This endocannabinoid-mediated retrograde feedback mechanism is the molecular basis of important short- and long-term changes in synaptic signaling. Our laboratory has generated mouse strains with deletions in both cannabinoid receptors. These animal models have been instrumental in the elucidation of ECS functions.
Thus, mice lacking CB1 receptors show a number of behavioral changes and they are resistant for most of the central nervous system effects of cannabinoids.
Importantly, many drugs of abuse are less rewarding in the absence of CB1 signaling, thus revealing the involvement of the ECS in drug addiction. CB1 receptor deficient mice also show an increased mortality and a rapid age-dependent decline in cognitive and memory performance. Mice without CB2 receptors show striking changes in immune and inflammatory responses.
In general, immune responses seem to be enhanced in the absence of CB2 signaling, which suggest a role for the ECS in the negative control of the immune system.
PHARMACOLOGY OF CANNABINOIDS
We have recently demonstrated that the lack of this inhibitory mechanism leads to a spread of spinal cord neuroinflammation associated with peripheral nerve injury. This in turn resulted in an increase in pain sensitivity that was also present in tissues that were not directly affected by the nerve damage. The endocannabinoid system is at the focus of many research projects within the Institute.
Atwood BK, Mackie K CB2: a cannabinoid receptor with an identity crisis. British journal of pharmacology 3 : Bab I, Zimmer A Cannabinoid receptors and the regulation of bone mass. British journal of pharmacology 2 : Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. The Journal of cell biology 3 : Di Marzo V The endocannabinoid system: its general strategy of action, tools for its pharmacological manipulation and potential therapeutic exploitation.
Pharmacol Res 60 2 : Brain monoglyceride lipase participating in endocannabinoid inactivation. Elphick MR, Egertova M The neurobiology and evolution of cannabinoid signalling. Treatment of mice with fluoxetine, sertraline or imipramine resulted in significant decrease in the immobility time compared to vehicle control group Fig. Effect of cannabis in combination with antidepressant drugs. By the day 21 of the study, however, the immobility time of the fluoxetine-cannabis group was significantly decreased compared with the cannabis only-treated group.
Sertraline or imipramine significantly decreased the immobility time in cannabis-treated mice by the day 16 and 18 of the study, respectively. Figure 4A illustrates the effect of cannabis extract on rearing activity. The rearing activity was significantly decreased by cannabis compared to vehicle control group. This decrease in the rearing behavior was dose and time-dependant and started 3 days after treatment with cannabis extract and continued throughout the study.
The rearing activity decreased at the end of the study by The results are shown in Fig. The rearing activity in mice treated cannabis was markedly and significantly increased by sertraline or fluoxetine compared with the cannabis-only treatment group. Sertraline resulted in significant increase in number of rears in mice after 12 days of treatment till the 24 th day Meanwhile, the administration of imipramine to mice resulted in significant decrease in the rearing behavior after 6 days of treatment till the end of the study, as compared to the vehicle control group Figure 4C demonstrates the rearing activity in mice following cannabis treatment in combination with antidepressant drugs.
The decrease in the rearing activity of mice that received imipramine and cannabis extract started after 6 days of administration till the end of the study The administration of cannabis altered the redox status in brain with the effect being significant with the higher doses of the extract.
Brain GSH showed significant increase by 25, 3. The level of nitric oxide, however, increased by There was a significant decrease in lipid peroxidation by The administration of cannabis extract thus resulted in depressive-like effects. These results also indicate the ability of sertraline or imipramine to alleviate chronic stress due to repeated forced swimming. The SSRIs share the common property of inhibiting the reuptake of serotonin at synaptic terminals Fuller, There is also an evidence suggesting inhibition of noradrenaline and dopamine reuptake by fluoxetine Pozzi et al. The tricyclic drug imipramine, on the other hand, is a dual inhibitor of the reuptake of both noradrenaline and serotonin Felton et al.
Other researchers have shown that treatment with an endocannabinoid uptake inhibitor or CB1 receptor agonist induced comparable decreases in immobility in the forced swim test in rats Hill and Gorzalka, Studies also suggested that females may be more sensitive to the effects of THC than males. Adolescent female rats treated with THC for 11 days and left until adulthood presented significant "behavioral despair' forced swim test paralleled by anhedonia sucrose preference.
In contrast, male rats showed no behavioral despair but did present anhedonia Rubino et al.
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Chronic 20 days adolescent but not adult daily injection of CB 1 receptor agonist led to anxiety and depression-like behavior in the forced swim and sucrose preference test in rats. Serotonergic hypoactivity and noradrenergic hyperactivity were observed Bambico et al.
It has been suggested that significant alterations in serotonergic systems may be rather related to acute activation of the endogenous cannabinoid system or to cannabis dependence accompanied by manifest depressive symptoms Rose et al. Studies in CB1-knockout on the other hand showed the opposite results. Thus, reduced exploration of the open arms of the plus-maze apparatus by CB1-knockout compared with wild-type animals was reported Haller et al. CB1 knockout mice also showed a higher sensitivity to exhibit depressive-like responses in the chronic unpredictable mild stress procedure suggesting an increased susceptibility to develop an anhedonic state Martin et al.
In humans, inconsistent data exists as regards whether cannabis causes depression or not. In one survey, daily or once weekly adult users of cannabis reported less depressed mood and more positive affect than non-users Densona and Earleywine, Other studies suggested that cannabis abuse was a risk factor for the development of depressive symptoms Gregory and Bovasso, and that cannabis dependence was highly associated with independent depression Dakwar et al. Cannabis-dependent subjects had lower levels of motivation, happiness, and satisfaction with life, with higher levels of depression Looby and Earleywine, Depressive disorders were Behavioral and biochemical effects of Cannabis Sativa and their modulation by antidepressant drugs Rev.
Moreover, among patients with bipolar disorder, cannabis users exhibited less compliance and higher level of overall illness severity compared with non-users van Rossum et al. The present findings also indicated that cannabis administration was associated with decreased rearing activity of mice. The latter is a frequently used measure of anxiety-like behavior Henderson et al.
It has been suggested that rearing is a useful marker of environmental novelty, that the hippocampal formation is a crucial component of the system controlling rearing in novel environments Lever et al.
The results of the present study are in accordance with other studies showing decreased rearing activity after chronic THC treatment in rats Miczek, , ; Miczek and Dixit, The rearing activity in rats was also decreased by the endogenous endocannabinoid anandamide Fride and Mechoulam, Studies also showed that THC strongly affects rearing activity more strongly than locomotion with tolerance being evident to the latter, but with no recovery of the reduced rearing activity when exposure to THC was continued for weeks Miczek and Dixit, ; Miller and Drew, In the present study, the decrease in rearing activity was ameliorated by the SSRIs fluoxetine or sertraline, suggesting amelioration of the effect of cannabis on exploratory behavior by the antidepressant drugs.
Oxidative stress has been implicated in pathogenesis of depression and several other brain disorders such as Parkinson's disease, Alzheimer's disease, bipolar disorder, major depression and schizophrenia Sian et al. In addition, there is evidence to support a benefit from increasing brain glutathione levels e. In the present study, the repeated administration of cannabis for 24 days was associated with significant and dose-dependent increase in brain GSH. The latter is a major antioxidant and plays an important role in the maintenance of the redox status of the cell and in protecting against oxidative damage by reactive oxygen species Wang and Ballatori, Malondialdehyde, a marker of lipid peroxidation Gutteridge, showed a significant decrease in brain by the highest dose of cannabis, suggesting an antioxidant effect for the extract.
Moreover, the co-administration of fluoxetine, sertraline or imipramine with cannabis was associated with a significant decrease of brain MDA. Indeed, a neuroprotective effect of cannabis has been suggested. Other studies, however, reported elevated plasma nitrate concentrations in depression Suzuki et al.
In the present study; nitric oxide is increased in the brain by fluoxetine. In contrast, nitric oxide is decreased by imipramine. The coadministration of fluoxetine or sertraline with cannabis was associated with near normal values of nitric oxide. In several studies antidepressant drugs have been shown to modulate nitric oxide release within the brain Ha et al. Studies also suggested the involvement of nitric oxide in depression and in the mood elevating action of antidepressant drugs.
Thus pre-treatment with L-arginine counteracted the antidepressant-like effect of imipramine, venlafaxine and bupropion Krass et al.
In those with lifetime major depressive disorder antidepressant medications were associated with higher NO in plasma Wagner et al. Meanwhile, the antidepressant action of imipramine and venlafaxine involves suppression of nitric oxide synthesis Krass et al. Cannabis sativa, however, contains more than different chemical compounds including over 70 different cannabinoids.
The involvement of 5-HT1A receptors has been suggested. The chemistry of cannabis is thus a complex one and it is likely that the final effect of the extract will depend on the relative abundance of different cannabinoids, their interaction as well as interaction with other non-cannabinoid constituents. The administration of cannabis for 24 days in mice resulted in decreased brain oxidative stress but induced a significant increase in immobility in the forced-swimming test and a decrease in the rearing activity, suggesting a depressant- and anxiety-like effect.
These latter effects were improved by antidepressant drugs. For the supply of Cannabis sativa plant the authors are indebted to the Ministry of Justice of the Arab Republic of Egypt. Ameri A The effects of cannabinoids on the brain. Progress in Neurobiology 58 Ashton CH Pharmacology and effects of cannabis: A brief review.
British Journal of Psychiatry Bambico FR, Nguyen NlT, Katz N, Gobbi G Chronic exposure to cannabinoids during adolescence but not during adulthood impairs emotional behavior and monoaminergic neurotransmission. Neurobiology of Disease 37 Behavioural Brain Research Brain Research Bulletin 72 Bovasso GB Cannabis abuse as a risk factor for depressive symptoms. American Journal of Psychiatry Biochemistry 37 Psychopharmacology Berl Pharmacology Biochemistry and Behavior American Journal on Addictions Addictive Behaviors 31 N- N-Ace-tylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development.
European Journal of Pharmacology Ellman GL Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics Naunyn Schmiedebergs Arch Pharmacol Fride E, Mechoulam R Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. European Journal of Pharmacology ; Fuller RW Uptake inhibitors increase extracellular serotonin concentration measured by brain microdialysis. Life Sciences ence 55 Gaoni Y, Mechoulam R Isolation, structure and partial synthesis of an active constituent of hashish.
Journal of the American Chemical Society Psychosomatic Medicine 73 International Journal of Neuropsychopharmacology 14 Alterations on the morphology, nitric oxide synthesis and activity of platelets reproduced in rats as possible biomarkers for depression are reversed by fluoxetine.
Planta Medica 72 Gutteridge JMC Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clinical Chemistry Neuroscience Letters European Journal of Neuroscience 16 Harte LC, Dow-Edwards D Sexually dimorphic alterations in locomotion and reversal learning after adolescent tetrahydrocannabinol exposure in the rat.
Neurotoxicology and Teratology 32 Behavior Genetics 34 Hill MN, Gorzalka BB Pharmacological enhancement of cannabinoid CB1 receptor activity elicits an antidepressant-like response in the rat forced swim test.zaphouresreness.gq
Pharmacological actions of cannabinoids.
European Neuropsychopharmacology Psychoneuroendocrinology 34 Forensic Science Review 14 Pharmacopsychiatry 43 PLoS One 6 :e Review of Neuroscience ; 17 Neuropharmacology Current Clinical Pharmacology 5 Looby A, Earleywine M Negative consequences associated with dependence in daily cannabis users. Substance Abuse Treatment, Prevention, and Policy 2 European Journal of Cancer Care Engl 17 Psychopharmacology Psychological Bulletin Nitric Oxide 5: International Journal of Neuropsychopharmacology Prostaglandins, Leuko-trienes and Essential Fatty Acids 66 Pertwee RG Pharmacological actions of cannabinoids.
Handbook of Experimental Pharmacology Pertwee RG The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta 9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin.