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Animal research highlights a therapeutic potential
of cannabinoids for the treatment of depression

Regina A. Mangieri
Department of Pharmacology, The University of Texas at Austin, Austin, TX 78712, USA Abstract
Long known for their mood altering effects, cannabinoids are currently under investigation for their therapeutic potential in the treatment of depression. Findings from multiple areas of basic re-search indicate that this system is indeed a viable target for novel antidepressant drugs. Rodent models of depression have been shown to alter levels of the endogenous cannabinoids and the cannabinoid CB1 receptor, implicating this system in the etiology of depression. Additionally, can- nabinoid drugs have demonstrated efficacy in rodent tests for antidepressant drug-like activity, and
these effects appear to share common mechanisms of action with current antidepressant drugs,
such as the selective-serotonin reuptake inhibitors. Thus, although the effects of cannabinoids on
depression in humans remain to be elucidated, animal studies have provided impetus to further
pursue this line of clinical research.
Key words: cannabinoid, depression, antidepressant, endocannabinoid, serotonin, cannabis
This article can be downloaded, printed and distributed freely for any non-commercial purposes, provided the original work is prop- erly cited (see copyright info below). Available online at Author's address: Regina A. Mangieri,
tion of the cannabinoid system might indeed be a use-ful therapy for depression. Findings from several areas Cannabinoid drugs, well known for their effects on of basic research substantiate this notion. First, in ani- mood, are currently being tested clinically for the mal models of depression (described below), there treatment of depression. In humans, depression is char- appears to be a down-regulation of endogenous can- acterized by the core symptoms of depressed mood nabinoid signaling in specific brain regions. Secondly, and/or loss of pleasure or interest in most activities a number of groups have found cannabinoid drugs to (anhedonia) [1]. Other signs of depression include be effective in rodent models of depression and tests changes in body weight, sleeping patterns, psychomo- for antidepressant-like activity. Finally, treatment with tor behavior, energy level, and cognitive functioning these drugs appears to share common mechanisms of [1]. Interestingly, activation of cannabinoid CB action with traditional antidepressant treatments. To- tors has been shown to affect pain perception, food gether, these lines of evidence provide a strong ration- intake, locomotor activity, cognition, and mood-related ale for the use of cannabinoids in the pharmacotherapy behaviors (for review, see Piomelli, 2003 [2]). This striking overlap between the physiological functions altered by depression and those modulated by cannabi- Studying depression in rodents
noid receptor signaling has implicated this system as a likely target for the treatment of mood disorders. Al- While mood is often thought to be a uniquely human though the effects of cannabis use on mood disorders in quality, depression can in fact be modeled in rodents humans is still a matter of debate [3], recent studies in using a chronic mild and/or unpredictable stress animals provide support for the suggestion that activa- (CMS/CUS) protocol. In this model, a random se- International Association for Cannabis as Medicine quence of mild stressors (such as food or water depri- mented by findings from human studies. In clinical vation, changes in light cycle, crowded housing, physi- trials of the CB1 receptor antagonist rimonabant for the cal restraint) presented daily over the course of several treatment of obesity, anxiety and depression are among weeks, produces a number of physiological and behav- the most frequent adverse events reported [8-12]. Addi- ioral alterations reminiscent of those seen in humans tionally, human studies suggest that the endocannabi- with depression, including changes in body weight, noid system is altered during depression. Hungund and cognitive functioning, and responsiveness to rewards colleagues reported an increase in both CB1 receptor [4]. Furthermore, as in humans, these changes are sen- mRNA and CB1 receptor-stimulated [35S]GTPγS bind- sitive to chronic, but not acute, treatment with antide- ing in the dorsolateral prefrontal cortex of subjects with pressant drugs, thus making this a highly valid model a life-time diagnosis of major depression who commit- of depression. This model can be used both to examine ted suicide, compared to normal controls (matched by the effects of chronic stress on the brain and to identify age, sex, and postmortem interval) who died by acci- treatments that confer antidepressant-like activity. dent or natural causes [13]. In another study, Hill and Another test used to study antidepressant-like treat- colleagues reported reduced serum 2-AG levels in ments in rodents, which has good predictive validity, drug-free females diagnosed with major depression but less face validity than the CMS model, is the forced compared to demographically-matched controls, with swim test. This test does not model features of depres- levels of 2-AG negatively correlated to the duration of sion, but rather is a useful tool for identifying antide- the depressive episode [14]. In the latter study, serum pressant-like treatments. Most antidepressant treat- anandamide was not associated with major depression, ments – for example, those modulating monoaminergic but was negatively correlated with measures of anxiety. systems (i.e., serotonin- or norepinephrine- reuptake Overall, these studies in both rodents and suggest that inhibitors) – decrease the time an animal spends im- endocannabinoid signaling is altered – in specific brain mobile and increase the amount of time a rodent spends regions and, perhaps, in the periphery – during depres- swimming or struggling while in a cylinder of water sion or negative affective states. Although the relation- from which it has learned it cannot escape. Thus, this ship between chronic stress and endocannabinoid sig- test also may be used to identify new drugs that might naling remains to be explored further, this limited, but possess antidepressant-like activity in humans. Both of compelling evidence indicates there is an alteration of these tests have been used by several groups to study the activity of this system during chronic-stress related the relationship between cannabinoid receptor signal- ing and mood-related behaviors in rodents.
Endocannabinoid alterations by chronic stress
Cannabinoids and modulation of mood-related
behaviors in rodents

There is a paucity of research on the effects of chronic stress on endogenous cannabinoid signaling, but recent Recent research from several groups has afforded sig- findings suggest that this system is altered by chronic nificant preclinical evidence for the utility of cannabi- stress models of depression in rodents. In rats subjected noids in the treatment of depression. Overall, the evi- to 3 weeks of CUS, Hill and colleagues found a signifi- dence indicates that low doses of cannabinoid agonists cant reduction in the levels of the endocannabinoid 2- exert anti-anxiety and antidepressant effects in rodents; however, these dose-dependent effects can be modu- 1 receptor protein in the hippocampus [5]. A similar study by Bortolato and colleagues reported lated by other factors, such as previous experience with the drug or environmental manipulations that alter the increased in the prefrontal cortex and decreased in the level of stress experienced by the animal [15]. For rat midbrain, and 2-AG levels were decreased in the example, the synthetic CB1 receptor agonist HU210 thalamus [6] These alterations observed in the hippo- (0.1 mg/kg, i.p.) has been reported to increase anxiety- campus, prefrontal cortex, midbrain, and thalamus are like behaviors after acute administration [16], but, at particularly interesting, given the involvement of these the same dose administered twice daily for 10 days, neural structures in the regulation of emotion [7]. Addi- exerted antidepressant-like effects in the forced swim tionally, in the study by Bortolato and colleagues, 5 test, and reduced anxiety-like behavior in another ro- weeks of treatment with URB597 (an inhibitor of the dent test for stress-related behaviors [17]. Other groups hydrolysis of the endocannabinoid anandamide; 0.3 also have found antidepressant-like effects of this can- mg/kg, i.p.) elevated levels of anandamide in the mid- nabinoid agonist. Recently, McLaughlin et al reported brain, thalamus, and striatum, while reversing chronic that when HU210 (1 and 2.5 µg) was infused directly stress-induced reductions in body weight gain and into the dentate gyrus of the dorsal hippocampus of consumption of a palatable sucrose solution [6] – fur- rats, animals showed an increase in swimming time and ther suggesting deficient endocannabinoid signaling as a reduction in the amount of time spent immobile dur- a factor in some of the depression-like symptoms in- ing the forced swim test [18]. Similarly Bambico et al recently reported that another cannabinoid agonist, These basic research results implicating endocannabi- WIN55,212-2, given in low doses (0.1 and 0.2 mg/kg, noid signaling in the modulation of affect are compli- i.p.) also decreased immobility by increasing swim- Cannabinoids Œ Vol 3, No 2 Œ June 22, 2008 Mini-review ming in the forced swim test, but was ineffective at peutic potential for the treatment of depression. A ro- higher doses (1 and 2 mg/kg, i.p.) [19]. Furthermore, in dent model of depression, the CMS/CUS protocol, the previously described CUS study by Hill and col- appears to induce a deficiency in endocannabinoid leagues, stressed animals demonstrated impairments in signaling, and enhancement of cannabinoid receptor reversal learning in the Morris water maze that were signaling reverses depression-like symptoms induced corrected by administration of HU210 (0.01 mg/kg, by this protocol. Furthermore, several cannabinoid i.p.) [5]. The findings from these studies highlight the receptor agonists also have demonstrated efficacy in ability of cannabinoid agonists to exert behavioral the forced swim test – a test with high predictive valid- effects similar to known antidepressant compounds, ity for the identification of antidepressant compounds. and to correct stress-induced disruptions in cognitive Finally, treatment with cannabinoid drugs produces functioning, a symptom of depression also observed in effects that appear to be common to current antidepres- sant treatments. Overall, recent findings from multiple areas of basic research have implicated the cannabinoid Cannabinoids and traditional antidepressants:
system in the etiology and treatment of depression, thus common effects
providing solid justification for investigation of these drugs as novel pharmacotherapeutic agents for the Although the mechanism(s) by which cannabinoids modulate mood-related behavior is not entirely eluci- dated at present, administration of cannabinoids ap- Acknowledgements
pears to produce effects similar to those observed fol- R.A.M. wishes to thank Dr. Daniele Piomelli for his lowing other antidepressant treatments, namely en- mentorship during her doctoral study of this subject. hancement of serotonergic signaling and hippocampal R.A.M. is currently supported by NIAAA training neurogenesis. In the study by Bambico et al, the anti- depressant-like effects of treatment with WIN55,212-2 were paralleled by increases in the firing rate of sero- References
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