermediate doses of methamphetamine might therapeutically reduce compulsive behaviors and suggest that there is not a direct participation of the endocannabinoid system in compulsive behavior on SIP. The research in the underlying neurochemical mechanisms of these psychoactive drugs might provide an additional insight on new therapeutic targets in compulsive neuropsychiatric disorders.


Compulsivity Schedule-induced polydipsia Psychoactive drugs Psychedelic drugs 



This work was supported by grants from the Ministerio de Economía y Competitividad, Spanish Government (grant number PSI2015-70037-R MINECO-FEDER).

Compliance with ethical standards

Conflict of interest

The authors declared that they have no conflicts of interest.


  1. Adamczyk P, Mccreary AC, Filip M (2008) Activation of endocannabinoid transmission induces antidepressant-like effects in rats. J Physiol Pharmacol 940:217–228Google Scholar
  2. Agarwal V, Yaduvanshi R, Arya A, Gupta PK, Sitholey P (2016) A study of phenomenology, psychiatric co-morbidities, social and adaptive functioning in children and adolescents with OCD. Asian J Psychiatr 22:69–73. PubMedCrossRefGoogle Scholar
  3. Amerio A, Odone A, Liapis CC, Ghaemi SN (2014) Diagnostic validity of comorbid bipolar disorder and obsessive-compulsive disorder: a systematic review. Acta Psychiatr Scand 129(5):343–358. PubMedCrossRefGoogle Scholar
  4. Amodeo DA, Yi J, Sweeney JA, Ragozzino ME (2014) Oxotremorine treatment reduces repetitive behaviors in BTBR T+ tf/J mice. Front Synaptic Neurosci 6:17. PubMedPubMedCentralCrossRefGoogle Scholar
  5. Baer L, Trivedi MH, Huz I, Rush AJ, Wisniewski SR, Fava M (2015) Prevalence and impact of obsessive-compulsive symptoms in depression. J Clin Psychiatry 76(12):1668–1674. PubMedCrossRefGoogle Scholar
  6. 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(43):11700–11711. PubMedCrossRefGoogle Scholar
  7. Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, Quevedo J, Roesler R, Schröder N, Nardi AE, Martín-Santos R, Hallak JE, Zuardi AW, Crippa JA (2011) Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology 36(6):1219–1226. PubMedPubMedCentralCrossRefGoogle Scholar
  8. Biojone C, Casarotto PC, Resstel LB, Zangrossi H Jr, Guimarães FS, Moreira FA (2011) Anti-aversive effects of the atypical antipsychotic, aripiprazole, in animal models of anxiety. J Psychopharmacol 25(6):801–807. doi:
  9. Blanco C, Potenza MN, Kim SW, Ibáñez A, Zaninelli R, Saiz-Ruiz J, Grant JE (2009) A pilot study of impulsivity and compulsivity in pathological gambling. Psychiatry Res 167(1–2):161–168. PubMedPubMedCentralCrossRefGoogle Scholar
  10. Brett LP, Levine S (1979) Schedule-induced polydipsia suppresses pituitary-adrenal activity in rats. J Comp Physiol Psychol 93(5):946–956. PubMedCrossRefGoogle Scholar
  11. Broekkamp CL, Rijk HW, Joly-Gelouin D, Lloyd KL (1986) Major tranquillizers can be distinguished from minor tranquillizers on the basis of effects on marble burying and swim-induced grooming in mice. Eur J Pharmacol 126(3):223–229. PubMedCrossRefGoogle Scholar
  12. Bruhn J, Scheffer GJ, van Geffen GJ (2017) Clinical application of perioperative multimodal analgesia. Curr Opin Support Palliat Care 11(2):106–111. PubMedCrossRefGoogle Scholar
  13. Cadet JL, Krasnova IN (2007) Interactions of HIV and methamphetamine: cellular and molecular mechanisms of toxicity potentiation. Neurotox Res 12(3):181–204. PubMedCrossRefGoogle Scholar
  14. Campolongo P, Ratano P, Manduca A, Scattoni ML, Palmery M, Trezza V, Cuomo V (2012) The endocannabinoid transport inhibitor AM404 differentially modulates recognition memory in rats depending on environmental aversiveness. Front Behav Neurosci 6:11. PubMedPubMedCentralCrossRefGoogle Scholar
  15. Campos AC, Fogaça MV, Sonego AB, Guimarães FS (2016) Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res 112:119–127. PubMedCrossRefGoogle Scholar
  16. Cardona D, López-Grancha M, Lopez-Crespo G, Nieto-Escamez F, Sanchez-Santed F, Flores P (2006) Vulnerability of long-term neurotoxicity of chlorpyrifos: effect on schedule-induced polydipsia and a delay discounting task. Psychopharmacology 189(1):47–57. PubMedCrossRefGoogle Scholar
  17. Cardona D, Lopez-Crespo G, Sanchez-Amate MC, Flores P, Sanchez-Santed F (2011) Impulsivity as long-term sequelae after chlorpyrifos intoxication: time course and individual differences. Neurotox Res 19(1):128–137. PubMedCrossRefGoogle Scholar
  18. Casarotto PC, Gomes FV, Resstel LB, Guimarães FS (2010) Cannabidiol inhibitory effect on marble-burying behaviour: involvement of CB1 receptors. Behav Pharmacol 21(4):353–358. PubMedCrossRefGoogle Scholar
  19. Chamberlain SR, Fineberg NA, Blackwell A, Robbins TW, Sahakian BJ (2006) Motor inhibition and cognitive flexibility in obsessive- compulsive disorder and trichotillomania. Psychiatry Interpers Biol Process 163(7):1282–1284Google Scholar
  20. Crippa JAS, Zuardi AW, Hallak JEC (2010) Therapeutical use of the cannabinoids in psychiatry. Rev Bras Psiquiatr 32(Suppl 1):S56–S66PubMedCrossRefGoogle Scholar
  21. Cruickshank CC, Dyer KR (2009) A review of the clinical pharmacology of methamphetamine. Addiction 104(7):1085–1099. PubMedCrossRefGoogle Scholar
  22. Dantzer R, Terlouw C, Mormède P, Le Moal M (1988a) Schedule-induced polydipsia experience decreases plasma corticosterone levels but increases plasma prolactin levels. Physiol Behav 43(3):275–279. PubMedCrossRefGoogle Scholar
  23. Dantzer R, Terlouw C, Tazi A, Koolhaas JM, Koob GF, Le Moal M (1988b) The propensity for schedule-induced polydipsia is related to differences in conditioned avoidance behaviour and in defense reactions in a defeat test. Physiol Behav 43(3):269–273. PubMedCrossRefGoogle Scholar
  24. Deiana S, Watanabe A, Yamasaki Y, Amada N, Arthur M, Fleming S, Woodcock H, Dorward P, Pigliacampo B, Close S, Platt B, Riedel G (2012) Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour. Psychopharmacology 219(3):859–873. PubMedCrossRefGoogle Scholar
  25. Delva NJ, Chang A, Hawken ER, Lawson JS, Owen JA (2002) Effects of clonidine in schizophrenic patients with primary polydipsia: three single case studies. Prog Neuro-Psychopharmacol Biol Psychiatry 26(2):387–392. CrossRefGoogle Scholar
  26. Diazgranados N, Ibrahim L, Brutsche N, Ameli R, Henter I, Luckenbaurgh D, Machado-Vieira R, Zarate C (2010) Rapid resolution of suicidal ideation after a single infusion of an NMDA antagonist in patients with treatment-resistent major depressive disorder. J Clin Psychiatry 71(12):1605–1611. PubMedPubMedCentralCrossRefGoogle Scholar
  27. Drug Enforcement Administration (2013). Methamphetamine. (accessed May 26 2017)
  28. Dundas B, Harris M, Narasimhan M (2007) Psychogenic polydipsia review: etiology, differential, and treatment. Curr Psychiatry Rep 9(3):236–241. PubMedCrossRefGoogle Scholar
  29. Espejo-Porras F, Fernández-Ruiz J, Pertwee RG, Mechoulam R, Gracía C (2013) Motor effects of the non-psychotropic phytocannabinoid cannabidiol that are mediated by 5-HT1A receptors. Neuropharmacology 75:155–163. PubMedCrossRefGoogle Scholar
  30. Evenson RC, Jos CJ, Mallya AR (1987) Prevalence of polydipsia among public psychiatric patients. Psychol Rep 60(3):803–807. PubMedCrossRefGoogle Scholar
  31. Falk JL (1961) Production of polydipsia in normal rats by an intermittent food schedule. Science 133(3447):195–196. PubMedCrossRefGoogle Scholar
  32. Falk JL (1966) Schedule-induced polydipsia as a function of fixed interval length1. J Exp Anal Behav 9(1):37–39. PubMedPubMedCentralCrossRefGoogle Scholar
  33. Feder A, Parides MK, Murrough JW, Perez AM, Morgan JE, Saxena S, Kirkwood K, aan het Rot M, Lapidus KAB, Wan L, Iosifescu D, Charney DS (2014) Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder. JAMA Psychiatry 71(6):681–188. PubMedCrossRefGoogle Scholar
  34. Feinstein C, Reiss AL (1998) Autism: the point of view from fragile X studies. J Autism Dev Disord 28(5):393–405. PubMedCrossRefGoogle Scholar
  35. Fineberg NA, Chamberlain SR, Goudriaan AE, Stein DJ, Vanderschuren LKMJ, Gillan CM, Shekar S, Gorwood PAPM, Voon V, Morein-Zamir S, Denys D, Sahakian BJ, Moeller FG, Robbins TW, Potenza MN (2014) New developments in human neurocognition: clinical, genetic, and brain imaging correlates of impulsivity and compulsivity. CNS Spectr 19(01):69–89. PubMedPubMedCentralCrossRefGoogle Scholar
  36. Furey ML, Khanna A, Hoffman EM, Drevets WC (2010) Scopolamine produces larger antidepressant and antianxiety effects in women than in men. Neuropsychopharmacology 35(12):2479–2488. PubMedPubMedCentralCrossRefGoogle Scholar
  37. Furey ML, Drevets WC, Hoffman EM, Frankel E, Speer AM, Zarate CA (2013) Potential of pretreatment neural activity in the visual cortex during emotional processing to predict treatment response to scopolamine in major depressive disorder. JAMA psychiatry 70(3):280–290. PubMedPubMedCentralCrossRefGoogle Scholar
  38. Gillan CM, Fineberg NA, Robbins TW (2017) A trans-diagnostic perspective on obsessive-compulsive disorder 1–21.
  39. Gomes FV, Resstel LB, Guimarães FS (2011) The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology 213(2–3):465–473. PubMedCrossRefGoogle Scholar
  40. Grant JE, Chamberlain SR, Odlaug BL, Potenza MN, Kim SW (2010) Memantine shows promise in reducing gambling severity and cognitive inflexibility in pathological gambling: a pilot study. Psychopharmacology 212(4):603–612. PubMedPubMedCentralCrossRefGoogle Scholar
  41. Greendyke RM, Bernhardt AJ, Tasbas HE, Lewandowski KS (1998) Polydipsia in chronic psychiatric patients: therapeutic trials of clonidine and enalapril. Neuropsychopharmacology 18(4):272–281. PubMedCrossRefGoogle Scholar
  42. Gueye AB, Trigo JM, Vemuri KV, Makriyannis A, Le Foll B (2016) Effects of various cannabinoid ligands on choice behaviour in a rat model of gambling. Behav Pharmacol 27(2-3 spec issue):258-69.
  43. de Haan L, Dudek-Hodge C, Verhoeven Y, Denys D (2009) Prevalence of psychotic disorders in patients with obsessive-compulsive disorder. CNS Spectr 14(8):415–417. PubMedCrossRefGoogle Scholar
  44. de Leon J, Verghese C, Tracy JI, Josiassen RC, Simpson GM (1994) Polydipsia and water intoxication in psychiatric patients: a review of the epidemiological literature. Biol Psychiatry 35(6):408–419. PubMedCrossRefGoogle Scholar
  45. de Leon J, Tracy J, McCann E, McGrory A (2002) Polydipsia and schizophrenia in a psychiatric hospital: a replication study. Schizophr Res 57(2-3):293–301. PubMedCrossRefGoogle Scholar
  46. dela Peña I, Lee JC, Lee HL, Woo TS, Lee HC, Sohn AR, Cheong JH (2012) Differential behavioral responses of the spontaneously hypertensive rat to methylphenidate and methamphetamine: lack of a rewarding effect of repeated methylphenidate treatment. Neurosci Lett 514(2):189–193. CrossRefGoogle Scholar
  47. Hagerman RJ, Hagerman PJ (2002) The fragile X premutation: into the phenotypic fold. Curr Opin Genet Dev 12(3):278–283. PubMedCrossRefGoogle Scholar
  48. Hawken ER, Delva NJ, Reynolds JN, Beninger RJ (2011) Increased schedule-induced polydipsia in the rat following subchronic treatment with MK-801. Schizophr Res 125(1):93–98. PubMedCrossRefGoogle Scholar
  49. Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11(2):563–583PubMedCrossRefGoogle Scholar
  50. Hollander E, Doernberg E, Shavitt R, Waterman RJ, Soreni N, Veltman DJ, Sahakian BJ, Fineberg NA (2016) The cost and impact of compulsivity: a research perspective. Eur Neuropsychopharmacol 26(5):800–809. PubMedCrossRefGoogle Scholar
  51. Íbias J, Miguéns M, Pellón R (2016) Effects of dopamine agents on a schedule-induced polydipsia procedure in the spontaneously hypertensive rat and in Wistar control rats. J Psychopharmacol 30(9):856–866. PubMedCrossRefGoogle Scholar
  52. Iftene F, Bowie C, Milev R, Hawken E, Talikowska-Szymczak E, Potopsingh D, Hanna S, Mulroy J, Groll D, Millson R (2013) Identification of primary polydipsia in a severe and persistent mental illness outpatient population: a prospective observational study. Psychiatry Res 210(3):679–683. PubMedCrossRefGoogle Scholar
  53. Ionescu DF, Luckenbaugh DA, Niciu MJ, Richards EM, Slonena EE, Vande Voort JL, Brutsche NE, Zarate CA (2014) Effect of baseline anxious depression on initial and sustained antidepressant response to ketamine. J Clin Psychiatry 75(09):e932–e938. PubMedCrossRefGoogle Scholar
  54. Ionita R, Postu PA, Beppe GJ, Mihasan M, Petre BA, Hancianu M, Cioanca O, Hritcu L (2017) Cognitive-enhancing and antioxidant activities of the aqueous extract from Markhamia tomentosa (Benth.) K. Schum. stem bark in a rat model of scopolamine. Behav Brain Funct 13(1):5. PubMedPubMedCentralCrossRefGoogle Scholar
  55. Jimenez-Gomez C, Osentoski A, Woods JH (2011) Pharmacological evaluation of the adequacy of marble burying as an animal model of compulsion and/or anxiety. Behav Pharmacol 22(7):711–713. PubMedPubMedCentralCrossRefGoogle Scholar
  56. Katz RJ, Hersh S (1981) Amitriptyline and scopolamine in an animal model of depression. Neurosci Biobehav Rev 5(2):265–271. PubMedCrossRefGoogle Scholar
  57. Kim M, Lee TH, Choi JS, Kwak YB, Hwang WJ, Kim T, Lee JY, Lim JA, Park M, Kim YJ, Kim SN, Kim DJ, Kwon JS (2017) Neurophysiological correlates of altered response inhibition in internet gaming disorder and obsessive-compulsive disorder: perspectives from impulsivity and compulsivity. Sci Rep 7:41742. PubMedPubMedCentralCrossRefGoogle Scholar
  58. Komaki A, Hashemi-firouzi N, Shojaei S, Souri Z, Heidari S, Shahidi S (2015) Study the effect of endocannabinoid system on rat behavior in elevated plus-maze. Basic Clin Neurosci 6(3):147–153PubMedPubMedCentralGoogle Scholar
  59. Krasnova IN, Cadet JL (2009) Methamphetamine toxicity and messengers of death. Brain Res Rev 60(2):379–407. PubMedPubMedCentralCrossRefGoogle Scholar
  60. Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA (2014) Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry 4(10):e469. PubMedPubMedCentralCrossRefGoogle Scholar
  61. Levin R, Almeida V, Peres FF, Calzavara MB, da Silva ND, Suiama MA, Niigaki ST, Zuardi AW, Hallak JE, Crippa JA, Abílio VC (2012) Antipsychotic profile of cannabidiol and rimonabant in an animal model of emotional context processing in schizophrenia. Curr Pharm Des 18(32):4960–4965. PubMedCrossRefGoogle Scholar
  62. Levin R, Peres FF, Almeida V, Calzavara MB, Zuardi AW, Hallak JE, Crippa JA, Abílio VC (2014) Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: the SHR strain. Front Pharmacol 5:10. PubMedPubMedCentralCrossRefGoogle Scholar
  63. Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, Klosterkötter J, Hellmich M, Koethe D (2012) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2(3):e94. PubMedPubMedCentralCrossRefGoogle Scholar
  64. López-Grancha M, Lopez-Crespo G, Sanchez-Amate MC, Flores P (2008) Individual differences in schedule-induced polydipsia and the role of GABAergic and dopaminergic systems. Psychopharmacology 197(3):487–498. PubMedCrossRefGoogle Scholar
  65. Lucey JV, Butcher G, Clare AW, Dinan TG (1993) The anterior pituitary responds normally to protirelin in obsessive-compulsive disorder: evidence to support a neuroendocrine serotonergic deficit. Acta Psychiatr Scand 87(6):384–388. PubMedCrossRefGoogle Scholar
  66. Marinova Z, Chuang D-M, Fineberg N (2017) Glutamate-modulating drugs as a potential therapeutic strategy in obsessive-compulsive disorder. Curr Neuropharmacol doi 15(7):977–995. CrossRefGoogle Scholar
  67. Merchán A, Navarro SV, Klein AB, Aznar S, Campa L, Suñol C, Moreno M, Flores P (2017) Tryptophan depletion affects compulsive behaviour in rats: strain dependent effects and associated neuromechanisms. Psychopharmacology 234(8):1223–1236. PubMedPubMedCentralCrossRefGoogle Scholar
  68. Micale V, Cristino L, Tamburella A, Petrosino S, Leggio GM, Drago F, Di Marzo V (2009) Altered responses of dopamine D3 receptor null mice to excitotoxic or anxiogenic stimuli: possible involvement of the endocannabinoid and endovanilloid systems. Neurobiol Dis 36(1):70–80. PubMedCrossRefGoogle Scholar
  69. Mittleman G, Jones GH, Robbins TW (1988) The relationship between schedule-induced polydipsia and pituitary-adrenal activity: pharmacological and behavioral manupulations. Behav Brain Res 28(3):315–324. PubMedCrossRefGoogle Scholar
  70. More SV, Choi D-K (2011) Promising cannabinoid-based therapies for Parkinson’s disease: motor symptoms to neuroprotection 10:17. doi:, Promising cannabinoid-based therapies for Parkinson’s disease: motor symptoms to neuroprotection, 1
  71. Moreira FA, Guimarães FS (2005) Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. Eur J Pharmacol 512(2-3):199–205. PubMedCrossRefGoogle Scholar
  72. Moreno M, Flores P (2012) Schedule-induced polydipsia as a model of compulsive behavior: Neuropharmacological and neuroendocrine bases. Psychopharmacology 219(2):647–659. PubMedCrossRefGoogle Scholar
  73. Moreno M, Cardona D, Gómez MJ, Sánchez-Santed F, Tobeña A, Fernández-Teruel A, Campa L, Suñol C, Escarabajal MD, Torres C, Flores P (2010) Impulsivity characterization in the Roman high- and low-avoidance rat strains: behavioral and neurochemical differences. Neuropsychopharmacology 35(5):1198–1208. PubMedPubMedCentralCrossRefGoogle Scholar
  74. Moreno M, Gutiérrez-Ferre VE, Ruedas L, Campa L, Suñol C, Flores P (2012) Poor inhibitory control and neurochemical differences in high compulsive drinker rats selected by schedule-induced polydipsia. Psychopharmacology 219(2):661–672. PubMedCrossRefGoogle Scholar
  75. Nardo M, Casarotto PC, Gomes FV, Guimarães FS (2014) Cannabidiol reverses the mCPP-induced increase in marble-burying behavior. Fundam Clin Pharmacol 28(5):544–550. PubMedCrossRefGoogle Scholar
  76. Navarro SV, Gutiérrez-Ferre V, Flores P, Moreno M (2015) Activation of serotonin 5-HT2 A receptors inhibits high compulsive drinking on schedule-induced polydipsia. Psychopharmacology 232(4):683–697. PubMedCrossRefGoogle Scholar
  77. Navarro SV, Alvarez R, Colomina MT, Sanchez-Santed F, Flores P, Moreno M (2016) Behavioral biomarkers of schizophrenia in high drinker rats: a potential Endophenotype of compulsive neuropsychiatric disorders. Schizophr bull pii: sbw141Google Scholar
  78. Ohmori T, Abekawa T, Koyama T (1995) Scopolamine prevents augmentation of stereotypy induced by chronic methamphetamine treatment. Psychopharmacology 121(2):158–163. PubMedCrossRefGoogle Scholar
  79. Patel S, Hillard CJ (2006) Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J Pharmacol Exp Ther 318(1):304–311. PubMedCrossRefGoogle Scholar
  80. Petryshen TL, Lewis MC, Dennehy KA, Garza JC, Fava M (2016) Antidepressant-like effect of low dose ketamine and scopolamine co-treatment in mice. Neurosci Lett 620:70–73. PubMedCrossRefGoogle Scholar
  81. Phelps L, Brutsche N (2009) Family history of alcohol dependence and initial antidepressant response to an NMDA antagonist. Biol Psychiatry 65(2):181–184. PubMedCrossRefGoogle Scholar
  82. Platt B, Beyer CE, Schechter LE, Rosenzweig-Lipson S (2008) Schedule-induced polydipsia: a rat model of obsessive-compulsive disorder Curr Protoc Neurosci Chapter 9:Unit 9.27. doi:
  83. Pratt WE, Kelley AE (2004) Nucleus accumbens acetylcholine regulates appetitive learning and motivation for food via activation of muscarinic receptors. Behav Neurosci 118(4):730–739. PubMedCrossRefGoogle Scholar
  84. Radford KD, Park TY, Lee BH, Moran S, Osborne LA, Choi KH (2017) Dose-response characteristics of intravenous ketamine on dissociative stereotypy, locomotion, sensorimotor gating, and nociception in male Sprague-Dawley rats. Pharmacol Biochem Behav 153:130–140. PubMedCrossRefGoogle Scholar
  85. Rau TF, Kothiwal AS, Rova AR, Brooks DM, Poulsen DJ (2012) Treatment with low-dose methamphetamine improves behavioral and cognitive function after severe traumatic brain injury. J Trauma Acute Care Surg 73(2 Suppl 1):S165–S172. PubMedCrossRefGoogle Scholar
  86. Rau T, Ziemniak J, Poulsen D (2016) The neuroprotective potential of low-dose methamphetamine in preclinical models of stroke and traumatic brain injury. Prog Neuro-Psychopharmacol Biol Psychiatry 64:231–236. CrossRefGoogle Scholar
  87. Refsgaard LK, Pickering DS, Andreasen JT (2017) Investigation of antidepressant-like and anxiolytic-like actions and cognitive and motor side effects of four N -methyl- D-aspartate receptor antagonists in mice. Behav Pharmacol 28(1):37–47. PubMedCrossRefGoogle Scholar
  88. Richards JB, Sabol KE, de Wit H (1999) Effects of methamphetamine on the adjusting amount procedure, a model of impulsive behavior in rats. Psychopharmacology 146(4):432–439. PubMedCrossRefGoogle Scholar
  89. Rickelt J, Viechtbauer W, Lieverse R, Overbeek T, van Balkom AJ, Marcelis M, Eikelenboom M, Tibi L, Schruers KRJ (2016) The relation between depressive and obsessive-compulsive symptoms in obsessive-compulsive disorder: results from a large, naturalistic follow-up study. J Affect Disord 203:241–247. PubMedCrossRefGoogle Scholar
  90. Ruehle S, Rey AA, Remmers F, Lutz B (2012) The endocannabinoid system in anxiety, fear memory and habituation. J Psychopharmacol 26(1):23–39. PubMedPubMedCentralCrossRefGoogle Scholar
  91. Russell VA (2017) Antihyperalgesic Activities of Endocannabinoids in a Mouse Model of Antiretroviral-Induced Neuropathic 8:1–11. doi:, Antihyperalgesic activities of endocannabinoids in a mouse model of antiretroviral-induced neuropathic pain
  92. Sanger DJ (1976) Scopolamine and adjunctive drinking in rats. Psychopharmacology 48(3):307–309. PubMedCrossRefGoogle Scholar
  93. Schubart CD, Sommer IEC, van Gastel WA, Goetgbuer RL, Kahn RS, Boks MPM (2011) Cannabis with high cannabidiol content is associated with fewer psychotic experiences. Schizophr Res 130(1-3):216–221. PubMedCrossRefGoogle Scholar
  94. Sos P, Klirova M, Novak T, Kohutova B, Horacek J, Palenicek T (2013) Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuro Endocrinol Lett 34(4):287–293PubMedGoogle Scholar
  95. Spano MS, Fattore L, Cadeddu F, Fratta W, Fadda P (2013) Chronic cannabinoid exposure reduces phencyclidine-induced schizophrenia-like positive symptoms in adult rats. Psychopharmacology 225(3):531–542. PubMedCrossRefGoogle Scholar
  96. Swets M, Dekker J, van Emmerik-van Oortmerssen K, Smid GE, Smit F, de Haan L, Schoevers RA (2014) The obsessive compulsive spectrum in schizophrenia, a meta-analysis and meta-regression exploring prevalence rates. Schizophr Res 152(2–3):458–468. PubMedCrossRefGoogle Scholar
  97. Tamaki R, Yoshikawa M, Shinomiya T, Hashimoto A, Kawaguchi M, Byrne DW, Kobayashi H (2008) Acute administration of methamphetamine decreases the mRNA expression of diazepam binding inhibitor in rat brain. Tokai J Exp Clin Med 33(1):51–56PubMedGoogle Scholar
  98. Tizabi Y, Bhatti BH, Manaye KF, Das JR, Akinfiresoye L (2012) Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female Wistar-Kyoto rats. Neuroscience 213:72–80. PubMedPubMedCentralCrossRefGoogle Scholar
  99. Torres AR, Ferrão YA, Shavitt RG, Diniz JB, Costa DL, do Rosário MC, Miguel EC, Fontenelle LF (2014) Panic disorder and agoraphobia in OCD patients: clinical profile and possible treatment implications. Compr Psychiatry 55(3):588–597. PubMedCrossRefGoogle Scholar
  100. Torres AR, Fontenelle LF, Shavitt RG, Ferrão YA, do Rosário MC, Storch EA, Miguel EC (2016) Comorbidity variation in patients with obsessive-compulsive disorder according to symptom dimensions: results from a large multicentre clinical sample. J Affect Disord 190:508–516. PubMedCrossRefGoogle Scholar
  101. Umathe SN, Manna SSS, Jain NS (2011) Involvement of endocannabinoids in antidepressant and anti-compulsive effect of fluoxetine in mice. Behav Brain Res 223(1):125–134. PubMedCrossRefGoogle Scholar
  102. Umathe SN, Manna SS, Jain NS (2012) Endocannabinoid analogues exacerbate marble-burying behavior in mice via TRPV1 receptor. Neuropharmacology Apr 62(5–6):2024–2033. CrossRefGoogle Scholar
  103. Veeraragavan S, Bui N, Perkins JR, Yuva-Paylor LA, Carpenter RL, Paylor R (2011a) Modulation of behavioral phenotypes by a muscarinic M1 antagonist in a mouse model of fragile X syndrome. Psychopharmacology 217(1):143–151. PubMedCrossRefGoogle Scholar
  104. Veeraragavan S, Bui N, Perkins JR, Yuva-Paylor LA, Paylor R (2011b) The modulation of fragile X behaviors by the muscarinic M4 antagonist, tropicamide. Behav Neurosci 125(5):783–790. PubMedPubMedCentralCrossRefGoogle Scholar
  105. Wu L-T, Pilowsky DJ, Schlenger WE, Galvin DM (2007) Misuse of methamphetamine and prescription stimulants among youths and young adults in the community. Drug Alcohol Depend 89(2-3):195–205. PubMedPubMedCentralCrossRefGoogle Scholar
  106. Xu P, Qiu Y, Zhang Y, Bai Y, Xu P, Liu Y, Kim JH, Shen HW (2016) The effects of 4-methylethcathinone on conditioned place preference, locomotor sensitization, and anxiety-like behavior: a comparison with methamphetamine. Int J Neuropsychopharmacol 19(4):1–7. CrossRefGoogle Scholar
  107. Yamazaki M, Okabe M, Yamamoto N, Yarimizu J, Harada K (2015) Novel 5-HT5A receptor antagonists ameliorate scopolamine-induced working memory deficit in mice and reference memory impairment in aged rats. J Pharmacol Sci 127(3):362–369. PubMedCrossRefGoogle Scholar
  108. Zanelati TV, Biojone C, Moreira FA, Guimarães FS, Joca SRL (2010) Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol 159(1):122–128. PubMedCrossRefGoogle Scholar
  109. Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8):856–864. PubMedCrossRefGoogle Scholar
  110. Zarate C, Duman RS, Liu G, Sartori S, Quiroz J, Murck H (2013) New paradigms for treatment-resistant depression. Ann N Y Acad Sci 1292(1):21–31. PubMedPubMedCentralCrossRefGoogle Scholar
  111. Zhang L-M, Zhou W-W, Ji Y-J, Li Y, Zhao N, Chen H, Xue R, Mei X, Zhang Y, Wang H, Li Y (2015) Anxiolytic effects of ketamine in animal models of posttraumatic stress disorder. Psychopharmacology 232(4):663–672.
  112. Zuardi AW, Morais SL, Guimarães FS, Mechoulam R (1995) Antipsychotic effect of cannabidiol. J Clin Psychiatry 56(10):485–486PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Psychology and CIAIMBITAL, CeiA3University of AlmeríaAlmeríaSpain

Personalised recommendations