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: 6.34). 11/2007; 27(43):11700-11. DOI: 10.1523/JNEUROSCI.1636-07.2007
Source: PubMed


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.

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    • "restingly , the systematic administration of URB597 , an inhibitor of fatty acid amide hydrolase ( FAAH ) , can enhance the firing of serotonergic neurons in DRN and increase the hippocampal levels of 5 - HT ( Gobbi et al . , 2005 ) . This effect is mimicked by local injection of CB 1 receptor agonists into the PFC and blocked by PFC transection ( Bambico et al . , 2007 ) . Hence , the eCB system seems to control PFC circuits which modulate the signaling toward the DRN . Furthermore , local activation of CB 1 receptor in the DRN reduces the strength of glutamatergic inputs onto DRN 5 - HT neurons , suggesting that CB 1 receptor - positive glutamatergic synapses control serotonergic neuron activity with"
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    ABSTRACT: The endocannabinoid (eCB) system possesses neuromodulatory functions by influencing the release of various neurotransmitters, including γ-aminobutyric acid (GABA) and glutamate. A functional interaction between eCBs and the serotonergic system has already been suggested. Previously, we showed that cannabinoid type-1 (CB1) receptor mRNA and protein are localized in serotonergic neurons of the raphe nuclei, implying that the eCB system can modulate serotonergic functions. In order to substantiate the physiological role of the CB1 receptor in serotonergic neurons of the raphe nuclei, we generated serotonergic 5-hydroxytryptamine (5-HT) neuron-specific CB 1 receptor-deficient mice, using the Cre/loxP system with a tamoxifen-inducible Cre recombinase under the control of the regulatory sequences of the tryptophan hydroxylase 2 gene (TPH2-CreER (T2)), thus, restricting the recombination to 5-HT neurons of the central nervous system (CNS). Applying several different behavioral paradigms, we revealed that mice lacking the CB1 receptor in serotonergic neurons are more anxious and less sociable than control littermates. Thus, we were able to show that functional CB1 receptor signaling in central serotonergic neurons modulates distinct behaviors in mice.
    Frontiers in Behavioral Neuroscience 09/2015; 9:235. DOI:10.3389/fnbeh.2015.00235 · 3.27 Impact Factor
    • "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. "
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    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 · 8.80 Impact Factor
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    • "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). "
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    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 · 3.54 Impact Factor
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