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COMENTARIO:La cocana produce sus efectos psicoactivos en el sistema lmbico, una red que regula el placer y lamotivacin. A corto plazo, incrementa los nivles de dopamina aumentando la euforia y el deseo de tomarla droga nuevamente. Los investigadores tratan de entender el mecanismo por el cual se producen elcraving as como las recadas. El autor se ha enfocado en la transcripcin del FosB, sus niveles en elsistema limbico se correlacionan con conductas adictivas en los ratones. Lo cual nos ayuda a entender los

pasos que se producen para llegar del abuso a la adiccin, as como los tratamientos para los ya adictos.

EFECTO INCIAL DE LA COCAINA: AUMENTO DE LA DOPAMINAInhalada, fuamada, o inyectada, la cocana entra directamente la torrente sanguneo y penetra al cerebro.Alcanza su efecto psicolgico aumentando la dopamina.La dopamine acta como un regulador en varias clulas del cerebro. En cada momento de nuestras vidas,la dopamina es responsable de mantener los niveles de alerta para completar nuestras actividiades ynecesidades. Cuando necesitamos movilizar nuestros musculos o nuestra mente de forma rpida yefectiva, la dopamina se ve involucrada en estos procesos.Se origina en nucleos dopaminergicos, la dopamine active los receptors de la misma, mientras a msreceptores se una mayor cantidad de neuronas son afectadas. Pero tambien son reguladas al recaptardopamina dentro de ellas.La cocana interfiere con este mecanismo: Se une al transportador de dopamina, ocmo resultado la

dopamina permanece libre en el espacio sinptico y sobreestimula las neuronas.Aunque la sdopamina tambien inhibe los transportadores de norepinefrina y srotonina, las accciones sobredopamina son ms importantes.COCANA, DOPAMINA Y EL SISTEMA LIMBICO.La cocana aumenta dopamina en cualquier region donde existan transportadores de la misma. Suhabilidad para producir placer, euforia, prdida de control y respuestas compulsivas pueden ser detectadas

por redes que conectan lulos frontales con el sistema lmbico. La respuesta de las celulas dopaminergicaen el sistema limbico es alta, principalmente en el ncleo accumbens (NAc). Cuando es estimulado por lacocana, se produce placer y satisfaccin. La funcin de esta respuesta es mantener la concentracin enlas actividades que ayudan a la supervivencia y la reproduccin.El sistema limbico tambien incluye importantes centro de memoria como la amigdala y el hipocampo.Los cuales asocian el placer en el nucleo accumbens. Cuando alguien experimenta altas dosis de cocanaestas regiones imprimen estas memorias as como tiempo y lugar en los cuales se consumi, lo que

cuando se reexperimenta la emocin asociada al consumo.Algunos centificos suponen que el continuar consumiendo, lleva a una compulsin en respuesta a la

busqueda de la droga. La regin frontral se integra la informacin.EFECTOS A MEDIANO PLAZO: CAMBIOS EN LA EXPRESION DE GENES.Causa muchas alteraciones en el funcionamiento de las clulas cerebrales. Aumento de los receptores ytransportadores de dopamina en la superficie de las clulas. Los primeros cambios se producen en elsistema lmbico.GENES Y EXPRESION.La cocana afecta la expresin de numerosos genes en el ncleo accumbens, los cuales influyen alglutamato y lols componentes opioides. Los investigadores se estan enfocando a una protena llamadaFosB.Esta protena permanece en la celula y estimula ciertos genes. Los cuales son factores de transcripcingentica. Esta protena est presente en discretas cantidades en el ncleo accumbens, pero en la

exposicin a largo plazo se produce en mayores cantidades. Lo cual puede influir en la transicin delconsumo a la adiccin.Una vez sintetizada tarda 6 a 8 smeanas en degradarse. Cada episodio de consumo exacerba la produccinde FosB que se ha acumulado de los episodios previos durante los ultimos 2 meses. Si se abusodiariamente los niveles estarn extremadamente elevados todo el tiempo.Los ratones con nieveles elevados de FosB muestran conductas adcitivas.

Resultados experimentales con FosBLos investigadores suponen que los niveles altos aumentan la conducta adictiva a pesar de niveles bajosde cocana. Por lo que se deben controlar los niveles de esta ultima protena a pesar del consumo decocana. A mayores niveles de FosB mayor sensibilidad a la sustancia de abuso (responden a un terciode la dosis requerida)

They showed more sensitivity to the drug (responded to doses one-third those required to produce aresponse in normal animals), self-administered more drug, and displayed greater drive (or craving) for

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cocaine (they worked two to three times as hard to get the drug) (McClung et al., 2004; Nestler, Barrot,and Self, 2001). Conversely, when we blocked the activity of FosB, we saw the opposite effects, anoverall blunting of the animals response to the drug. These results suggest that cocaines buildup ofFosB is both necessary and sufficient for some of the drugs behavioral effects and, in particular, itsability to increase drug craving and drug taking (Nestler, 2001).Further Clues About FosBs Significance

The NAc is the only brain region where FosB is found in normal animals. However, chronicadministration of cocaine has recently been shown to increase FosB in several additional brain regions,such as the frontal cortex and amygdala (McClung et al., 2004). The accumulations of FosB are muchsmaller in these regions than those that cocaine causes in the NAc, and their behavioral consequences arestill unknown. It is tempting to speculate, though, that the presence of FosB in the frontal cortex maycontribute to the loss of frontal cortex control over cocaine urges that is seen in addiction. Although wedo not yet have direct evidence of this possibility, it represents an additional mechanism by which FosBmay contribute to a state of addiction.Scientists currently are working to identify which specific genes FosB stimulates to produce its effects.Comparisons of genes expressed in NAc nerve cells in mice that make FosB versus mice that lack thetranscription factor have revealed more than a hundred FosB-mediated changes in gene expression(McClung and Nestler, 2003). This work has also indicated that FosB causes more than 25 percent of allchronic cocaine-induced changes in gene expression in the NAca finding that highlights the dominant

role of this transcription factor in mediating cocaines genetic effects in the brain. One of the genesstimulated by FosB is an enzyme, cyclin-dependent kinase-5 (CDK5), which promotes nerve cellgrowth. This finding has shed new light on mechanisms underlying cocaines very long-lasting effects onthe brain (Nestler, 2001).COCAINES LONG-TERM EFFECTS: CHANGES IN NERVE CELL STRUCTUREWith its 2-month lifespan, FosB does not last long enough to explain why former cocaine abuserscontinue to experience cravings and relapse after months and years of abstinence. The extreme

persistence of those features of addiction indicates that cocaine must cause some equally long-lastingneurobiological effects. Scientists have identified one potentially key type of cocaine-related change thatappears to last for many months after the last cocaine exposure, and perhaps longer: an alteration in the

physical structure of nerve cells in the NAc. Chronic cocaine exposure causes these cells to extend andsprout new offshoots on their dendrites (Nestler, 2001; Robinson and Berridge, 2001). Dendrites are the

branch-like fibers that grow out from nerve cell bodies and collect incoming signals from other nerve

cells. Just as a bigger antenna picks up more radio waves, more dendrite branches in the NActheoretically will collect a greater volume of nerve signals coming from other regionsfor example, thehippocampus, amygdala, and frontal cortex. This will give those other regions an enhanced influence overthe NAc, which could drive some of the very long-lived behavioral changes associated with addiction.For example, enhanced inputs from the hippocampus and amygdala could be responsible for the intensecraving that occurs when drug-associated memories are stimulated (e.g., by drug paraphernalia).While we do not yet know how cocaine triggers NAc nerve cells to grow and sprout new offshoots,FosB appears to be involved. Recall that one of the genes stimulated by FosB is CDK5, a knownregulator of nerve cell growth. When laboratory animals are treated with a compound that deactivatesCDK5 in the NAc and then are given cocaine, the nerve cell growth normally associated with exposure tothe drug does not occur.INDIVIDUAL RISK FOR COCAINE ADDICTIONWhat makes certain individuals particularly vulnerable to addiction and others relatively resistant?

Extensive epidemiological studies show that roughly half of a persons risk for addiction to cocaine orother drugs is genetic (Goldstein, 2001; Nestler and Malenka, 2004). This degree of heritability exceedsthat of many other conditions that are considered highly heritable,such as type 2 (non-insulin-dependent) diabetes, hypertension, and breast cancer.The specific genes that confer risk for cocaine addiction remain unknown. One possibility is that at leastsome of them are the same genes that are affected by cocaine exposure. For example, variations in thegenes encoding FosB or any of hundreds of other genes affected by cocaine could conceivablycontribute to the genetic risk for addiction. It is easy to imagine, by way of illustration, that an individualwith a gene that expresses FosB at high levels might be more prone to addiction; such a person would

be analogous to the experimental mice that are engineered to produce more FosB and are, consequently,more addiction prone. It is also possible that other genesgenes not affected by cocaine exposureareresponsible. Work is now under way to examine these alternatives.Finding addiction vulnerability genes will enable us to identify individuals who are at particular risk foran addictive disorder and target them for educational and other preventive measures. It will also help usunderstand how factors other than genetics contribute to the development of addiction. For example, it

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has long been known that stress can increase an individuals risk for addiction, but how stress producesthis effect, and why it does so in some individuals but not others, remains a mystery.

CLINICAL RAMIFICATIONSResearch to understand the neurobiology of cocaine addiction is essential because the available treatmentsdo not work for everyone, and the surest path toward definitive treatments and even cures, as well as

prevention, is through greater appreciation of the underlying neurobiological mechanisms (Goldstein,2001; OBrien, 2003). The identification of underlying biological mechanisms has been crucial for allmajor advances in treatment of other medical disorders, and there is no reason to think addiction will beany different.To date, most efforts to develop new medications for treatment of cocaine addiction have focused on

preventing or suppressing the drugs acute effects. Cocaine vaccines, for example, are designed to bindcocaine molecules in the blood with antibodies and so keep them from getting into the brain. A relatedapproach seeks to develop a medication that keeps cocaine from tying up the dopamine transporterwithout itself interfering with the transporters normal function of dopamine retrieval. Still otherapproaches attempt to take advantage of the fact that cocaines acute effects on the brain involveincreased activation of dopamine receptors. NAc nerve cells make five types of dopamine receptors;drugs that affect the functioning of one or more of them could, in theory, produce a palliative effect oncocaine addiction. Efforts are under way in each of these areas, including clinical trials, but so far no clear

breakthrough has been reported.A potential limitation of these approaches is that they focus on cocaines initial actions, not on the long-lasting changes that are present in the brain once addiction has been established. A medication aimed at

preventing or reversing such changes might be an effective approach for treating cocaine addiction. Thereare literally hundreds of proteins that could be targeted in development of such a medication. Forexample, FosB, or any of the hundred or so proteins it regulates, represent possible drug targets. Thesame is true for numerous additional molecular changes that have been implicated in cocaine addiction.Glutamate receptors and receptors for the brains natural opioid-like substances (e.g., opioid receptors)are two examples.Effective medications for treating cocaine addiction will eventually be developed, and the best strategyfor progress in this area is to target neurobiological mechanisms, such as those described above. Althoughthe process takes a very long timeit can take 10 to 20 years to advance from identification of a diseasemechanism to development of a new treat-mentthis work is in progress and represents the best hope for

those who are addicted.People often ask: Is it possible to treat a drug addiction with another drug? Isnt addiction a complex

psychological and social phenomenon that requires psychological and social treatments? The answer toboth questions is yes.Even though psychological and social factors predominate in the presentation and diagnosis of addiction,the disease is at its core biological: changes that a physical substance (drug) causes in vulnerable bodytissue (brain). Todays treatments do not effectively control the biology of addiction, leaving the addictedindividual with a dramatically altered limbic system. He or she must then work against powerful

biological forces to recover from addiction; thosewho succeed often do so only after many attempts, and many do not succeed.While a medication that counters the powerful biological forces of addiction is essential, it will not be amagic bullet. People in recovery from addiction will always need support and rehabilitation to rebuildtheir lives. Presumably, effective psychosocial treatments for addiction work by causing changes in the

brain, perhaps even some of the same changes that will be produced by effective medications. While verylittle information is currently available on the neurobiological mechanisms underlying psychosocialtreatments, this is a topic of great interest.CONCLUSIONIn the last two decades, scientists have determined how cocaine produces intoxication through its initialeffects in the brains limbic system, and we are beginning to understand the neurobiological mechanismsunderlying the drugs later developing and longer lasting effects of craving and relapse vulnerability.Among the most intriguing of these mechanisms is elevation of the genetic transcription factor FosB, amolecule that lasts for approximately 2 months and theoretically can promote neuron structural changesthat have potentially lifelong persistence. The most important goal for the next decade is to translate theknowledge we have already gained, along with any future advances we make, into better treatments foraddiction.