Compartment-specific localization of cannabinoid 1 (CB1) and μ-opioid receptors in rat nucleus accumbens

Pickel, Virginia M.; Chan, June; Kash, Thomas L.; Toledo-Rodriguez, Maria; Mackie, Ken

doi:10.1016/j.neuroscience.2004.05.015

Cited by 230 publications

(183 citation statements)

References 77 publications

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“…In rat nucleus accubens core where μOR and CB 1 R are abundantly expressed, both receptors may physically associate and simultaneous stimulation of the receptors resulted in non-additive glutamate release and synergistic GABA release, suggesting the existence of functional μOR/ CB 1 R heterodimers distinct from their parental receptors in the tissue (28). Electron microscopic studies on localization of CB 1 R and μOR in rat nucleus accumbens also supported coexistence of these receptors within the same neuron (29). The results reported by Rios et al (7) and those of the present study showed that μOR formed a heterodimer with CB 1 R. In their report, simultaneous activation of μOR/ CB 1 R heterodimer leads to a significant attenuation of the extracellular receptor-regulated kinase (ERK) activity compared to the responses seen upon activation of the individual receptor (7).…”

Section: Discussionmentioning

confidence: 73%

μ-Opioid Receptor Forms a Functional Heterodimer With Cannabinoid CB1 Receptor: Electrophysiological and FRET Assay Analysis

et al. 2008

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Abstract. Interactions between μ-opioid receptor (μOR) and cannabinoid CB 1 receptor (CB 1 R) were examined by morphological and electrophysiological methods. In baby hamster kidney (BHK) cells coexpressing μOR fused to the yellow fluorescent protein Venus and CB 1 R fused to the cyan fluorescent protein Cerulean, both colors were detected on the cell surface; and fluorescence resonance energy transfer (FRET) analysis revealed that μOR and CB 1 R formed a heterodimer. Coimmunoprecipitation and Western blotting analyses also confirmed the heterodimers of μOR and CB 1 R. [D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]enkephalin (DAMGO) or CP55,940 elicited K + currents in Xenopus oocytes expressing μOR or CB 1 R together with G protein activated-inwardly rectifying K + channels (GIRKs), respectively. In oocytes coexpressing both receptors, either of which was fused to the chimeric Gα protein G qi5 that activates the phospholipase C pathway, both DAMGO and CP55,940 elicited Ca 2+ -activated Cl − currents, indicating that each agonist can induce responses through G qi5 fused to either its own receptor or the other. Experiments with endogenous G i/o protein inactivation by pertussis toxin (PTX) supported the functional heterodimerization of μOR/ CB 1 R through PTX-insensitive G qi5(m) fused to each receptor. Thus, μOR and CB 1 R form a heterodimer and transmit a signal through a common G protein. Our electrophysiological method could be useful for determination of signals mediated through heterodimerized G protein-coupled receptors.

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Section: Discussionmentioning

confidence: 73%

μ-Opioid Receptor Forms a Functional Heterodimer With Cannabinoid CB1 Receptor: Electrophysiological and FRET Assay Analysis

et al. 2008

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“…The fact that the direction in which low-dose naltrexone interacted with THC differed in marijuana smokers and nonmarijuana smokers suggests that chronic marijuana use alters the interaction between opioids and cannabinoids in humans. CB1 and mu opioid receptors are closely interrelated in the ventral striatum, often localized on the same neuron or on synaptically-linked neurons (Hoffman and Lupica, 2001;Pickel et al, 2004). As reviewed in the Introduction, data from laboratory animals demonstrate that chronic cannabinoid exposure decreases CB1-mediated activity while increasing opioid synthesis, receptor activity, and behavioral effects.…”

Section: Discussionmentioning

confidence: 99%

Opioid Antagonism of Cannabinoid Effects: Differences between Marijuana Smokers and Nonmarijuana Smokers

Haney

2006

Neuropsychopharmacol

102

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In non-human animals, opioid antagonists block the reinforcing and discriminative-stimulus effects of D 9 -tetrahydrocannabinol (THC), while in human marijuana smokers, naltrexone (50 mg) enhances the reinforcing and subjective effects of THC. The objective of this study was to test a lower, more opioid-selective dose of naltrexone (12 mg) in combination with THC. The influence of marijuana-use history and sex was also investigated. Naltrexone (0, 12 mg) was administered 30 min before oral THC (0-40 mg) or methadone (0-10 mg) capsules, and subjective effects, task performance, pupillary diameter, and cardiovascular parameters were assessed in marijuana smoking (Study 1; n ¼ 22) and in nonmarijuana smoking (Study 2; n ¼ 21) men and women. The results show that in marijuana smokers, low-dose naltrexone blunted the intoxicating effects of a low THC dose (20 mg), while increasing ratings of anxiety at a higher THC dose (40 mg). In nonmarijuana smokers, low-dose naltrexone shifted THC's effects in the opposite direction, enhancing the intoxicating effects of a low THC dose (2.5 mg) and decreasing anxiety ratings following a high dose of THC (10 mg). There were no sex differences in these interactions, although among nonmarijuana smokers, men were more sensitive to the effects of THC alone than women. To conclude, a low, opioid-selective dose of naltrexone blunted THC intoxication in marijuana smokers, while in nonmarijuana smokers, naltrexone enhanced THC intoxication. These data demonstrate that the interaction between opioid antagonists and cannabinoid agonists varies as a function of marijuana use history.

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“…Anatomical overlap suggests the possibility that both endocannabinoid and opioid signals might act on the same local circuits to amplify hedonic impact. It is of interest that CB1 receptors and opioid receptors are reported to interact, can occur in the same striatal synapses, and even be colocalized on the same neurons in nucleus accumbens shell and core (Tanda et al, 1997;Hohmann and Herkenham, 2000;Rodriguez et al, 2001;Pickel et al, 2004;Caille and Parsons, 2006). If colocalization occurs in hotspot neurons, this would support the possibility that endocannabinoid and opioid neurochemical signals in nucleus accumbens might interact to enhance 'liking' reactions to the sensory pleasure of sucrose.…”

Section: Hottest Spot In Dorsal Medial Shellmentioning

confidence: 94%

“…Many functional effects of endocannabinoids in brain are thought to occur via CB1 receptors (Piomelli, 2003). CB1 receptors are located on GABAergic presynaptic axons in the nucleus accumbens shell (Matyas et al, 2006), and are often colocalized with m opioid receptors at the same synapses and in the same cells in striatum (Pickel et al, 2004;Schoffelmeer et al, 2006). CB2 receptors have also been reported to occur on glial cells and neurons in ventral striatum, though less is known about their synaptic localization or function (Gong et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Endocannabinoid Hedonic Hotspot for Sensory Pleasure: Anandamide in Nucleus Accumbens Shell Enhances ‘Liking’ of a Sweet Reward

Mahler

Smith

Berridge

2007

Neuropsychopharmacol

306

262

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Cannabinoid drugs such as D 9 -THC are euphoric and rewarding, and also stimulate food intake in humans and animals. Little is known about how naturally occurring endogenous brain cannabinoids mediate pleasure from food or other natural sensory rewards. The taste reactivity paradigm measures effects of brain manipulations on affective orofacial reactions to intraorally administered pleasant and unpleasant tastes. Here we tested if anandamide microinjection into medial nucleus accumbens shell enhances these affective reactions to sweet and bitter tastes in rats. Anandamide doubled the number of positive 'liking' reactions elicited by intraoral sucrose, without altering negative 'disliking' reactions to bitter quinine. Anandamide microinjections produced Fos plumes of approximately 0.02-1 mm 3 volume. Plume-based maps, integrated with behavioral data, identified the medial shell of accumbens as the anatomical hotspot responsible for hedonic amplification. Anandamide produced especially intense hedonic enhancement in a roughly 1.6 mm 3 'hedonic hotspot' in dorsal medial shell, where anandamide also stimulated eating behavior. These results demonstrate that endocannabinoid signals within medial accumbens shell specifically amplify the positive hedonic impact of a natural reward (though identification of the receptor specificity of this effect will require future studies). Identification of an endocannabinoid hotspot for sensory pleasure gives insight into brain mechanisms of natural reward, and may be relevant to understanding the neural effects of cannabinoid drugs of abuse and therapeutic agents.

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Compartment-specific localization of cannabinoid 1 (CB1) and μ-opioid receptors in rat nucleus accumbens

Cited by 230 publications

References 77 publications

μ-Opioid Receptor Forms a Functional Heterodimer With Cannabinoid CB1 Receptor: Electrophysiological and FRET Assay Analysis

μ-Opioid Receptor Forms a Functional Heterodimer With Cannabinoid CB1 Receptor: Electrophysiological and FRET Assay Analysis

Opioid Antagonism of Cannabinoid Effects: Differences between Marijuana Smokers and Nonmarijuana Smokers

Endocannabinoid Hedonic Hotspot for Sensory Pleasure: Anandamide in Nucleus Accumbens Shell Enhances ‘Liking’ of a Sweet Reward

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