El cerebro, las drogas y los genes / Brain, drugs and genes

ABSTRACT

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.

RESUMEN

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 (<euforia de mayor duración. Estos efectos son consecuencia del incremento de la liberación de dopamina. Entre los efectos adversos aparecen insomnio, incremento en la actividad física (por lo cual suele ser consumida por deportistas) y disminución del apetito (este es un motivo adicional de consumo), incremento de la temperatura corporal, aumento en el ritmo cardíaco y la presión arterial. La 3,4-metilenedioximetanfetamina, MDMA o éxtasis, es estimulante y psicodélico. Produce un efecto vigorizante, distorsiona la percepción, incluida la del tiempo. Su principal efecto es inhibir el trasportador de serotonina, pero también aumenta la disponibilidad de noradrenalina y dopamina. La adicción depende de factores sociales y psicológicos, pero la contribución genética es muy importante. Nuestros genes pueden hacernos vulnerables al consumo de drogas. Algunos polimorfismos de diversos genes nos pueden volver sensibles a la adicción o incluso dificultar la eficiencia de los tratamientos orientados a la rehabilitación. Uno de los polimorfismos más estudiados es el de las enzimas hepáticas (CYP450), asociados a la vulnerabilidad para la adicción al tabaco, el alcohol y la heroína. Adicionalmente, debemos considerar que nuestro material genético responde a los estímulos ambientales (epigénesis), de tal forma que condiciones ambientales inadecuadas, v. gr. pobre cuidado maternal, puede cambiar nuestra conducta (baja respuesta al estrés) y tornarnos vulnerables a la adicción.