Cannabinoid CB<sub>2</sub> receptor‐mediated regulation of impulsive‐like behaviour in DBA/2 mice

Pérez‐Ortiz, José Manuel; Navarrete, Francisco

doi:10.1111/j.1476-5381.2011.01542.x

Cited by 70 publications

(58 citation statements)

References 53 publications

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“…This is consistent with our previous findings that systemic or local administration of JWH133 into the nucleus accumbens inhibits cocaine self-administration (22), and that transgenic up-regulation of brain CB 2 Rs attenuates cocaine self-administration and cocaine-induced increased locomotion (19). The present findings are also congruent with recent reports that brain CB 2 Rs have important roles in other DArelated functions and/or CNS disorders (12,25,51,52).…”

Section: Discussionsupporting

confidence: 83%

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Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Zhang

Gao

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

304

353

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Cannabinoid CB 2 receptors (CB 2 Rs) have been recently reported to modulate brain dopamine (DA)-related behaviors; however, the cellular mechanisms underlying these actions are unclear. Here we report that CB 2 Rs are expressed in ventral tegmental area (VTA) DA neurons and functionally modulate DA neuronal excitability and DA-related behavior. In situ hybridization and immunohistochemical assays detected CB 2 mRNA and CB 2 R immunostaining in VTA DA neurons. Electrophysiological studies demonstrated that activation of CB 2 Rs by JWH133 or other CB 2 R agonists inhibited VTA DA neuronal firing in vivo and ex vivo, whereas microinjections of JWH133 into the VTA inhibited cocaine self-administration. Importantly, all of the above findings observed in WT or CB 1 −/− mice are blocked by CB 2 R antagonist and absent in CB 2 −/− mice. These data suggest that CB 2 R-mediated reduction of VTA DA neuronal activity may underlie JWH133's modulation of DA-regulated behaviors.T he presence of functional cannabinoid CB 2 receptors (CB 2 Rs) in the brain has been controversial. When CB 2 Rs were first cloned, in situ hybridization (ISH) failed to detect CB 2 mRNA in brain (1). Similarly, Northern blot and polymerase chain reaction (PCR) assays failed to detect CB 2 mRNA in brain (2-5). Therefore, CB 2 Rs were considered "peripheral cannabinoid receptors" (1, 6).In contrast, other studies using ISH and radioligand binding assays detected CB 2 mRNA and receptor binding in rat retina (7), mouse cerebral cortex (8), and hippocampus and striatum of nonhuman primates (9). More recent studies using RT-PCR also detected CB 2 mRNA in the cortex, striatum, hippocampus, amygdala, and brainstem (9-14). Immunoblot and immunohistochemistry (IHC) assays detected CB 2 R immunoreactivity or immunostaining in various brain regions (13,(15)(16)(17)(18)(19)(20). The specificities of the detected CB 2 R protein and CB 2 -mRNA remain questionable, however, owing to a lack of controls using CB 1 −/− and CB 2 −/− mice in most previous studies (21). A currently accepted view is that brain CB 2 Rs are expressed predominantly in activated microglia during neuroinflammation, whereas brain neurons, except for a very small number in the brainstem, lack CB 2 R expression (21).On the other hand, we recently reported that brain CB 2 Rs modulate cocaine self-administration and cocaine-induced increases in locomotion and extracellular dopamine (DA) in the nucleus accumbens in mice (22). This finding is supported by recent studies demonstrating that systemic administration of the CB 2 R agonist O-1966 inhibited cocaine-induced conditioned place preference in WT mice, but not in CB 2 −/− mice (23), and that increased CB 2 R expression in mouse brain attenuates cocaine self-administration and cocaine-enhanced locomotion (19). In addition, brain CB 2 Rs may be involved in several DA-related CNS disorders, such as Parkinson's disease (24), schizophrenia (25), anxiety (26), and depression (27). The cellular mechanisms underlying CB 2 R modulation of DA-related behav...

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Section: Discussionsupporting

confidence: 83%

“…More recent studies using RT-PCR also detected CB 2 mRNA in the cortex, striatum, hippocampus, amygdala, and brainstem (9)(10)(11)(12)(13)(14). Immunoblot and immunohistochemistry (IHC) assays detected CB 2 R immunoreactivity or immunostaining in various brain regions (13,(15)(16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Zhang

Gao

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

304

353

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“…Coronal brain sections (500 mm) beginning at plates 19-20 (Paxinos and Franklin, 2001) were obtained in a cryostat ( À 10 1C). The VTA was microdissected according to a modification of the Palkovits method (Palkovits, 1983) as previously described (Navarrete et al, 2012). Total RNA was isolated from brain tissue micropunches using Trizol reagent (Invitrogen, Madrid, Spain) and subsequently retrotranscribed to cDNA.…”

Section: Real-time Pcr Analysesmentioning

confidence: 99%

Role of CB2 Cannabinoid Receptors in the Rewarding, Reinforcing, and Physical Effects of Nicotine

Navarrete

Rodrı́guez-Arias

Martín‐García

et al. 2013

Neuropsychopharmacol

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108

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This study was aimed to evaluate the involvement of CB2 cannabinoid receptors (CB2r) in the rewarding, reinforcing and motivational effects of nicotine. Conditioned place preference (CPP) and intravenous self-administration experiments were carried out in knockout mice lacking CB2r (CB2KO) and wild-type (WT) littermates treated with the CB2r antagonist AM630 (1 and 3 mg/kg). Gene expression analyses of tyrosine hydroxylase (TH) and a3-and a4-nicotinic acetylcholine receptor subunits (nAChRs) in the ventral tegmental area (VTA) and immunohistochemical studies to elucidate whether CB2r colocalized with a3-and a4-nAChRs in the nucleus accumbens and VTA were performed. Mecamylamine-precipitated withdrawal syndrome after chronic nicotine exposure was evaluated in CB2KO mice and WT mice treated with AM630 (1 and 3 mg/kg). CB2KO mice did not show nicotine-induced place conditioning and selfadministered significantly less nicotine. In addition, AM630 was able to block (3 mg/kg) nicotine-induced CPP and reduce (1 and 3 mg/kg) nicotine self-administration. Under baseline conditions, TH, a3-nAChR, and a4-nAChR mRNA levels in the VTA of CB2KO mice were significantly lower compared with WT mice. Confocal microscopy images revealed that CB2r colocalized with a3-and a4-nAChRs. Somatic signs of nicotine withdrawal (rearings, groomings, scratches, teeth chattering, and body tremors) increased significantly in WT but were absent in CB2KO mice. Interestingly, the administration of AM630 blocked the nicotine withdrawal syndrome and failed to alter basal behavior in saline-treated WT mice. These results suggest that CB2r play a relevant role in the rewarding, reinforcing, and motivational effects of nicotine. Pharmacological manipulation of this receptor deserves further consideration as a potential new valuable target for the treatment of nicotine dependence.

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“…In DBA/2J mice, which show high trait impulsivity, a CB2 agonist decreased impulsive responding and delay discounting, while a CB2 antagonist decreased novelty-seeking behavior and improved prepulse inhibition (PPI) [60]. In another study, the anticonvulsant and mood stabilizer topiramate reduced novelty-seeking behavior, impulsive responding and delay discounting in DBA/2J mice [61].…”

Section: Mouse 'Externalizing' Endophenotypes In Drug Discoverymentioning

confidence: 97%

Role of murine models in psychiatric illness drug discovery: a dimensional view

Hoffman

2013

Expert Opinion on Drug Discovery

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Considering animal models within the context of endophenotypes associated with psychopathological 'dimensions', rather than focusing on modeling specific disorders, might facilitate the discovery of new pharmacotherapies. Mouse models will be powerful tools for exploring how environmental factors interact with genetic vulnerability to cause psychopathology, possibly leading to novel preventative treatment strategies. Future pharmacotherapies for neuropsychiatric disorders such as depression might comprise drugs or drug combinations that target key components of multiple systems, including neurotransmitter systems, cytokine production, oxidative stress and the HPA axis.

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Cannabinoid CB₂ receptor‐mediated regulation of impulsive‐like behaviour in DBA/2 mice

Cited by 70 publications

References 53 publications

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Role of CB2 Cannabinoid Receptors in the Rewarding, Reinforcing, and Physical Effects of Nicotine

Role of murine models in psychiatric illness drug discovery: a dimensional view

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Cannabinoid CB2 receptor‐mediated regulation of impulsive‐like behaviour in DBA/2 mice

Cited by 70 publications

References 53 publications

Cannabinoid CB 2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Cannabinoid CB 2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Role of CB2 Cannabinoid Receptors in the Rewarding, Reinforcing, and Physical Effects of Nicotine

Role of murine models in psychiatric illness drug discovery: a dimensional view

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Product

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Cannabinoid CB₂ receptor‐mediated regulation of impulsive‐like behaviour in DBA/2 mice

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice