Paradoxical action of the cannabinoid WIN 55,212‐2 in stimulated and basal cyclic AMP accumulation in rat globus pallidus slices

Maneuf, Yannick P.; Brotchie, Jonathan M.

doi:10.1038/sj.bjp.0701101

Cited by 107 publications

(78 citation statements)

References 7 publications

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“…Although the exact mechanism responsible for the elevation in [Ca 2ϩ ] i by cannabinoids has not been elucidated, it is tempting to speculate that cannabinoid receptors coupled to G␣ s in lymphocytes to mediate the cannabinoid-induced elevation in [Ca 2ϩ ] i . In fact, the ability of cannabinoid receptors to couple to G␣ s has been suggested, particularly for CB1 (Glass and Felder, 1997;Maneuf and Brotchie, 1997). Another interesting observation was the gradual rise in [Ca 2ϩ ] i induced by cannabinol.…”

Section: Discussionmentioning

confidence: 89%

Evidence for Cannabinoid Receptor-Dependent and -Independent Mechanisms of Action in Leukocytes

Kaplan¹,

Rockwell²,

Kaminski³

2003

The Journal of Pharmacology and Experimental Therapeutics

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Cannabinoids exhibit immunosuppressive actions that include inhibition of interleukin-2 production in response to a variety of T cell activation stimuli. Traditionally, the effects of these compounds have been attributed to cannabinoid receptors CB1 and CB2, both of which are expressed in mouse splenocytes. Therefore, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorphenyl)-4-methyl-H-pyrazole-3 carboxyamidehydrochloride (SR141716A), a CB1 antagonist, and N- [(1S)-endo-1,3,3,-trimethyl-bicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528), a CB2 antagonist, were used to investigate the role of cannabinoid receptors in the cannabinoid-induced inhibition of phorbol ester plus calcium ionophore (PMA/Io)-stimulated interleukin-2 production by mouse splenocytes. PMA/Io-stimulated interleukin-2 production was inhibited by cannabinol, cannabidiol, and both WIN 55212-2 stereoisomers with a rank order potency of R-(ϩ)- [2,3-dihydro-5-methyl-3-[(morpholinyl)tion of PMA/Io-stimulated interleukin-2 was not attenuated by the presence of both SR144528 and SR141716A. Using pertussis toxin to address the role of G protein-coupled receptors in this response, it was determined that pertussis toxin treatment did not attenuate cannabinol-induced inhibition of PMA/Io-stimulated interleukin-2. With the demonstration that cannabinoid-induced inhibition of PMA/Iostimulated interleukin-2 was not mediated via CB1 or CB2, alternative targets of cannabinoids in T cells were examined. Specifically, it was demonstrated that cannabinoids elevated intracellular calcium concentration in resting splenocytes and that the cannabinol-induced elevation in intracellular calcium concentration was attenuated by treatment with both SR144528 and SR141716A. Interestingly, pretreatment of splenocytes with agents that elevate intracellular calcium concentration inhibited PMA/Io-stimulated interleukin-2 production, suggesting that an elevation in intracellular calcium concentration might be involved in the mechanism of interleukin-2 inhibition. These studies suggest that immune modulation produced by cannabinoids involves multiple mechanisms, which might be both cannabinoid receptordependent and -independent.Cannabinoids are plant-derived molecules that produce a variety of biological effects of which the most extensively studied have been on the central nervous system and immune system. Specifically in the immune system, cannabinoids modulate innate and acquired (humoral, cell-mediated) immunity (for review, see Berdyshev, 2000). With respect to acquired immunity, modulation of interleukin-2 production is one of the more sensitive targets of cannabinoids. It is interesting that cannabinoids either enhance or inhibit interleukin-2 secretion, depending on the experimental conditions, including age of the animals and magnitude of cellular activation (Nakano et al., 1992(Nakano et al., , 1993Jan and Kaminski, 2001). Using an optimum stimulatory concentration of PMA/ Io, cannabinol treatment inh...

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Section: Discussionmentioning

confidence: 89%

Evidence for Cannabinoid Receptor-Dependent and -Independent Mechanisms of Action in Leukocytes

Kaplan¹,

Rockwell²,

Kaminski³

2003

The Journal of Pharmacology and Experimental Therapeutics

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“…The ability of CP55,940 and AM404 to stimulate DARPP-32 phosphorylation at Thr34 is somewhat unexpected, because CB1 receptors are known to inhibit the activity of adenylyl cyclase and reduce the levels of cAMP via coupling to Gi/o-proteins (Howlett et al, 1986;Bidaut-Russell et al, 1990) (but see Maneuf and Brotchie, 1997). This notion, however, rests on studies performed in isolated systems such as cultured cells, brain membranes, or tissue slices, which do not take into account the effects of systemic activation of CB1 receptors under normal physiological circumstances.…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid Action Depends on Phosphorylation of Dopamine- and cAMP-Regulated Phosphoprotein of 32 kDa at the Protein Kinase A Site in Striatal Projection Neurons

Andersson¹,

Usiello²,

Borgkvist³

et al. 2005

J. Neurosci.

104

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“…However, cannabinoid receptors can also couple to G s proteins (Glass and Felder 1997) to stimulate the AC-PKA pathway under certain conditions (Maneuf and Brotchie 1997). In the present study, WIN55,212-2-induced inhibition of LTD in the LA required the activation of G i/o proteins and an inhibition of the AC-PKA pathway.…”

Section: +mentioning

confidence: 61%

“…However, they may also couple to G s proteins under certain conditions (Glass and Felder 1997;Maneuf and Brotchie 1997). To investigate whether the effect of CB1 receptor activation on LTD induction involves pertussis toxin-sensitive G i/o proteins, slices were incubated with pertussis toxin (5 µg/ mL) for 5-7 h at 37°C.…”

mentioning

confidence: 99%

Activation of CB1 specifically located on GABAergic interneurons inhibits LTD in the lateral amygdala

Azad¹,

Kurz²,

Marsicano³

et al. 2008

Learn. Mem.

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Previously, we found that in the lateral amygdala (LA) of the mouse, WIN55,212-2 decreases both glutamatergic and GABAergic synaptic transmission via activation of the cannabinoid receptor type 1 (CB1), yet produces an overall reduction of neuronal excitability. This suggests that the effects on excitatory transmission override those on inhibitory transmission. Here we show that CB1 activation by WIN55,212-2 and ⌬ 9-THC inhibits long-term depression (LTD) of basal synaptic transmission in the LA, induced by low-frequency stimulation (LFS; 900 pulses/1 Hz). The CB1 agonist WIN55,212-2 blocked LTD via G i/o proteins, activation of inwardly rectifying K + channels (K ir s), inhibition of the adenylate cyclase-protein kinase A (PKA) pathway, and PKA-dependent inhibition of voltage-gated N-type Ca 2+ channels (N-type VGCCs). Interestingly, WIN55,212-2 effects on LTD were abolished in CB1 knock-out mice (CB1-KO), and in conditional mutants lacking CB1 expression only in GABAergic interneurons, but were still present in mutants lacking CB1 in principal forebrain neurons. LTD induction per se was unaffected by the CB1 antagonist SR141716A and was normally expressed in CB1-KO as well as in both conditional CB1 mutants. Our data demonstrate that activation of CB1 specifically located on GABAergic interneurons inhibits LTD in the LA. These findings suggest that CB1 expressed on either glutamatergic or GABAergic neurons play a differential role in the control of synaptic transmission and plasticity.The amygdala integrates inputs from various brain regions such as the hippocampus, the prefrontal cortex, and the thalamus, providing a common output and playing an important role in fear memory, triggered reminders of past aversive experiences, and also pain processing (Le Doux 2000;Davis and Whalen 2001;Neugebauer et al. 2004). We previously showed that endocannabinoids released in the amygdala are important for the extinction of aversive memory (Marsicano et al. 2002). Most behavioral effects of exogenously applied cannabinoids (Manning et al. 2001;Pertwee 2001) . In the amygdala, electrophysiological findings also speak in favor of both glutamatergic and GABAergic localization of CB1 receptors. In the lateral amygdala (LA), the agonist WIN55,212-2 reduced isolated glutamatergic and GABAergic currents ) via activation of CB1 receptors. Although it may be assumed that these effects may compensate each other, the application of WIN55,212-2 induced an overall decrease of basal synaptic transmission. This indicates that in the LA, cannabinoid-induced modulation of neuronal activity is mainly determined by CB1 receptors located on excitatory pyramidal neurons.Earlier studies showed that CB1 receptor activation also modulates synaptic plasticity, since cannabinoids influence long-term potentiation and long-term depression (LTD) of synaptic transmission in different brain regions (Misner and Sullivan 1999;Auclair et al. 2000). However, little is known about the mechanisms and the neuronal sites where these CB1-mediated effects are e...

show abstract

Paradoxical action of the cannabinoid WIN 55,212‐2 in stimulated and basal cyclic AMP accumulation in rat globus pallidus slices

Cited by 107 publications

References 7 publications

Evidence for Cannabinoid Receptor-Dependent and -Independent Mechanisms of Action in Leukocytes

Evidence for Cannabinoid Receptor-Dependent and -Independent Mechanisms of Action in Leukocytes

Cannabinoid Action Depends on Phosphorylation of Dopamine- and cAMP-Regulated Phosphoprotein of 32 kDa at the Protein Kinase A Site in Striatal Projection Neurons

Activation of CB1 specifically located on GABAergic interneurons inhibits LTD in the lateral amygdala

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