Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference

Liu, Qingrong; Canseco-Alba, Ana; Zhang, Hai Ying; Tagliaferro, Patricia; Chung, Monika; Dennis, Eugene; Sanabria, Branden; Schanz, Norman; Escosteguy-Neto, João Carlos; Ishiguro, Hiroki; Lin, Zhicheng; Sgro, Susan; Leonard, Claire M.; Santos-Junior, Jair Guilherme; Gardner, Eliot L.; Egan, Josephine M.; Lee, Jeung Woon; Xi, Zheng‐Xiong; Onaivi, Emmanuel S.

doi:10.1038/s41598-017-17796-y

Cited by 130 publications

(166 citation statements)

References 69 publications

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“…Our goal here was to summarize the protocol used to measure alcohol preference in combination with stress-induced alcohol consumption. We also provide evidence that the endocannabinoid system plays a role in alcohol preference following dopaminergic neuron specific deletion of CB2Rs in the mouse model (Liu et al ., 2017). …”

Section: [Background]supporting

confidence: 55%

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Behavioral Evaluation of Seeking and Preference of Alcohol in Mice Subjected to Stress

et al. 2018

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The alcohol preference model is one of the most widely used animal models relevant to alcoholism. Stressors increase alcohol consumption. Here we present a protocol for a rapid and useful tool to test alcohol preference and stress-induced alcohol consumption in mice. In this model, animals are given two bottles, one with a diluted solution of ethanol in water, and the other with tap water. Consumption from each bottle is monitored over a 24-h period over several days to assess the animal’s relative preference for the ethanol solution over water. In the second phase, animals are stressed by restraining them for an hour daily and their subsequent preference of tap water or the ethanol solution is evaluated. Preference is measured by the volume and/or weight or liquid consumed daily, which is then converted to a preference ratio. The alcohol preference model was combined with the conditioned place preference paradigm to determine alcohol conditioning and preference following the deletion of CB2 cannabinoid receptors in dopaminergic neurons in the DAT-Cnr2 Cre-recombinant conditional knockout (cKO) mice in comparison with the wild-type control mice.

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Section: [Background]supporting

confidence: 55%

“…We are also thankful for the technical assistant of Sneha Tammareddy, Eugene Dennis, Branden Sanabria, Paola Velandia, Steve Gross, and Monika Chung while working in the laboratory of ESO. This protocol and figures are adapted from our previous work (Liu et al , 2017). …”

Section: Acknowledgmentsmentioning

confidence: 99%

Behavioral Evaluation of Seeking and Preference of Alcohol in Mice Subjected to Stress

et al. 2018

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“…These findings are consistent with an early report indicating that deletion of CB 2 receptors in CB 2 ‐KO mice failed to alter Δ 9 ‐THC‐induced hypothermia and immobility (Buckley et al, ). Furthermore, Onaivi et al () have recently reported that selective deletion of CB 2 receptors on dopaminergic neurons reduced WIN55212‐2‐induced catalepsy and altered WIN55212‐2‐induced analgesia (as assessed in a tail flick test) but had no effect on WIN55212‐2‐induced hypothermia and hypoactivity (Liu et al, ), which provides additional evidence supporting brain CB 2 receptor involvement in cannabinoid‐induced pharmacological effects. We note that pretreatment with AM251 almost completely blocked, while AM630 only partially attenuated Δ 9 ‐THC‐ or WIN55212‐2‐induced analgesia and catalepsy, suggesting that CB 1 receptors play a more important role than CB 2 receptors in cannabinoid action.…”

Section: Discussionmentioning

confidence: 95%

“…We have recently reported that brain CB 1 and CB 2 receptors mediate cannabis reward versus aversion, respectively, as assessed in a brain stimulation reward paradigm in rats (Spiller et al, ). Selective deletion of CB 2 receptors from midbrain dopamine neurons altered multiple behavioural effects in mice produced by WIN55212‐2, a synthetic cannabinoid (Liu et al, ), suggesting a possible involvement of brain CB 2 receptors in cannabinoid‐induced tetrad effects. In addition, GPR55, another putative cannabinoid receptor (Baker, Pryce, Davies, & Hiley, ; Moriconi, Cerbara, Maccarrone, & Topai, ), was also found in brain regions involved in locomotion and nociception (Martínez‐Pinilla et al, ; Ryberg et al, ; Wu et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…However, little is known about other non-CB 1 receptor mechanisms in cannabinoid action. We and others have recently reported that functional CB 2 receptors are also expressed in the brain (see a comprehensive review by Jordan & Xi, 2019) and are involved in multiple behavioural effects of Δ 9 -THC or other cannabinoids in experimental animals (DeLong, Wolf, Poklis, & Lichtman, 2010;Lesniak et al, 2019;Liu et al, 2017). Although, little is known if brain CB 2 receptors are also involved in cannabinoidinduced tetrad effects.…”

Section: Introductionmentioning

confidence: 99%

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Different receptor mechanisms underlying phytocannabinoid‐ versus synthetic cannabinoid‐induced tetrad effects: Opposite roles of CB₁/CB₂ versus GPR55 receptors

Xiaofei

Galaj

et al. 2020

British J Pharmacology

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Background and Purpose Cannabis or cannabinoids produce characteristic tetrad effects—analgesia, hypothermia, catalepsy and suppressed locomotion, which are believed to be mediated by the activation of cannabinoid CB1 receptors. Given recent findings of CB2 and GPR55 receptors in the brain, we examined whether these receptors are also involved in cannabinoid action. Experimental Approach We compared Δ9‐tetrahydrocannabinol (Δ9‐THC)‐, WIN55212‐2‐, or XLR11‐induced tetrad effects between wild‐type (WT) and each genotype of CB1‐, CB2‐ or GPR55‐knockout (KO) mice and then observed the effects of antagonists of these receptors on these tetrad effects in WT mice. Key Results Systemic administration of Δ9‐THC, WIN55212‐2 or XLR11 produced dose‐dependent tetrad effects in WT mice. Genetic deletion or pharmacological blockade of CB1 receptors abolished the tetrad effects produced by all three cannabinoids. Unexpectedly, genetic deletion of CB2 receptor abolished analgesia and catalepsy produced by Δ9‐THC or WIN55212‐2, but not by XLR11. Microinjections of Δ9‐THC into the lateral ventricles also produced tetrad effects in WT, but not in CB1‐KO mice. CB2‐KO mice displayed a reduction in intraventricular Δ9‐THC‐induced analgesia and catalepsy. In contrast to CB1 and CB2 receptors, genetic deletion of GPR55 receptors caused enhanced responses to Δ9‐THC or WIN55212‐2. Antagonisim of CB1, CB2 or GPR55 receptors produced alterations similar to those observed in each genotype mouse line. Conclusions and Implications These findings suggest that in addition to CB1, both CB2 and GPR55 receptors are also involved in some pharmacological effects produced by cannabinoids. CB1/CB2, in contrast to GPR55, receptors appears to play opposite roles in cannabinoid action.

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Role of the endocannabinoid system in a mouse model of Fragile X undergoing neuropathic pain

Ramírez-López

Pastor

Torre

et al. 2021

European Journal of Pain

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Background Neuropathic pain is a complex condition characterized by sensory, cognitive and affective symptoms that magnify the perception of pain. The underlying pathogenic mechanisms are largely unknown and there is an urgent need for the development of novel medications. The endocannabinoid system modulates pain perception and drugs targeting the cannabinoid receptor type 2 (CB2) devoid of psychoactive side effects could emerge as novel analgesics. An interesting model to evaluate the mechanisms underlying resistance to pain is the fragile X mental retardation protein knockout mouse (Fmr1KO), a model of fragile X syndrome that exhibits nociceptive deficits and fails to develop neuropathic pain. Methods A partial sciatic nerve ligation was performed to wild‐type (WT) and Fmr1KO mice having (HzCB2 and Fmr1KO‐HzCB2, respectively) or not (WT and Fmr1KO mice) a partial deletion of CB2 to investigate the participation of the endocannabinoid system on the pain‐resistant phenotype of Fmr1KO mice. Results Nerve injury induced canonical hypersensitivity in WT and HzCB2 mice, whereas this increased pain sensitivity was absent in Fmr1KO mice. Interestingly, Fmr1KO mice partially lacking CB2 lost this protection against neuropathic pain. Similarly, pain‐induced depressive‐like behaviour was observed in WT, HzCB2 and Fmr1KO‐HzCB2 mice, but not in Fmr1KO littermates. Nerve injury evoked different alterations in WT and Fmr1KO mice at spinal and supra‐spinal levels that correlated with these nociceptive and emotional alterations. Conclusions This work shows that CB2 is necessary for the protection against neuropathic pain observed in Fmr1KO mice, raising the interest in targeting this receptor for the treatment of neuropathic pain. Significance Neuropathic pain is a complex chronic pain condition and current treatments are limited by the lack of efficacy and the incidence of important side effects. Our findings show that the pain‐resistant phenotype of Fmr1KO mice against nociceptive and emotional manifestations triggered by persistent nerve damage requires the participation of the cannabinoid receptor CB2, raising the interest in targeting this receptor for neuropathic pain treatment. Additional multidisciplinary studies more closely related to human pain experience should be conducted to explore the potential use of cannabinoids as adequate analgesic tools.

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Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference

Cited by 130 publications

References 69 publications

Behavioral Evaluation of Seeking and Preference of Alcohol in Mice Subjected to Stress

Behavioral Evaluation of Seeking and Preference of Alcohol in Mice Subjected to Stress

Different receptor mechanisms underlying phytocannabinoid‐ versus synthetic cannabinoid‐induced tetrad effects: Opposite roles of CB₁/CB₂ versus GPR55 receptors

Role of the endocannabinoid system in a mouse model of Fragile X undergoing neuropathic pain

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Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference

Cited by 130 publications

References 69 publications

Behavioral Evaluation of Seeking and Preference of Alcohol in Mice Subjected to Stress

Behavioral Evaluation of Seeking and Preference of Alcohol in Mice Subjected to Stress

Different receptor mechanisms underlying phytocannabinoid‐ versus synthetic cannabinoid‐induced tetrad effects: Opposite roles of CB1/CB2 versus GPR55 receptors

Role of the endocannabinoid system in a mouse model of Fragile X undergoing neuropathic pain

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Different receptor mechanisms underlying phytocannabinoid‐ versus synthetic cannabinoid‐induced tetrad effects: Opposite roles of CB₁/CB₂ versus GPR55 receptors