El cerebro y las drogas, sus mecanismos neurobiológicos / Brain, drugs, its neurobiological mechanisms

ABSTRACT

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.

RESUMEN

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.