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involve dysfunction of dopamine signaling. The name anandamide is derived from the Indian Sanskrit term ananda, meaning. 'bliss and tranquillity'1, ...
© 1999 Nature America Inc. • http://neurosci.nature.com

© 1999 Nature America Inc. • http://neurosci.nature.com

news and views

within the ventral telencephalon that would normally express MASH1 show premature differentiation, again suggesting that the continued expression of MASH1 may normally serve to inhibit progression to the fully differentiated state. How then can we explain the apparently opposite effects of BMPs in olfactory and neural crest lineages? It is of course possible that BMPs might somehow produce opposite effects on MASH1 in each cell type. A more attractive possibility, however, is that underlying signaling pathways are fundamentally similar in the two cases (Fig. 1c), and that BMPs can induce both the appearance and the degradation of MASH1 in both lineages (David Anderson, personal communication). This would allow BMPs to act as both promoters and inhibitors of neuronal fates, depending on precisely when they act. In such a model, the choice between differentiation and death could depend on the exact timing and amount of BMP signaling relative to the progenitor cells’ changing responsiveness over time. Clearly, the function of BMPs in the olfactory epithelium is far from resolved, and the findings of Shou and colleagues raise a number of interesting questions. Does the BMP-mediated degradation of MASH1 actually cause the cessation of cell division and the onset of apoptosis? What is the molecular link between BMP signaling and the proteolysis of MASH1? Is MASH1 the only molecule targeted by BMPs for degradation, or are there others? Does the level of one or more BMP act to control the rate of olfactory neurogenesis in vivo? No doubt, future experiments will soon address these issues. In the interim, it seems that BMPs have once again dropped a question on our plate. 1. Graziadei, P. P. & Graziadei, G. A. J. Neurocytol. 8, 1–18 (1979). 2. Calof, A. L., Mumm, J. S., Rim, P. C. & Shou, J. J. Neurobiol. 36, 190–205 (1998). 3. Schwartz-Levey, S., Chikaraishi, D. M. & Kauer, J. S. J. Neurosci. 11, 3556–3564 (1991). 4. Holcomb, J. D., Mumm, J. S. & Calof, A. L. Dev. Biol. 172, 307–323 (1995). 5. Hogan, B. L. Genes Dev. 10, 1580–1594 (1996). 6. Mumm, J. S., Shou, J. & Calof, A. L. Proc. Natl. Acad. Sci. USA 93, 11167–11172 (1996). 7. Cau, E., Gradwohl, G., Fode, C. & Guillemot, F. Development 124, 1611–1621 (1997). 8. Guillemot, F. et al. Cell 75, 463–476 (1993). 9. Shah, N. M., Grove, A. & Anderson, D. J. Cell 85, 331–343 (1996).

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10. Anderson, D. J. & Jan, Y. N. in Molecular and Cellular Approaches to Neural Development (eds. Cowan, W. M., Jessell, T. M. & Zipursky, S. L.) 26–63 (Oxford Univ. Press, New York, 1997). 11. Gordon, M. K., Mumm, J. S., Davis, R., Holcomb, J. D. & Calof, A. L. Mol. Cell. Neurosci. 6, 363–379 (1995). 12. Lo, L., Johnson, J. E., Wuenschell, C. W.,

Saito, T. & Anderson, D. J. Genes Dev. 5, 1524–1537 (1991). 13. Lo, L., Sommer, L. & Anderson, D. J. Curr. Biol. 7, 440–450 (1997). 14. Lo, L., Tiveron, M.-C. & Anderson, D. J. Development 125, 609–620 (1998). 15. Casarosa, S., Fode, C. & Guillemot, F. Development 126, 525–534 (1999).

Anandamide: a candidate neurotransmitter heads for the big leagues David W. Self Activation of dopamine receptors triggers release of anandamide, an endogenous cannabinoid, in vivo, leading to inhibition of dopamine-mediated locomotor behavior. Endocannabinoids are endogenous substances that mimic the psychoactive effects of marijuana on cannabinoid receptors1. The story of their discovery goes back to the last decade, when pharmacological and molecular studies2,3 led to the identification of a G-protein-coupled receptor that was activated by ∆9-tetrahydrocannabinol (∆9THC), the major psychoactive substance in marijuana. Just as the existence of opioid receptors led to the discovery of endogenous opioid neurotransmitters in the 1970s4, the identification of the brain cannabinoid receptor CB1 spurred a search for naturally occurring ligands within the brain. Several endogenous ligands for the CB1 receptor have been discovered, but none has yet been shown to function as a neurotransmitter. In this issue of Nature Neuroscience, Giuffrida and colleagues report that local depolarization can trigger the release of anandamide, the first endocannabinoid identified, in the striatum of awake, freely moving rats5. They also show that anandamide release can be stimulated by dopamine receptors, and that this leads to the inhibition of dopamine-mediated locomotor behavior via cannabinoid receptors. Their findings promise to propel anandamide from candidate status to bona fide neurotransmitter, and may also open the door to novel treatments for diseases that David Self is in the Division of Molecular Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, 34 Park St., New Haven, Connecticut 06508, USA. e-mail: [email protected]

involve dysfunction of dopamine signaling. The name anandamide is derived from the Indian Sanskrit term ananda, meaning ‘bliss and tranquillity’1, undoubtedly in reference to psychoactive effects of cannabinoids in humans. Anandamide belongs to a class of molecules called eicosaniods, and it was first isolated based on its hydrophobic properties, by analogy with exogenous cannabinoids such as ∆9-THC6. It is expressed throughout the brain, and it is most prevalent in the hippocampus, striatum, cerebellum and cortex, structures that regulate learning, movement and cognition, among other behaviors. Another endocannabinoid, 2-arachidonylglycerol (2-AG), which was discovered more recently, is even more highly expressed in the brain1. Both molecules fulfill at least some of the criteria for neurotransmitter status. They both activate the brain cannabinoid receptor CB1, and both have putative biosynthetic pathways. (They are synthesized from arachidonic acid and phospolipids.) Anandamide also has a putative mechanism for its inactivation via re-uptake and intracellular degradation. Being hydrophobic molecules, neither anandamide nor 2-AG is packaged into synaptic vesicles (in contrast to conventional neurotransmitters); instead, they are thought to be released by phospholipase-mediated cleavage followed by passive diffusion across the plasma membrane1. Because of their low (micromolar) affinities for the CB1 receptor, however, many investigators were skeptical as to whether anandamide or 2-AG ever attain sufficient concentrations to activate the 303

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antagonist potentiated D2-receptor-induced hyperactivity, whereDopamine as it had no effect on baseline D2 Receptor activity. Their results suggest that CB1 Receptor anandamide can reach a sufficient concentration to produce functional effects, but only after stimulation of D2 receptors. Dopamine Thus, the released anandamide terminal seems to function as a ‘brake’ that limits the behavioral response to D2 receptor activation. Although the source of the released anandamide in the stria? tum is not yet known, both pre+ and postsynaptic elements of striatal architecture contain D2 receptors that could trigger anandamide release (Fig. 1). Presy+ naptic D2 receptors could ? stimulate anandamide release from dopamine terminals to pro+ vide negative feedforward regulation of postsynaptic D2Locomotor activation receptor-mediated locomotor Amy Center behavior, in conjunction with the Fig. 1. Possible pathways by which D2 dopamine receptors presynaptic D2 receptor’s negacould trigger anandamide release. Presynaptic D2 receptors, tive feedback effects on dopamine which inhibit dopamine release, could further reduce its behavioral effects by causing anandamide release, which release itself. Alternatively, postinhibits dopamine-induced locomotion. Alternatively, postsy- synaptic D2 receptors could stimnaptic D2 receptors could cause anadamide release, reducing ulate anandamide release from striatal neurons as a negative their locomotor effects by negative feedback. feedback mechanism on the same CB1-receptor-containing neurons. In view of the latter possibility, it is interesting that CB1 receptors receptor in the brain. Although certain memory- and anxiety-enhancing effects of apparently switch coupling from inhibition the cannabinoid receptor antagonist to activation of adenylyl cyclase when stimSR 141716 suggest that endocannabinoids ulated concurrently with D 2 receptors, are tonically active, the new findings of Giufthereby counteracting the inhibitory effects frida and colleagues5 lay this concern to rest of D2 receptors on the cyclase7. Yet another for anandamide. possibility is that anandamide release is trigThe authors focused on the striatum, gered indirectly by other neurotransmitter which expresses high levels of CB1 receptors. systems within the striatum that are modulated by D2 dopamine receptors. They induced depolarization in the striatum of awake rats and showed that this leads The pleasant psychoactive effects of to the release of anandamide. Release of 2cannabinoids in humans are well known, AG, in contrast, did not reach detectable levand some studies have reported that laboels either before or after stimulation. This ratory animals will self-administer cannabisuggests that anandamide is the main lignoids intravenously8,9. However, other and for striatal cannabinoid receptors, studies suggest that systemically adminisalthough it remains possible that other tered cannabinoids produce anxiety and endocannabinoids might also be involved. dysphoria and oppose reward mechanisms The authors found that anandamide in rodents1. Because dysphoria and anherelease could also be induced by pharmacodonia have been associated with reduced logical activation of the D2 class of dopamine levels in striatal subregions10, dopamine receptors, which are known to be cannabinoid-induced inhibition of important in striatal function. D2 receptor dopamine-mediated behavior may contribute to these aversive effects of exogenous activation causes rats to become hyperaccannabinoids. tive, so the authors asked whether ananIn any event, the interaction of endogedamide release might be involved in this nous cannabinoids with dopaminergic sysbehavioral response. They found that blocktems reported by Giuffrida and colleagues ing the CB1 receptor with a pharmacological

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may have important therapeutic implications for the development of treatments for movement disorders. For example, drugs that block endocannabinoid effects at the CB1 receptor could potentiate or prolong the therapeutic efficacy of dopamine-based treatment strategies currently used in Parkinson’s disease while having minimal effects on their own. In contrast, drugs that stimulate the CB1 receptor could reduce dyskinesias associated with Huntington’s disease or antipsychotic treatment, possibly at doses with minimal psychoactive effects. Indeed, CB1 receptor binding is decreased in target regions of striatal neurons during the early stages of Huntington’s disease11,12, suggesting that alterations in endocannabinoid signaling possibly contribute to the disease pathology itself. Given their diffuse localization throughout the brain, it is likely that anandamide and other endocannabinoids interact with multiple neurotransmitters in ways that are yet to be discovered. In addition to reward and anxiety, behavioral studies suggest an interaction between endocannabinoid systems and appetite, pain, epilepsy and other behavioral states1. As these complex interactions are unraveled and understood, endocannabinoid systems are likely to gain appreciation as a prominent signaling pathway in the brain, which could open the door to new treatment strategies for a variety of disorders associated with these behaviors. 1. Felder, C. C. & Glass, M. Annu. Rev. Pharmacol. Toxicol. 38, 179–200 (1998). 2. Howlett, A. C. & Fleming, R. M. Mol. Pharmacol. 26, 532–538 (1984). 3. Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C. & Bonner, T. I. Nature 346, 561–564 (1990). 4. Kosterlitz, H. W. & McKnight, A. T. Adv. Intern. Med. 26, 1–36 (1980). 5. Giuffrida, A. et al. Nat. Neurosci. 2, 358–363 (1999). 6. Devane, W. A. et al. Science 258, 1946–1949 (1992). 7. Terranova, J. P. et al. Psychopharmacology 126, 165–172 (1996). 8. Navarro, M. et al. Neuroreport 8, 491–496 (1997). 9. Glass, M. & Felder, C. C. J. Neurosci. 17, 5327–5333 (1997). 10. Van Ree, J. N., Slangen, J. F. & De Wied, D. J. Pharmacol. Exp. Ther. 204, 547–557 (1978). 11. Takahashi, R. N. & Singer, G. Pharmacol. Biochem. Behav. 11, 737–740 (1979). 12. Koob, G. F. & LeMoal, M. Science 278, 52–58 (1997). 13. Glass, M., Faull, R. L. & Dragunow, M. Neuroscience 56, 523–527 (1993). 14. Richfield, E. K. & Herkenham, M. Ann. Neurol. 36, 577–584 (1994).

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