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Hooking CB2 Receptor Into Drug Abuse?

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Hooking CB2 Receptor Into Drug Abuse? BETWEEN BEDSIDE AND BENCH ■ BENCH TO BEDSIDE Hooking CB2 receptor into drug abuse? Marisela Morales1 & Antonello Bonci1–3 Despite considerable interest in developing Local MSN or local parvalbumin neuron Neuron Chronic cocaine administration effective medications and behavioral inter- From cortex ventions to treat cocaine addiction, there is, Glutamate ? unfortunately, no effective treatment. A recent terminal study by Xi et al.1 sheds unexpected light on MSN Upregulation of a potential new path toward developing anti- CB2 CB2 receptors in addiction therapies, showing that activation agonists neurons and of brain cannabinoid type 2 (CB2) receptors microglia attenuated both the rewarding and the psycho- Activated microglia motor-stimulating effects of cocaine. However, before we get into more detail, let’s Rewarding and Cholinergic From take a step back. The endocannabinoid system CB2 Dopaminergic psychomotor- terminal VTA is composed of the cannabinoid receptors, CB1 Local neuron terminal stimulating effects and CB2, endogenous ligands (endocannabi- Katie Vicari Figure 1 In the NAcc, CB2 receptors may be expressed by resident neurons (GABA medium spiny noids) and proteins involved in endocannabi- neurons (MSN), GABA parvalbumin neurons or cholinergic neurons) or by neurons that project to the 2,3 noid synthesis and inactivation . Increasing NAcc (glutamatergic neurons from cortex or hippocampus or dopaminergic neurons from the ventral evidence indicates that endocannabinoids tegmental area (VTA)). Activation of CB2 receptors within dopamine terminals could potentially inhibit mediate various forms of short- and long- its release. Alternatively, the function of MSNs may be influenced by the levels of presynaptic release of term plasticity in brain regions involved in the GABA, acetylcholine or glutamate, under CB2 control. In addition, modulation of the cytokine secretion etiology of drug addiction. CB1 receptors are through activation of microglia CB2 receptors may influence neuronal signaling. highly expressed through the brain in diverse types of neurons4,5, where they regulate neu- tor agonists modulate brain cocaine effects ation of cocaine self-administration, which rotransmitter release and synaptic strength. emphasize the importance of future studies to was blocked by intra-NAcc co-administration In contrast, several studies in vivo have shown investigate the role of central CB2 receptors in of AM630, a CB2 receptor antagonist. These that although CB2 receptors are not present in neuronal signaling and drug abuse. findings indicate that the inhibitory effects microglia in the healthy brain, they are induced The authors found that systemic admin- of JWH133 on cocaine consumption may be by changes in the microenvironment, includ- istration of the selective CB2 receptor ago- mediated by activation of brain CB2 recep- ing neuroinflammatory conditions6. nist JWH133 inhibits self-administration of tors in the NAcc. Peripheral administration © 2012 Nature America, Inc. All rights reserved. America, Inc. © 2012 Nature Although still controversial7–9, the expres- intravenous cocaine in wild-type and CB1- of JWH133 diminished baseline and cocaine- sion of CB2 receptors in the brain seems to deficient mice, but not in CB2-deficient mice1. induced locomotor activity in wild-type mice be low and limited to a few neurons in the Pretreatment with the CB2 receptor antago- and those lacking CB1, but not in those lacking npg brainstem and cerebellum in rats, mice and nist AM630 prevented this effect in wild-type CB2 (ref. 1). Moreover, the authors showed that ferrets9,10 and some neurons in the cortex, hip- mice. These results suggest that the attenuating intra-NAcc local administration of JWH133 pocampus and globus pallidus in monkeys11, effects of JWH133 are mediated by CB2 recep- not only decreased baseline locomotor activ- yet these receptors are particularly associated tors. In support of this suggestion, systemic ity but also reduced dopamine release in the with immune tissue such as the spleen and thy- administration of GW405833, a CB2 receptor NAcc in wild-type mice and mice lacking mus and circulating immune cells7,12. Owing agonist structurally different from JWH133, CB1 receptors. Intra-NAcc local administra- to this peculiar distribution, research on CB2 also attenuated cocaine self-administration in tion of the CB2 receptor antagonist had the receptors has been focused mostly on eluci- wild-type mice. Intranasal infusion of JWH133 opposite effect. However, these effects were dating how they modulate the immune system in wild-type mice also attenuated cocaine self- not observed in mice lacking CB2 receptors, activity. This is the main reason why the find- administration, presumably by acting on brain suggesting that their activation mediates the ings by Xi et al.1 showing that brain CB2 recep- CB2 receptors1. In contrast, JWH133 delivered inhibitory effects of JWH133 on locomotor by intravenous injections, acting on periph- activity and dopamine release within the NAcc. Marisela Morales and Antonello Bonci are in the eral CB2 receptors, did not affect cocaine self- The study by Xi et al.1 raises several new Intramural Research Program, National Institute on administration. questions, including whether the pharma- Drug Abuse, Baltimore, Maryland, USA. As the nucleus accumbens (NAcc) is a brain cological observations suggesting regula- Antonello Bonci is also in the Department of structure key in the regulation of the reinforc- tion of dopamine release by CB2 receptors Neurology, University of California–San Francisco, ing and psychomotor properties of cocaine, Xi could be documented by electrophysiological San Francisco, California, USA, and at the Solomon et al.1 tested the effects of local administration approaches, how these modulatory effects H. Snyder Neuroscience Institute, Johns Hopkins of JWH133 into NAcc on cocaine self-admin- by CB2 receptors on cocaine intake in mice University School of Medicine, Baltimore, Maryland, istration, locomotor activity and dopamine translate in other animal models, and how USA. release. In the wild-type mice, but not in the much central CB2 receptors modulate intake e-mail: [email protected] CB2-deficient mice, this resulted in attenu- of other drugs of abuse. In this regard, a recent 504 VOLUME 18 | NUMBER 4 | APRIL 2012 NATURE MEDICINE BETWEEN BEDSIDE AND BENCH study shows that neuronal CB2 receptors do together with functional (electrophysiological, influence dopamine levels or neuronal signal- not seem to be involved in the reinforcing pharmacological) and biochemical (single-cell ing. In this regard, emerging evidence suggests effects of nicotine or in the re-instatement of RT-PCR) approaches. To have an understand- that under normal conditions microglia play a nicotine-seeking behavior induced by either ing of the functional role of CB2 receptor in part in remodeling synaptic circuits, influence cues or nicotine priming in rats13. the brain under different conditions, including synaptic structure in an experience-dependent Future studies are required to determine intake of drugs of abuse and withdrawal, and of manner and establish dynamic interactions how CB2 receptors modulate dopamine neu- the potential therapeutic applications of CB2 with presynaptic and postsynaptic elements14. rotransmission in the NAcc and cocaine-tak- agonists, it is fundamental to determine where The possibility of developing selective drugs ing behavior; finding the precise distribution and under what conditions CB2 receptors are for the treatment of cocaine addiction aimed of CB2 receptors within the NAcc is crucial to expressed in the brain. at selectively modulating CB2 receptors is answer these questions. However, there is cur- At present, there is no experimental evidence intriguing, and it is plausible to hypothesize rently no anatomical evidence in humans or that could shed light on the underlying cellular that CB2 receptor agonists might soon be animal models supporting the presence of CB2 and molecular mechanisms of how CB2 recep- tested as novel agents to treat cocaine addic- receptors in the NAcc. Moreover, whether (and tors modulate dopamine neurotransmission tion. which) neurons express CB2 receptors under and cocaine self-administration. Nevertheless, normal conditions is still a matter of debate. considering that CB2 receptors are inhibi- COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. On one hand, initial studies that used an oli- tory G protein–coupled receptors3 and that goprobe for the cellular detection of mRNA intra-NAcc administration of a CB2 recep- 1. Xi, Z.-X. et al. Nat. Neurosci. 14, 1160–1166 (2011). encoding CB2 receptors led to the conclu- tor agonist decreases extracellular dopamine 2. Di Marzo, V., Bifulco, M. & De Petrocellis, L. Nat. Rev. Drug Discov. 3, 771–784 (2004). sion that CB2 receptors are not expressed in in the NAcc, there is the possibility that CB2 3. Howlett, A.-C. et al. Pharmacol. Rev. 54, 161–202 rat brain7. But later studies using antibodies receptors—if present in local dopamine termi- (2002). against CB2 receptors reported high levels of nals—may inhibit dopamine release (Fig. 1). 4. Matsuda, L.A. et al. Nature 346, 561–564 (1990). 5. Mackie, K. J. Neuroendocrinol. 20, 10–14 (2008). CB2 receptor immunoreactivity in the majority Alternatively, CB2 receptors may influence the 6. Stella, N. Glia 58, 1017–1030 (2010). of rat neurons8. The apparent nondiscrimina- activity of resident GABAergic (medium spiny
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