LECTURE 28 Marijuana & Nero Transmitters

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68 SCIENTIFIC AMERIC AN COPYRIGHT 2004 SCIENTIFIC AMERICAN, INC. DECEMBER 20 04 marijuana Research into natural chemicals that mimic marijuana’s effects in the brain could help to explain—and suggest treatments for—pain, anxiety, eating disorders, phobias and other conditions By Roger A. Nicoll and Bradley E. Alger COPYRIGHT 2004 SCIENTIFIC AMERICAN, INC. brain’s own the M arijuana is a drug with a mixed history. Mention it to one person, and it will conjure images of potheads lost in
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  68   SCIENTIFIC AMERICAN DECEMBER 2004   COPYRIGHT 2004 SCIENTIFIC AMERICAN, INC.  marijuana   the  brain’s     own Research into natural chemicals thatmimic marijuana’s effects in the braincould help to explain—and suggesttreatments for—pain, anxiety, eatingdisorders, phobias and other conditions By Roger A. Nicolland Bradley E. Alger COPYRIGHT 2004 SCIENTIFIC AMERICAN, INC.   M arijuana is a drug with a mixed history. Men-tion it to one person, and it will conjure images of potheads lost in a spaced-out stupor. To another,it may represent relaxation, a slowing down of modern madness. To yet another, marijuana means hope forcancer patients suffering from the debilitating nausea of che-motherapy, or it is the promise of relief from chronic pain. Thedrug is all these things and more, for its history is a long one,spanning millennia and continents. It is also something every-one is familiar with, whether they know it or not. Everyonegrows a form of the drug, regardless of their political leaningsor recreational proclivities. That is because the brain makes itsown marijuana, natural compounds called endocannabinoids (after the plant’s formal name, Cannabis sativa ).The study of endocannabinoids in recent years has led toexciting discoveries. By examining these substances, research-ers have exposed an entirely new signaling system in the brain:a way that nerve cells communicate that no one anticipatedeven 15 years ago. Fully understanding this signaling systemcould have far-reaching implications. The details appear to holda key to devising treatments for anxiety, pain, nausea, obesity,brain injury and many other medical problems. Ultimately suchtreatments could be tailored precisely so that they would not ini-tiate the unwanted side effects produced by marijuana itself.  A Checkered Past marijuana and its various alter egos, such as bhangand hashish, are among the most widely used psychoactivedrugs in the world. How the plant has been used varies by cul-ture. The ancient Chinese knew of marijuana’s pain-relievingand mind-altering effects, yet it was not widely employed forits psychoactive properties; instead it was cultivated as hempfor the manufacture of rope and fabric. Likewise, the ancientGreeks and Romans used hemp to make rope and sails. Insome other places, however, marijuana’s intoxicating proper-ties became important. In India, for example, the plant wasincorporated into religious rituals. During the Middle Ages,its use was common in Arab lands; in 15th-century Iraq it wasused to treat epilepsy; in Egypt it was primarily consumed asan inebriant. After Napoleon’s occupation of Egypt, Europe-ans began using the drug as an intoxicant. During the slavetrade, it was transported from Africa to Mexico, the Carib-bean and South America.Marijuana gained a following in the U.S. only relativelyrecently. During the second half of the 19th century and thebeginning of the 20th, cannabis was freely available without aprescription for a wide range of ailments, including migraineand ulcers. Immigrants from Mexico introduced it as a rec-reational drug to New Orleans and other large cities, whereit became popular among jazz musicians. By the 1930s it hadfallen into disrepute, and an intense lobbying campaign de-monized “reefer madness.” In 1937 the U.S. Congress, againstthe advice of the American Medical Association, passed theMarijuana Tax Act, effectively banning use of the drug bymaking it expensive and difficult to obtain. Ever since, mari-juana has remained one of the most controversial drugs inAmerican society. Despite efforts to change its status, it re-mains federally classified as a Schedule 1 drug, along withheroin and LSD, considered dangerous and without utility.Millions of people smoke or ingest marijuana for its in-toxicating effects, which are subjective and often describedas resembling an alcoholic “high.” It is estimated that ap-proximately 30 percent of the U.S. population older than 12have tried marijuana, but only about 5 percent are current us-ers. Large doses cause hallucinations in some individuals butsimply trigger sleep in others. The weed impairs short-termmemory and cognition and adversely affects motor coordina- 70   SCIENTIFIC AMERICAN DECEMBER 2004     V    V    G    /    S    C    I    E    N    C    E     P    H    O    T    O     L    I    B    R    A    R    Y     (    n   e   u   r   o   n      )    A    N    D     R    I    C    E    R    G    E    N    B    R    I    G    H    T     C   o   r    b    i   s       (     l   e   a   v   e   s      )     (    p   r   e   c   e    d    i   n   g    p   a   g   e   s      )   ;    T    O    M    M    Y    M    O    O    R    M    A    N      (     t    h    i   s    p   a   g   e      ) COOOHOHCONOHCH 3 OH 3 CH 3 COH ■ Marijuana and related drugs affect behavior by actingon receptors for compounds called endocannabinoidsthat are produced by the brain. ■ These endocannabinoids participate in regulating pain,anxiety, hunger and vomiting, among other processes.This wide range of effects explains why the use of marijuana seems to elicit so many different responses. ■ By developing drugs that can mimic specific beneficialactions of endocannabinoids—without triggering someof the adverse effects of marijuana—researchers hopeto find new treatments for diverse problems. Overview/ Brain’s Marijuana DESPITE DIFFERENCES in their structures, THC, produced by themarijuana plant, and the brain chemicals anandamide and 2-AG canall activate the same receptor (CB1) in the brain. Delta-9-Tetrahydrocannabinol (THC)Anandamide2-Arachidonoyl glycerol (2-AG) COPYRIGHT 2004 SCIENTIFIC AMERICAN, INC.  tion, although these setbacks seem to be reversible once thedrug has been purged from the body. Smoking marijuana alsoposes health risks that resemble those of smoking tobacco.On the other hand, the drug has clear medicinal bene-fits. Marijuana alleviates pain and anxiety. It can preventthe death of injured neurons. It suppresses vomiting and en-hances appetite — useful features for patients suffering thesevere weight loss that can result from chemotherapy. Finding the Responsible Agent figuring out how the drug exerts these myriad effectshas taken a long time. In 1964, after nearly a century of workby many individuals, Raphael Mechoulam of the Hebrew Uni-versity in Jerusalem identified delta-9-tetrahydrocannabinol(THC) as the compound that accounts for virtually all thepharmacological activity of marijuana. The next step was toidentify the receptor or receptors to which THC was binding.Receptors are small proteins embedded in the membranesof all cells, including neurons, and when specific molecules bindto them — fitting like one puzzle piece into another — changes inthe cell occur. Some receptors have water-filled pores or chan-nels that permit chemical ions to pass into or out of the cell.These kinds of receptors work by changing the relative voltageinside and outside the cell. Other receptors are not channels butare coupled to specialized proteins called G-proteins. TheseG-protein-coupled receptors represent a large family that setin motion a variety of biochemical signaling cascades withincells, often resulting in changes in ion channels.In 1988 Allyn C. Howlett and her colleagues at St. LouisUniversity attached a radioactive tag to a chemical deriva-tive of THC and watched where the compound went in rats’brains. They discovered that it attached itself to what cameto be called the cannabinoid receptor, also known as CB1.Based on this finding and on work by Miles Herkenham of the National Institutes of Health, Lisa Matsuda, also at the NIH , cloned the CB1 receptor. The importance of CB1 in theaction of THC was proved when two researchers workingindependently — Catherine Ledent of the Free University of Brussels and Andreas Zimmer of the Laboratory of Molecu-lar Neurobiology at the University of Bonn — bred mice thatlacked this receptor. Both investigators found that THC hadvirtually no effect when administered to such a mouse: thecompound had nowhere to bind and hence could not triggerany activity. (Another cannabinoid receptor, CB2, was laterdiscovered; it operates only outside the brain and spinal cordand is involved with the immune system.)As researchers continued to study CB1, they learned thatit was one of the most abundant G-protein coupled receptorsin the brain. It has its highest densities in the cerebral cortex,hippocampus, hypothalamus, cerebellum, basal ganglia, brain www.sciam.com SCIENTIFIC AMERICAN   71     A    L    I    C    E     C    H    E    N CEREBELLUM Center for motor controland coordination HYPOTHALAMUS Controls appetite,hormonal levels andsexual behavior  AMYGDALA  Responsible foranxiety, emotionand fear HIPPOCAMPUS Important for memoryand the learning of facts, sequences andplaces BRAIN STEM AND SPINAL CORD Important in the vomiting reflexand the sensation of pain NEOCORTEX Responsible for highercognitive functions andthe integration of sensory information BASAL GANGLIA  Involved in motorcontrol andplanning, as well asthe initiation andtermination of action WHERE MARIJUANA ACTS The drug Cannabis sativa binds to the brain’s own cannabinoidreceptors in many different areas, including those highlightedbelow. This widespread influence accounts for the diverse effectsthe drug—and its relatives made by the brain—can have andoffers exciting opportunities for devising medications that canspecifically target certain sites to control, say, appetite or pain.COPYRIGHT 2004 SCIENTIFIC AMERICAN, INC.
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