RESUMEN
In this second paper of the Brain, Drugs and Genes review we would like to discuss illicit drugs and the genetics that may predispose subjects to addiction. We describe the effects, action sites and pathophysiological consequences of the use of these illicit drugs. The drugs that are reviewed are marijuana, heroin, cocaine, methamphetamine and 3,4-methylenedioxymethamphetamine or MDMA, also known as ecstasy. All of them cause an effect on the brain, modifying the activity of the neuronal systems, altering the activity or availability of the neurotransmitters or emulating their actions. The risk of dependence is related to the velocity with which these drugs induce plastic changes in the brain, very much like a learning process. Such changes underlie the patient's dependence to drugs. Therefore when a long term user quits and deprives the brain abruptly of these drugs, an abstinence syndrome is precipitated and it may be quite severe. Only for marijuana it seems to be mild, misleading people to believe this drug does not cause physical dependence. Marijuana (Cannabis sativa) is a plant which has its active principle A9-tetrahydrocannabinol (THC) in almost all its parts, i. e. the flowers, stems, seeds and leaves. It actually contains over 60 cannabinoids as well as other chemical compounds. Marijuana causes euphoria followed by relaxation and several other reinforcing effects. Among the adverse effects marijuana causes: alteration of short-term memory, slowness of reflexes, depression and anxiety, bronchitis and lung infections. Marijuana effects depend on the activation of the CB1 and CB2 receptors, distributed in the entire body. The CB1 receptor is mainly present in the brain. In medicine, A9-THC has been useful in treating symptoms caused by chemotherapy, and in treating the anorexia caused by the Acquired Immune Deficiency Syndrome. Also, an antagonist of the CB1 receptor, Rimonabant, has been used to treat morbid obesity with certain degree of success. However, despite this promising application of Rimonabant, the side effects it caused led to its withdrawal from the market in Europe, Canada and Mexico. Heroin, derived from morphine, which in turn is isolated from opium, causes euphoria and analgesia, suppresses hunger, increases energy and induces sleepiness. The adverse effects are liver and kidney diseases as well as a decrease in breathing and heart rates. This drug acts on the opioid receptors: MOR, DOR and KOR. Cocaine, derived from the coca plant (Erythroxylum coca) produces immediate rewarding effects that last between 30 to 60 min, and causes anxiety once its serum concentration drops. Due to its very short half-life, it is the most addictive of all drugs. Cocaine reduces hunger, thirst and sleep. The most used forms of cocaine are powder and crack (available as rock). The mechanism of action by which cocaine and related compounds induce their effects is the blockade of the dopamine transporter at the synapsis, leaving dopamine available for a longer time at the synapses of the motivation-reward system. Cocaine and related compounds induce blood vessel constriction, muscular spasm, chest pain, and an increase in heart rate and blood pressure, thus augmenting the risk of cardiac arrest and stroke. The methamphetamine, a synthetic stimulant, is a crystalline, odorless, bitter drug which causes a pleasant feeling and euphoria. Its action mechanism is the blockade of the dopamine transporter, same as cocaine. The effects pursued by the users of crystal methamphetamine are increased alertness, increase in physical activity and decrease in hunger. Its side effects include increase in body temperature, heart rate and blood pressure, thus augmenting the risk for stroke. Methamphetamine also triggers violent behavior, anxiety, irritability, confusion, paranoia and hallucinations. This compound has been used for medical reasons, such as in the treatment of narcolepsy and obesity. 3,4-methylenedioxymethamphetamine, MDMA or ecstasy, is a synthetic compound with stimulant and hallucinatory effects. Its action is exerted mainly on the serotonin transporter, leaving serotonin available at the synapsis for a longer time. After clearance from the bloodstream this drug causes severe depression. Ecstasy is also combined with other stimulants. All the drugs discussed here induce body changes that compromise the life of the user, or his health at the very least. Despite this fact, the highly reinforcing effects the drugs produce by over activating the motivation-rewarding system compel their repetitive use. Not all users, however, are equally vulnerable to becoming addicted or respond the same way to the use of drugs. The individual response depends, in part, on genetic factors, as we discuss in the following section. It is evident that not only environmental factors account for the vulnerability to addiction. Genetic factors also have a substantial contribution. In order to facilitate the understanding of the interaction environment-gene, we define the following concepts: gene, allele, mutation, polymorphism, heritability and epigenesis. Apparently, the genetic contribution to addiction vulnerability varies depending on the drug. For example, cocaine and opiates are much more dependant on genetic factors to trigger addiction than are nicotine, alcohol or marijuana. Mutations or polymorphisms carried by several genes might make the difference between being at high or low risk for addiction. They may also underlie the degree of response to rehabilitation treatments. Addiction, then, is a result of an interaction between environment and genes. Environmental demands make the organism modify its structure and physiology in order to cope efficiently to such demands. One crucial way to do so is by changing gene expression. Changes in gene expression may be a consequence of chemical rearrangements in the chromatin structure, which lead to transcriptional modifications that affect the expression of the proteins the genes encode. Consequently, the normal functions of such proteins in different systems are also altered. These adaptive rearrangements in the chromatin structure are called epigenesis. The epigenetic changes induced by environmental stimuli have been proved to affect the expression of several neurotransmitter receptors and trophic factors, among many other molecules crucial for the proper functioning of the Central Nervous System. Hence, these chromatin's structural changes, triggered by environmental demands, are most likely to help the subject cope with such specific demands. However, this adaptation is not free of charge, and requires a toll to be paid which is: vulnerability to addiction. Finally, one question arises: Who is the person most likely to seek a drug of abuse? Statistics have shown that those patients suffering from a psychiatric illness. This hypothesis suggests that addiction is a symptom or a disease caused by a psychiatric illness such as a personality disorder, depression or schizophrenia. Hence, at the end, drug addiction would be a co-morbid entity, generating what in Spanish we call the dual-disease. On the other hand, the self-medication hypothesis also makes sense, at least for an extensive group of patients. This hypothesis suggests that patients take drugs of abuse to relief the symptoms caused by their psychiatric pathology. The present review discusses the interaction between brain circuits, drugs and genes to generate an addict patient. We do not intend to revise each field exhaustively, but rather we intend to give the reader a general scenario on the convergence of these three worlds. Thus it may be better understood how addiction develops and how it may be treated.
En este segundo artículo sobre el tema reseñamos brevemente las drogas de abuso ilícitas. Describiremos también cómo la genética contribuye en forma importante en el desarrollo de la adicción. La marihuana (Cannabis sativa) es una de las drogas más populares entre los jóvenes. Se presenta para su consumo en dos formas: hachís, como un triturado de la planta seca y como aceite. Una vez consumida, sus efectos tardan en aparecer según la vía de administración. Por ejemplo, cuando se inhala, sus efectos aparecen en unos cuantos segundos. Después de que el principio activo de la marihuana (A9-THC) llega al cerebro y se une a sus receptores (CB1), produce euforia seguida de relajación, se perciben más intensamente los olores, los sabores y los sonidos y parece que el tiempo pasa lentamente. Su consumo, al igual que todas las drogas de abuso, tiene efectos adversos. Sin embargo, la marihuana cuenta con un potencial uso en la medicina por sus propiedades antieméticas, orexigénicas y analgésicas. La heroína es derivada de la morfina (ingrediente activo del opio, Papaver somniferum). El opio se fuma o se utiliza como un extracto disuelto en alcohol (láudano), y la heroína se aspira o fuma. Sus efectos aparecen rápidamente e incluyen euforia, aumento de la energía, supresión del hambre, analgesia y somnolencia. La heroína, así como el opio y la morfina, ejercen su efecto a través de los receptores opioides. Su consumo deteriora el hígado, los riñones, los pulmones y el corazón. La cocaína (Erythroxylum coca) es una droga estimulante altamente adictiva. Al consumirla se experimenta mejoría de la autoestima y la auto-confianza, acompañada de excitación. Estos efectos son inmediatos y duran entre 30 y 60 minutos y son consecuencia de la inhibición de la recaptura de dopamina. Adicionalmente la cocaína inhibe el apetito y el sueño. Sus efectos adversos son la contracción de los vasos sanguíneos, espasmos musculares, dolor de pecho, embolias o derrames cerebrales, aumento en la frecuencia cardiaca y muerte. La metanfetamina se sintetiza fácilmente a partir de la anfetamina (derivado de la efedrina), lo que facilita su fabricación en laboratorios clandestinos. Cuando se fuma o se inyecta por vía intravenosa produce una sensación sumamente placentera (<
RESUMEN
The pleasant sensation experienced when, for example eating or having sex is regulated by the motivation-rewarding system. This rewarding sensation makes the subject to repeat the behavior in order to obtain the reinforcer once more. This system can be corrupted by drugs of abuse by triggering an «intense feeling of pleasure¼ and inducing plastic changes. In normal conditions, a natural reinforcer is a stimulus generating a benefit to the organism. For example, food will provide energy and structure among many other benefits. Sex, in turn, accomplishes the function of giving new beings to the species and to create boundaries between subjects to generate groups and culture. Due to these facts, it is crucial to reinforce this kind of behaviors. They are crucial for the subject's life. In contrast, drugs do not produce any benefit to the subject or group. Although in ancient times human beings used drugs as a means to develop and practice their mysticism, such practice is no longer associated with the use of drugs. With the exception of present time aboriginal communities, none of the regular users in our countries consume drugs with ritual-mystical purposes. Hence, we have to accept that drugs are of no use for human beings. They do not help us as species to have more adapted, intelligent or developed subjects in our communities. However, their ability to stimulate the rewarding system makes them popular and dangerous to the individual's health and life. The motivation-rewarding system is regulated by numerous neurotransmitters, among them dopamine, that is released in the nucleus accumbens (NAc) and synthesized by the neurons located in the ventral tegmetal area (VTA). There are other substances that modulate the activity of the dopaminergic neurons in the VTA, such as serotonin, acetylcholine, gamma-aminobutyric acid (GABA) and glutamate. The activation of the VTA and its consequent activation of the NAc enhance the release of neuromodulators such as endorphins and endocannabinoids, thus generating the subjective sensation of pleasure. All these interactions trigger the activity of memory systems generating a memory trace encoding the characteristics of the substance or behavior causing pleasure. This occurs in the context that the brain accepts these substances or behaviors as beneficial to the organism. The punishment system is also a very important system working in tight communication with the pleasure system. Fear is one of the most critical adapting behaviors for any subject in the animal kingdom. Fear helps us to avoid dangerous stimulus and behaviors. There is also pleasure involved in escaping this kind of situations. It seems like there is an interaction between the motivation-rewarding and the punishment systems. As a result, there is a balance at times in favor of pleasure, at times in favor of punishment depending on the quality of the stimulus. This balance gives the valence to the emotion triggered by the stimulus. A stimulus with a positive valence will increase the probability of exhibiting the behavior displayed to obtain it, while a stimulus with a negative valence will increase the probability of exhibiting the behavior displayed to avoid it. In this context, the so-called non-natural reinforcers such as drugs of abuse act directly on the pleasure system. For example, nicotine acts on the nicotinic receptor of ACh, alcohol, on the receptor of GABAa and glutamate (NMDA), marihuana on the endocannabinoid receptor (CB1 R), located in the motivation-rewarding system triggering an «intense sensation of pleasure¼. However, two main shortcomings make drugs of abuse dangerous: first, their effect is short and, second, they do not convey any beneficial effect to the organism whatsoever. Brain mechanisms not very well defined detect this lack of benefit; hence, the motivation-rewarding system reduces its response by means of at least two plastic changes, reducing the availability of receptors (epigenetic changes induced by the drug) and by increasing the activity of the punishment system to maintain the balance. As a result, the subject does not experience the same pleasure with the same dose of the drug. In the clinic we call this phenomenon tolerance. If the individual insists in pursuing the same intensity of pleasure, he/she has to consume more of the drug, forcing the brain to strengthen its plastic changes. In this context, we can say that these systems are defending themselves against the action of the drug. Then, why do subjects insist in pursuing the effect of drugs? Very likely because the substrate of the subject's disorder resides anywhere in the brain but in the pleasure system. If so, this indicates that drug addiction is a disorder caused by another disease, very likely a psychiatric one. Several factors contribute to generate drug addiction, i. e. social, psychological and genetic. Genes contribute in different ways to generate the subject's vulnerability to suffer an addiction. A gene mutation (alteration in genetic information) or a given polymorphism (the existence of multiple alleles of a gene in a population) can produce a dysfunctional protein or alter its normal levels. Such changes may make some individuals vulnerable to the initial use of drugs of abuse. However, those genes facilitating adjustments in the motivation-rewarding system that occur after the repeated consumption of drugs of abuse seem to be functioning normally, as we can infer from the development of tolerance. The heritability of these genes, making subjects vulnerable to addiction, has been studied in many ways, including studies of families, adoptees, and twins (monozygotic and dizygotic). From these studies it has been possible to calculate the heritability index, a measure which indicates how much variance of a trait in a specific sample is associated to genetic factors and how much to the environment. The heritability index has a range from 1, meaning the maximum genetic influence, to 0, meaning the maximum environment influence. At present, a significant number of genes have been involved in facilitating addiction to drugs, and also very important, to the response to treatment for rehabilitation. The expression of the genes is regulated by a series of processes called epigenesis. Epigenetic changes can be a result of the interaction between genes and environment. This interaction results in chemical processes that modify chromatin structure. For example, cytosine nucleotide methylation causes chromatin condensation, which interferes with gene transcription; hence, the protein encoded by this gene will be reduced, and the function in which it participates will be altered. As an example, when the methylation of the gene encoding for the glucocorticoid receptor occurs in rats, it reduces the bioavailability of this receptor and increases the release of corticosterone when rats are stressed. At the behavioral level, rats seem to be more stressed most of the time as compared with rats without methylation of this gene. Almost every stimulus in the environment is a potential promoter of epigenesis. Epigenesis is important to occur, since it is an adaptive response of the organism to the environment. It seems like the switches of the genes are turned on or off according to environment circumstances. These genetic changes will be ultimately expressed as plastic changes pursuing the right adaptation of the subject to the environment. Parental care seems to be one crucial contributor to these epigenetic modifications. For example, when a mother-rat provides poor care (feeding, grooming, and physical contact) to its litter during the neonate period, facilitates the methylation of genes, as it has been proved for the glucocorticoid receptor. These changes generate subjects with poor stress management and less capability for learning. Likewise, it makes them susceptible to drug addiction. These results highlight the importance of parental care as provider of a healthy environment, which is modeling the expression of their genes, hence their behavior.
La definición de adicción propuesta por la Organización Mundial de la Salud, dicha de manera sucinta, indica que es una enfermedad cerebral que provoca una búsqueda compulsiva de la droga y su uso, a pesar de las consecuencias adversas que ésta provoque. La fisiopatología de la enfermedad sugiere una interacción entre mecanismos cerebrales, cambios genéticos y medio ambiente. El objetivo de este artículo es discutir la evidencia que existe sobre los sistemas cerebrales que son afectados por las drogas, qué genes participan y cómo el medio ambiente tiene una participación crucial para generar esta enfermedad. Discutiremos tres secciones: el cerebro, las drogas y los genes. La primera trata sobre cómo el cerebro responde ante estímulos reforzantes y cómo estos sistemas cerebrales promueven que el individuo repita la conducta que lo llevó a adquirir el reforzador originalmente, para obtenerlo de nuevo. A este sistema se le denomina sistema de motivación-recompensa. Este sistema responde muy activamente ante reforzadores naturales (estímulos que buscan preservar la vida del individuo), pero también a reforzadores no naturales. En este grupo de estímulos están las drogas de abuso. El sistema de motivación-recompensa está modulado por diversas estructuras subcorticales y corticales que incluyen un sistema de castigo. Estos sistemas util izan una gran diversidad de neurotransmisores y neuromoduladores que inducirán una sensación de placer ante la presencia del estímulo reforzante. Todas las drogas de abuso provocan un efecto sobre los receptores y sobre los transportadores de los neurotransmisores, al igual que sobre las enzimas que participan en la síntesis y degradación de estos mediadores químicos. El uso repetido de la droga modifica así estructural y funcionalmente al cerebro. Estos cambios plásticos desarrollados en el sistema de la motivación-recompensa y también en el de castigo, provocan un nuevo balance entre ellos que lleva al individuo a un estado de alostasis, en el cual la droga se convierte en una necesidad. En otro artículo haremos una reseña sobre drogas lícitas e ilícitas; sus efectos, sus sitios de acción y las consecuencias adversas de su uso. La última sección versará sobre la genética: definimos los conceptos de gen y alelo, de mutación y polimorfismo, heredabilidad y epigenética, a fin de entender qué hace a un individuo vulnerable a la adicción de una droga de abuso. Si bien para la adicción existe una contribución ambiental, la contribución genética es importante. Esta contribución no es igual para las diferentes drogas. La cocaína y los opiáceos, no solamente son las drogas más adictivas, sino también las que mayor contribución genética tienen en comparación con otras (v. gr. nicotina, alcohol o marihuana). Los polimorfismos en diversos genes hacen vulnerable a un cerebro para convertirse en adicto a alguna droga o, por el contrario, dificultan la eficiencia de los tratamientos en contra de la adicción. Entre los polimorfismos que se han descrito son de interés los genes que codifican para las enzimas hepáticas citocromo P450, ya que estos polimorfismos modifican la vulnerabilidad para la adicción al tabaco, al alcohol y a la heroína. Es menester considerar la influencia genética en la adicción puesto que las variaciones a este nivel harán responder diferencialmente al tratamiento a personas con el mismo tipo de adicción. Por ello, hay que enfatizar el uso individualizado de la terapia. Por último, planteamos que quienes buscarán con mayor probabilidad el uso de una droga son quienes presentan una enfermedad psiquiátrica de fondo, así que la adicción representa sólo una parte de una enfermedad dual o comorbilidad. En este contexto, la hipótesis de la automedicación sugiere que los pacientes buscan la droga con el fin de controlar su patología inicial. Esta revisión busca integrar la interacción entre el cerebro, las drogas y los genes, pero no pretende ser exhaustiva. Nuestro interés es dar un panorama al lector sobre cómo estos tres mundos convergen, para entender cómo ocurre esta enfermedad y tratarla diferencialmente entre los individuos.
