Cannabinoids elicit antidepressant-like Behavior and activate Serotonergic neurons through the medial prefrontal cortex

Department of Psychiatry, McGill University, Montréal, Quebec, Canada
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 11/2007; 27(43):11700-11. DOI: 10.1523/JNEUROSCI.1636-07.2007
Source: PubMed

ABSTRACT Preclinical and clinical studies show that cannabis modulates mood and possesses antidepressant-like properties, mediated by the agonistic activity of cannabinoids on central CB1 receptors (CB1Rs). The action of CB1R agonists on the serotonin (5-HT) system, the major transmitter system involved in mood control and implicated in the mechanism of action of antidepressants, remains however poorly understood. In this study, we demonstrated that, at low doses, the CB1R agonist WIN55,212-2 [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate] exerts potent antidepressant-like properties in the rat forced-swim test (FST). This effect is CB1R dependent because it was blocked by the CB1R antagonist rimonabant and is 5-HT mediated because it was abolished by pretreatment with the 5-HT-depleting agent parachlorophenylalanine. Then, using in vivo electrophysiology, we showed that low doses of WIN55,212-2 dose dependently enhanced dorsal raphe nucleus 5-HT neuronal activity through a CB1R-dependent mechanism. Conversely, high doses of WIN55,212-2 were ineffective in the FST and decreased 5-HT neuronal activity through a CB1R-independent mechanism. The CB1R agonist-induced enhancement of 5-HT neuronal activity was abolished by total or medial prefrontocortical, but not by lateral prefrontocortical, transection. Furthermore, 5-HT neuronal activity was enhanced by the local microinjection of WIN55,212-2 into the ventromedial prefrontal cortex (mPFCv) but not by the local microinjection of WIN55,212-2 into the lateral prefrontal cortex. Similarly, the microinjection of WIN55,212-2 into the mPFCv produced a CB1R-dependent antidepressant-like effect in the FST. These results demonstrate that CB1R agonists possess antidepressant-like properties and modulate 5-HT neuronal activity via the mPFCv.

Download full-text


Available from: Gabriella Gobbi, Jul 29, 2015
  • Source
    • "In accordance with this premise, local pharmacological blockade of CB 1 receptors in the prelimbic cortex attenuates panic-like behavior and fear-induced antinociception in an experimental model of panic attack (de Freitas et al., 2013), thus providing further evidence that endocannabinoid signaling in the medial PFC critically mediates escape behaviors. These findings correspond well with the results obtained in the FST described above, where local pharmacological facilitation of CB 1 receptor activity in the ventromedial PFC similarly elicited escape-directed active coping responses (Bambico et al., 2007; McLaughlin et al., 2012). Together, these data highlight the important role of prefrontocortical AEA/CB 1 receptor signaling in promoting an anxiolytic phenotype and escape-directed behaviors specifically during emotionally aversive encounters. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The prefrontal cortex (PFC) provides executive control of the brain in humans and rodents, coordinating cognitive, emotional, and behavioral responses to threatening stimuli and subsequent feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis. The endocannabinoid system has emerged as a fundamental regulator of HPA axis feedback inhibition and an important modulator of emotional behavior. However, the precise role of endocannabinoid signaling within the PFC with respect to stress coping and emotionality has only recently been investigated. This review discusses the current state of knowledge regarding the localization and function of the endocannabinoid system in the PFC, its sensitivity to stress and its role in modulating the neuroendocrine and behavioral responses to aversive stimuli. We propose a model whereby steady-state endocannabinoid signaling in the medial PFC indirectly regulates the outflow of pyramidal neurons by fine-tuning GABAergic inhibition. Local activation of this population of CB1 receptors increases the downstream targets of medial PFC activation, which include inhibitory interneurons in the basolateral amygdala, inhibitory relay neurons in the bed nucleus of the stria terminalis and monoamine cell bodies such as the dorsal raphe nucleus. This ultimately produces beneficial effects on emotionality (active coping responses to stress and reduced anxiety) and assists in constraining activation of the HPA axis. Under conditions of chronic stress, or in individuals suffering from mood disorders, this system may be uniquely recruited to help maintain appropriate function in the face of adversity, while breakdown of the endocannabinoid system in the medial PFC may be, in and of itself, sufficient to produce neuropsychiatric illness. Thus, we suggest that endocannabinoid signaling in the medial PFC may represent an attractive target for the treatment of stress-related disorders.
    Neuroscience & Biobehavioral Reviews 05/2014; 42. DOI:10.1016/j.neubiorev.2014.02.006 · 10.28 Impact Factor
  • Source
    • "In contrast, Hill et al. (2008c) indicated that tranylcypromine increases the level of 2-AG and enhances the density of CB 1 receptors in the prefrontal cortex (Hill et al. 2008c). However, other reports have demonstrated that CB 1 receptors in the prefrontal cortex can participate in the antidepressant actions of CB 1 receptor agonists and that increases in local AEA signaling can modulate stress coping behaviors via the activation of serotonergic neurons in the raphe nucleus (Bambico et al. 2007; McLaughlin et al. 2012). Additionally, chronically administering fluoxetine can fully reverse the enhanced CB 1 -receptor signaling seen in bulbectomized rats (Rodriguez-Gaztelumendi et al. 2009) and can also modulate the function (but not the density) of CB 1 receptors in the prefrontal cortex (Mato et al. 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The endocannabinoid (eCB) system has recently been implicated in both the pathogenesis of depression and the action of antidepressants. Here, we investigated the effect of acutely or chronically administering antidepressants [imipramine (IMI) (15 mg/kg), escitalopram (ESC) (10 mg/kg), and tianeptine (10 mg/kg)] on the levels of both eCBs [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)] and N-acylethanolamines (NAEs) [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)] in various rat brain regions. We also examined the ability of the acute and chronic administration of N-acetylcysteine (NAC) (a mucolytic drug; 100 mg/kg) or URB597 (a fatty acid amide hydrolase inhibitor; 0.3 mg/kg), which have both elicited antidepressant activity in preclinical studies, to affect eCB and NAE levels. Next, we determined whether the observed effects are stable 10 days after the chronic administration of these drugs was halted. We report that the chronic administration of all investigated drugs increased AEA levels in the hippocampus and also increased both AEA and 2-AG levels in the dorsal striatum. NAE levels in limbic regions also increased after treatment with IMI (PEA/OEA), ESC (PEA), and NAC (PEA/OEA). Removing chronic ESC treatment for 10 days affected eCB and NAE levels in the frontal cortex, hippocampus, dorsal striatum, and cerebellum, while a similar tianeptine-free period enhanced accumbal NAE levels. All other drugs maintained their effects after the 10-day washout period. Therefore, the eCB system appears to play a significant role in the mechanism of action of clinically effective and potential antidepressants and may serve as a target for drug design and discovery.
    Neurotoxicity Research 03/2014; 26(2). DOI:10.1007/s12640-014-9465-0 · 3.15 Impact Factor
  • Source
    • "Therefore, these data further support the concept that adolescence is a critical period in which protracted direct CB1 activation by affecting the monoaminergic system could influence mood control (Rubino et al., 2012). To confirm the antidepressant-like effects of CB1 agonists, the endogenous cannabinoid AEA (Hayase, 2011a; Umathe et al., 2011) and the synthetic nonspecific cannabinoid CB1/ CB2 receptor agonists WIN55,212-2 (Bambico et al., 2007), HU-210 (Hill & Gorzalka, 2005; Jiang et al., 2005; McLaughlin et al., 2007; Morrish et al., 2009) and CP55,940 (Adamczyk et al., 2008) or the selective CB1 agonist arachidonoyl 2′-chloroethylamide (ACEA) (Rutkowska & Jachimczuk, 2004) improved the behavioral responses of rodents through a CB1-and 5-HTergic or NEergic-mediated mechanisms. Evidence also suggests that cannabinoids, by modulating the physiological and behavioral response to stressful conditions, elicit anxiolityc-like responses (Riebe & Wotjak, 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The endocannabinoid system (ECS), comprising two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana's psychoactive principle Δ(9)-tetrahydrocannabinol [Δ(9)-THC]), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and the proteins for endocannabinoid biosynthesis and degradation, has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during physiopathological conditions. In the brain activation of this system modulates the release of excitatory and inhibitory neurotransmitters and of cytokines from glial cells. As such, the ECS is strongly involved in neuropsychiatric disorders, particularly in affective disturbances such as anxiety and depression. It has been proposed that synthetic molecules that inhibit endocannabinoid degradation can exploit the selectivity of endocannabinoid action, thus activating cannabinoid receptors only in those tissues where there is perturbed endocannabinoid turnover due to the disorder, and avoiding the potential side effects of direct CB1 and CB2 activation. However, the realization that endocannabinoids, and AEA in particular, also act at other molecular targets, and that these mediators can be deactivated by redundant pathways, has recently led to question the efficacy of such approach, thus opening the way to new multi-target therapeutic strategies, and to the use of non-psychotropic cannabinoids, such as cannabidiol (CBD), which act via several parallel mechanisms, including indirect interactions with the ECS. The state of the art of the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in mood disorders is discussed in this review article.
    Pharmacology [?] Therapeutics 12/2012; 138(1). DOI:10.1016/j.pharmthera.2012.12.002 · 7.75 Impact Factor
Show more