Document Type : Original Article

Authors

1 MSc., Department of General Biology, School of Biology, Damghan University, Damghan, Iran.

2 Assistant Professor, Department General Biology, School of Biology, Damghan University, Damghan, Iran.

3 ssociate Professor, Department General Biology, School of Biology, Damghan University, Damghan, Iran.

Abstract

Objectives Posttraumatic stress disorder is a severe anxiety disorder caused by exposure to traumatic events. Traumatic memory impairment is one of the clinical signs of this disorder. Cannabis sativa is full of cannabinoid compounds that are effective on memory extinction. We evaluated the combined effects of Cannabis leave extract and exposure therapy on memory extinction in this disease.
Methods Modified single prolonged stress model was used to induce PTSD. A week later, rats were placed in a shock chamber and received a shock. After 24 hours, for the first time exposure, rats were returned to the chamber for 9 minutes, without receiving any footstock. Two other exposures were performed with one day interval. Cannabis leave extract (at three different doses) was injected 30 minutes before exposures. 14 days later, for fear memory evaluation, again rats were placed in the chamber. In order to evaluate the participation of cannabinoid system in the effects of cannabis, second experiment was accomplished. Effective dose of cannabis extract and cannabinoid receptor antagonist (Rimonabant) were simultaneously injected, as in the first experiment.
Results Results of the first experiment showed that 25 mg/kg cannabis leave extract significantly decreased the percent of freezing as compared to control group. In the second experiment, percent of freezing in rats treated with extract and antagonist increased as compared to related control group.
Conclusion Simultaneous treatment with exposure therapy and cannabis leave extract, with 25 mg/kg dosage, intensely led to condition memory extinction. Maybe this kind of treatment enhanced and consolidated the memory extinction by affecting cannabinoid system through CB1 receptor.

Keywords

Zwissler B, Hauswald A, Koessler S, Ertl V, Pfeiffer A, Wohrmann C, et al. Memory control in post-traumatic stress disorder: evidence from item method directed forgetting in civil war victims in Northern Uganda. Psychological Medicine. 2012; 42(6):1283-291. doi: 10.1017/s0033291711002273 
Siegmund A, Wotjak CT. A mouse model of posttraumatic stress disorder that distinguishes between conditioned and sensitised fear. Journal of Psychiatric Research. 2007; 41(10):848-60. doi: 10.1016/j.jpsychires.2006.07.017 
Wessa M, Flor H. Failure of extinction of fear responses in posttraumatic stress disorder: evidence from second-order conditioning. American Journal of Psychiatry. 2007; 164(11):1684-692. doi: appi.ajp.2007.07030525.
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004; 47(1):345-58. doi: 10.1016/j.neuropharm.2004.07.030 
Alger BE. Retrograde signaling in the regulation of synaptic transmission: Focus on endocannabinoids. Progress in Neurobiology. 2002; 68(4):247-86. doi: 10.1016/s0301-0082(02)00080-1 
Norrholm SD, Jovanovic T, Olin IW, Sands LA, Bradley B, Ressler KJ. Fear extinction in traumatized civilians with posttraumatic stress disorder: relation to symptom severity. Biological Psychiatry. 2011; 69(6):556-63. doi: 10.1016/j.biopsych.2010.09.013 
Komorowski J, Stepien H. The role of the endocannabinoid system in the regulation of endocrine function and in the control of energy balance in humans. Postepy Higieny i Medycyny Doswiadczalnej (Online). 2007; 61:99-105. 
Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nature Reviews Drug Discovery. 2004; 3(9):771-84. doi: 10.1038/nrd1495 
Lutz B. The endocannabinoid system and extinction learning. Molecular Neurobiology. 2007; 36(1):92-101. doi: 10.1007/s12035-007-8004-x 
Harloe JP, Thorpe AJ, Lichtman AH. Differential endocannabinoid regulation of extinction in appetitive and aversive Barnes maze tasks. Learning & Memory. 2008; 15(11):806-09. doi: 10.1101/lm.1113008 
Tambaro S, Bortolato M. Cannabinoid-related agents in the treatment of anxiety disorders: current knowledge and future perspectives. Recent Patents on CNS Drug Discovery. 2012; 7(1):25-40. doi: 10.2174/157488912798842269 
Alikhanzade M, Tehranipour M, Khayatzade J. The neuroprotective effect of alcoholic and aqueous extracts of Achillea biebersteinii leaves on spinal motoneurons denegation after sciatic nerve compression in rats. Advanced Herbal Medicine. 2015; 1(1):8-16.
Tehranipour M, Kehtarpour M, Javadmoosavi B, Mahdavi-Shahri N. [Evaluation of Cannabis sativa leaves aquatic extract effect on triple regions of hippocampus neuronal density in male rats (Persian)]. Journal of Shahrekord Uuniversity of Medical Sciences. 2012; 14(1):20-27.
Bitencourt RM, Pamplona FA, Takahashi RN. Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats. European Neuropsychopharmacology. 2008; 18(12):849-59. doi: 10.1016/j.euroneuro.2008.07.001 
Wessa M, Flor H. Failure of extinction of fear responses in posttraumatic stress disorder: evidence from second-order conditioning. American Journal of Psychiatry. 2007; 164(1):1684-692. doi: 10.1176/appi.ajp.2007.07030525 
Lafenêtre P, Chaouloff F, Marsicano G. The endocannabinoid system in the processing of anxiety and fear and how CB1 receptors may modulate fear extinction. Pharmacological Research. 2007; 56(5):367-81. doi: 10.1016/j.phrs.2007.09.006 
Lin HC, Mao SC, Su CL, Gean PW. The role of prefrontal cortex CB1 receptors in the modulation of fear memory. Cerebral Cortex. 2009; 19(1):165-75. doi: 10.1093/cercor/bhn075 
Ameri A. The effects of cannabinoids on the brain. Progress in Neurobiology. 1999; 58(4):315-48. doi: 10.1016/s0301-0082(98)00087-2 
Alger BE. Retrograde signaling in the regulation of synaptic transmission: Focus on endocannabinoids. Progress in Neurobiology. 2002; 68(4):247-86. doi: 10.1016/s0301-0082(02)00080-1 
Varvel S, Anum E, Lichtman A. Disruption of CB1 receptor signaling impairs extinction of spatial memory in mice. Psychopharmacology. 2004; 179(4):863-72. doi: 10.1007/s00213-004-2121-2 
Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature. 2002; 418(6897): 530-34. doi:
Marsicano G, Lafenêtre P. Roles of the endocannabinoid system in learning and memory. Behavioral Neurobiology of the Endocannabinoid System. 2009; 1:201-230. doi: 10.1007/978-3-540-88955-7_8
Morey RA, Gold AL, LaBar KS, Beall SK, Brown VM, Haswell CC, et al. Amygdala volume changes in posttraumatic stress disorder in a large case-controlled veterans group. Archives of General Psychiatry. 2012; 69(11):1169-178. doi: 10.1001/archgenpsychiatry.2012.50 
Courtin J, Bienvenu T, Einarsson E, Herry C. Medial prefrontal cortex neuronal circuits in fear behavior. Neuroscience. 2013; 240:219-42. doi: 10.1016/j.neuroscience.2013.03.001