INTRODUÇÃO
O entendimento das bases neurofisiológicas da dependência química continua desafiando os pesquisadores. De acordo com estudos, o sistema dopaminérgico vem sendo considerado como o mais importante no que se refere ao uso abusivo de substâncias, sendo a via dopaminérgica mesocorticolímbica a mais referida. Juntamente com a dopamina, outros neurotransmissores em conjunto parecem colaborar para a atividade da via dopaminérgica com o chamado “sistema de recompensa”. Incluem-se à dopamina, por exemplo: o ácido gama-aminobutírico (GABA), o glutamato, a serotonina e os peptídeos opióides. Além de atuar sobre o sistema de recompensa, o sistema dopaminérgico apresenta importante função sobre o sistema motor, além de funções refinadas de cognição e memória. Já o sistema opióide é responsável pelo componente hedônico (de prazer) do sistema de recompensa cerebral além de estar relacionado também à dor e ao processamento das emoções.
Quando observamos os mecanismos de ação das diferentes drogas de abuso verificamos que todas apresentam uma relação direta ou indireta com um ou mais destes neurotransmissores.
Mecanismos de ação das diferentes droga de abuso
Cocaína
A cocaína se liga aos transportadores de dopamina (DAT), serotonina (5-HTT) e noradrenalina. Entretanto, os efeitos subjetivos e comportamentais desta substância são geralmente atribuídos à sua ação sobre o sistema dopaminérgico. Acredita-se que 50% de ocupação de transportador de dopamina seja necessário para que um indivíduo perceba os efeitos da substância e que, para a sensação de euforia, pelo menos 60% dos sítios de DAT devem estar ocupados. Nas três vias de administração – aspirada, injetada e fumada (crack) - a ocupação de DAT é superior a 60% .
A cocaína per se provoca efeitos deletérios indiscutíveis, mas quando é ingerida concomitante ao álcool, leva a formação de um metabólito conjugado chamado cocaetileno. Esse metabólito apresenta propriedades psicoativas importantes e uma meia-vida muito maior do que se a cocaína e o álcool fossem ingeridos separadamente e seu acúmulo leva rapidamente a um quadro de intoxicação.
Metanfetamina e Ecstasy (MDMA -3,4-metilenodiox,metanfetamina)
As drogas classificadas como derivados anfetamínicos podem atuar no Sistema Nervoso Central (SNC) de formas distintas. Seu alvo principal são as monoaminas cerebrais: dopamina, serotonina e noradrenalina. Assim, farmacologicamente são classificadas como agonistas indiretos pois não atuam específicamente sobre receptores monoaminérgicos pós-sinápticos mas, indiretamente da seguinte forma:
1º Impedem a recaptação dos neurotransmissores através do bloqueio competitivo do transportador de dopamina e noradrenalina e em altas doses, também de serotonina;
2º Inibem a atividade das enzimas de metabolismo (monoaminoxidase - MAOA e MAOB);
3º Estimulam a liberação do neurotransmissor independente de Ca++ (ou seja independente da despolarização do botão sináptico).
Maconha
O principal componente psicoativo da maconha é o Δ9-tetrahidrocanabinol (THC). Seu mecanismo de ação do THC ainda não foi completamente elucidado, mas acredita-se que ele atue no SNC através de receptores canabinóides CB1 e CB2. As áreas cerebrais com maior densidade de receptores CB1 são o córtex frontal, núcleos da base, cerebelo e hipocampo. Estudos com animais têm demonstrado que o THC e a anandamida (canabinóide endógeno mais estudado), aumentam a concentração de dopamina no estriado e no sistema mesolímbico5 .
Nicotina
A nicotina é a principal substância do cigarro responsável pelos efeitos psicoativos e pela dependência de tabaco. No entanto, há milhares de compostos químicos na fumaça do cigarro e alguns deles podem contribuir para os efeitos comportamentais e tóxicos do tabaco. Nicotina é um agonista direto em receptores colinérgicos nicotínicos onde age acetilcolina endógena e estão amplamente
distribuídos no SNC. Os receptores nicotínicos implicados na ação da Nicotina6 estão localizados no sistema dopaminérgico mesocorticolímbico.
Álcool
Os mecanismos pelos quais o álcool atua no cérebro assim como as alterações cerebrais produzidas pelo seu consumo crônico ainda não estão compreendidos sendo que a maioria dos estudos indica a participação dos sistemas dopaminérgicos, serotoninérgicos e principalmente gabaérgicos.
O sistema de recompensa associado ao uso do álcool, além dos neurônios dopaminérgicos da área tegmental ventral e núcleo accumbens, inclui também estruturas que usam o ácido gama-aminobutírico (GABA) como transmissor, tais como o córtex, cerebelo, hipocampo, colículos superiores, inferiores e a amígdala.
Opióides
Os opióides modulam a liberação de neurotransmissores como a acetilcolina, serotonina, noradreanlina, além de outros peptídeos, como a substância P. O locus coeruleos, responsável pela maior parte da produção de noradrenalina no SNC, apresenta-se estimulado na síndrome de abstinência a opiáceos, o que provoca os típicos sintomas de estimulação simpática.
O sistema de recompensa aos opiáceos, além das estruturas antes mencionadas inclui também áreas que usam como neurotransmissores opiáceos endógenos, tais como o núcleo arqueado, a amígdala, o locus coeruleos e a área cinzenta periaquedutal dorsal.
A BEHAVIORAL/SYSTEMS APPROACH TO THE NEUROSCIENCE OF DRUG ADDICTION
Drug addiction is presently viewed as a complex neuroadaptive process through which drugs of abuse alter cellular and molecular aspects of neural function in such a way as to render the brain circuits mediating various behavioral effects of these drugs more, or less, responsive to those effects. This process guides behavior in maladaptive directions during which severe physical and social consequences engulf and disable the addict. Cellular and molecular mechanisms of tolerance, sensitization (reverse tolerance), and dependence are rapidly being identified for almost all classes of abused drugs, and both established and new molecules are being investigated intensively using the most modern and advanced technologies available to neuroscience (Nestler, 2001b ,d ). As the neurobiology of drug addiction has advanced, the discovery of precise cellular and molecular adaptations related to the addictive process has been substantial. Alterations in many molecules have been newly implicated. From long-suspected involvement of the cAMP pathway in tolerance to and dependence on opiates (Sharma et al., 1975 ), we have identified a dedicated role of cAMP-related molecules in the actions of several drugs of abuse. The cAMP-dependent protein kinase and the cAMP response element-binding protein are but two examples. Molecules that interact both upstream and downstream of these effectors are also implicated and include various neurotransmitter receptors, inhibitory and stimulatory G-proteins, protein kinases and phosphatases, ion channels, immediate early genes, and gene transcription factors (for review, see Berke and Hyman, 2000 ; Nestler, 2001a ,b ). At the cellular level, alterations in synaptic and whole-cell plasticity accompany sensitization and withdrawal (Bonci and Williams, 1996 ; Zhang et al., 1998 ; Thomas et al., 2001 ; Ungless et al., 2001 ), as do structural changes in dendrites (Robinson and Kolb, 1997 , 1999 ).
Clearly, dopamine (DA) is the molecule most directly implicated in the positive reinforcing (rewarding, pleasurable) effects of all drugs of abuse. The ability of addictive drugs to enhance DA neurotransmission, particularly within the mesocorticolimbic DA system, is a well documented commonality among the various classes of abused drugs (for review, see Wise and Bozarth, 1987 ; Koob, 1992 ; White, 1996 ; Spanagel and Weiss, 1999 ). This DA reward system, which originates in the midbrain ventral tegmental area (VTA; A10 DA neurons) and projects to the nucleus accumbens (NAc), prefrontal cortex (PFC), and other limbic areas, has long been the major focus of our attempts to identify cellular and molecular mechanisms underlying addiction. However, the past decade has witnessed an emerging willingness to place the DA system within a broader context of neuronal circuitry engaged by specific drugs and particular behavioral sequences involved in the acts of drug seeking, drug taking, and recovery from drug actions (withdrawal, relapse, etc.).
One critical component of this broader conceptualization of drug reward circuitry is the glutamate neuronal system innervating and directly influencing the mesocorticolimbic DA system. Glutamatergic inputs to the VTA and NAc, arising from the PFC, hippocampus, and basolateral amygdala, have all been implicated in addiction. Indeed, a recurring theme in modern addiction research is the extent to which neuroadaptations responsible for various aspects of the addiction process are similar to those responsible for other forms of neural plasticity studied in cellular models of learning, such as long-term potentiation and long-term depression (Wolf, 1998 ; Berke and Hyman, 2000 ; Nestler, 2001c ); however, glutamate is not the only other system under intense scrutiny. We have long been baffled by the role of other monoamine transmitters in the actions of drugs of abuse. In recent years, a new emphasis on both serotonin and norepinephrine has reemerged, along with clear implications for various neuropeptide systems, including the opioid peptides and the stress-related peptides of the hypothalamus-pituitary-adrenal axis (Kreek and Koob, 1998 ). Moreover, as will be seen in several of the mini-reviews, brain GABAergic and cholinergic systems are fruitful avenues for continued research. Finally, conceptualization of the role of DA pathways has been enlarged to include the nigrostriatal system as it becomes engaged in stereotypic responses that define the process of addiction (Everitt and Wolf, 2002 ).
A concerted interplay between cellular/molecular and behavioral/systems neuroscience with respect to the process of addiction has never been so crucial. Identifying the systems involved in specific behaviors directs cellular/molecular studies of both acute and chronic drug actions. Similarly, identification of new molecules selectively altered by repeated drug administration, perhaps in brain areas not "routinely" considered with addiction circuits, can expand our concepts of brain circuitry modulating the addiction process. We are fortunate that the neuroscientists who have agreed to provide the six mini-reviews in this series work at both levels of analysis, thereby providing a comprehensive multidisciplinary perspective on the neurobiology of addiction. In putting together the teams of scientists to provide these reviews, I have specifically paired two investigators who do not necessarily collaborate directly, so that they mold perhaps different perspectives to provide a consensus as to the most important new developments in drug addiction research. As these reviews emphasize, our efforts to tie specific brain circuits to precise aspects of behavioral changes has broadened considerably the number of affected brain regions and highlighted the need to expand cellular and molecular studies to these areas. This has been made possible by the refinement of sophisticated behavioral approaches coupled to systems neuroscience.
When surveying the advances made with respect to the neuroscience of drug addiction, it is easy for the nonspecialist to get the incorrect impression that brain circuits have evolved to allow maladaptive patters of behavior. Actually, brain reward circuits subserve a much more critical evolutionary function: reward induced by natural reinforcers such as food and sexual interactions. Accordingly, we begin our series of reviews with a look at how the neuroscience of natural rewards is related to addictive drugs. Kelley and Berridge (2002) review current thinking of how the DA reward system encodes specific aspects of the reward process and how such encoding is impacted by natural rewards. They also provide compelling arguments for commonalities in the actions of natural rewards and drugs of abuse within both traditional reward areas and brain regions not normally considered within such circuitry.
After considering natural rewards, the next three reviews focus on the major classes of illicit drugs of abuse: psychomotor stimulants (amphetamine, cocaine), opiates (morphine, heroin), and cannabinoids (marijuana). In a somewhat expanded mini-review, Everitt and Wolf (2002) summarize the rapidly expanding field of psychostimulant addiction from a systems perspective. We have allowed this more detailed treatment not only because more work has focused on this class of drugs but also because these authors provide excellent descriptions of most of the sophisticated behavioral procedures that are also touched on in the other mini-reviews. The interested reader would be well served by first reading this mini-review to become familiar with the animal models used to study drug-seeking, conditioned reinforcement, and behavioral sensitization.
As pointed out by De Vries and Shippenberg (2002) , in contrast to psychostimulants, considerably less is known regarding the mechanisms of opiate addiction and relapse to opiates after withdrawal. Their commentary in this regard is well informed given that these authors could just as easily have reviewed the psychostimulants. This is another feature of the scientists whom I have chosen to participate in this series; many of them work across different drug classes, giving unique perspectives on the similarities and differences between various drugs of abuse. In this case, De Vries and Shippenberg emphasize that recent findings challenge previous notions regarding the role of one neurotransmitter or brain region in opiate addiction and point to activity of several neurotransmitter and neuropeptide systems in brain circuits mediating mood and affect underlying the addiction process.
Maldonado and Rodriguez de Fonseca (2002) tackle the job of integrating an explosive recent literature regarding the perhaps controversial concept of cannabinoid addiction. As social issues swirl with respect to the medical use and possible decriminalization of marijuana, neuroscientists have taken advantage of the relatively recent cloning of cannabinoid receptors, the identification of endogenous cannabinoids, and the development of specific and potent cannabinoid compounds to begin the identification of circuits involved in cannabinoid reward, dependence, and withdrawal. Maldonado and Rodriguez de Fonseca (2002) beautifully integrate discoveries at the behavioral/systems level with those at the cellular/molecular level to argue persuasively that addiction to cannabinoids shares common features with other drugs of abuse. The remarkable interactions between cannabinoid and opioid systems are particularly emphasized.
The last two mini-reviews turn to the two major licit drugs of abuse: alcohol and nicotine. Weiss and Porrino (2002) describe the unique challenges in alcohol addiction research that emerge from the multiple molecular targets of ethanol in several brain circuits. We have come far from the days of considering ethanol as a "modifier of membrane fluidity." Specific binding sites for ethanol within GABA-A and NMDA receptors provide particular challenges given the almost ubiquitous expression of these receptors throughout the nervous system. Weiss and Porrino (2002) clearly and concisely review the involvement of DA, opioid, and other systems in ethanol motivation and reward, adaptations relevant for the transition to dependence and relapse, and issues relevant to the treatment of alcoholism.
Finally, Picciotto and Corrigall (2002) team up to review the neuronal system involved in behaviors related to nicotine addiction and the molecular genetics that have identified which subtypes of nicotinic acetylcholine receptors are implicated in distinct brain regions. Nicotine presents its own challenges given that one does not typically identify this drug as exerting the profound euphoria associated with other drugs of abuse. Yet the DA reward system is again clearly implicated in the addictive properties of nicotine, but so are several other neurochemical systems and brain circuits. One primary example is the involvement of the pedunculopontine tegmental nucleus, a brain region not traditionally linked to the actions of other drugs of abuse, in the acquisition of nicotine self-administration [however, see Bechara et al. (1998) ].
Although not addressed in this set of reviews, it is important to point out that brain imaging studies have clearly indicated that many of the brain structures related to drug reward systems are also engaged by other rewards such as money (Knutson et al., 2001 ), romantic love (Bartels and Zeki, 2000 ), and maternal attachment (Lorberbaum et al., 1999 ). As one progresses through this series of mini-reviews, it will become apparent that there are many commonalities between different drugs with respect to the systems involved in similar aspects of behaviors associated with the addiction process. Yet there are also many important differences. I am hopeful that the reader will sense the excitement that exists in the neurobiology of addiction and the need for continued research to identify what some refer to as the molecular "switch" (Leshner, 1998 ) and the various components of the "spiraling distress-addiction cycle" (Kreek and Koob, 1998 ) that underlies the transition from drug taking to drug addiction.
NEUROBIOLOGIA DE LAS DROGAS DE ABUSO
Diversos neurotransmisores se han implicado en los efectos de las drogas de abuso (GABA, glutamato, acetilcolina, dopamina, serotonina, o las endorfinas). De estos, la dopamina se ha asociado de forma consistente con el efecto de refuerzo de la mayoría de las drogas de abuso. Estas aumentan las concentraciones de dopamina extracelular en regiones límbicas, incluyendo el núcleo accumbens. Específicamente, dichos efectos de refuerzo parecen deberse a su capacidad para sobrepasar la magnitud y la duración de los incrementos rápidos de dopamina que desencadenan los refuerzos naturales como la comida o el sexo. Dichas diferencias cuantitativas y cualitativas con respecto al incremento de dopamina que las drogas inducen explicarían porqué los refuerzos naturales no conducirían a la adicción.
El efecto sobre la dopamina es directo en algunas drogas (cocaína, anfetamina, éxtasis), mientras que otras sustancias afectan a neurotransmisores implicados en la regulación de la dopamina (nicotina, alcohol, opiáceos o marihuana).
Según parece, y a diferencia de lo que se creía hasta ahora, los incrementos de dopamina no se relacionan directamente con la recompensa, sino con la predicción de recompensa y con la “relevancia”. La relevancia se refiere a la capacidad de ciertos estímulos o cambios ambientales para producir una activación o desencadenar un cambio atencional-conductual. La relevancia, que añadida a la recompensa, se aplica a los estímulos aversivos, nuevos e inesperados, afecta a la motivación para buscar la anticipada recompensa y facilita el aprendizaje condicionado. Esto proporciona una perspectiva diferente de las drogas, ya que implica que los incrementos de dopamina inducidos por las drogas motivarán inherentemente la búsqueda de más droga, independientemente de si los efectos de la droga son conscientemente percibidos como placenteros o no.
Los incrementos de dopamina inducidos por las drogas facilitan asimismo el aprendizaje condicionado, de manera que los estímulos neutros que se asocian con la droga quedan condicionados (por ejemplo encuentros con cierta gente, ciertos lugares como discotecas, etc.). Una vez condicionados, pueden por sí mismos aumentar la dopamina y desencadenar el deseo de consumir. Esto puede explicar el riesgo de las personas con una adicción de recaer cuando se exponen a un entorno en el que previamente se ha consumido la droga, y englobaría parte de lo que Ingelmo y cols. han denominado el “contexto drogado” (Ingelmo y cols., 2000).
NEUROBIOLOGIA DE LA ADICCIÓN A LAS DROGAS
La adicción es probablemente el resultado de los cambios neurobiológicos asociados con alteraciones crónicas e intermitentes a niveles suprafisiológicos de los sistemas dopaminérgicos. Volkow y cols. (Volkow y cols., 2004) han postulado que las adaptaciones en estos circuitos dopaminérgicos hacen al adicto más sensible a los picos (incrementos rápidos) de dopamina que se producen con las drogas de abuso, y menos sensibles a los incrementos fisiológicos producidos por los refuerzos naturales (comida y sexo). Estas adaptaciones ocurren tanto a nivel de la fisiología celular (alteración de factores de transcripción, que regulan la expresión de determinados genes, algunos en particular implicados en plasticidad de las sinapsis), como a nivel morfológico en los circuitos cerebrales regulados por la dopamina. Por ejemplo, la administración crónica de cocaína o anfetaminas a roedores produce un aumento de la densidad tanto de dendritas como de espinas sinápticas en el núcleo accumbens y en la corteza prefrontal. Este cambio morfológico se cree que facilita un incremento de la valencia motivacional de la droga.
Igualmente, hay cambios a nivel de los neurotransmisores, no sólo para dopamina, sino también para el glutamato, el GABA, la serotonina o los opiáceos. Estos cambios determinan un funcionamiento alterado de determinados circuitos cerebrales, algunos de los cuales están implicados en la asignación de relevancia o el control de la inhibición; alteración que se asocia a conducta compulsiva (corteza orbitofrontal) y desinhibición (circunvolución anterior del cíngulo). Dichas anomalías en estas regiones frontales del cerebro pudieran estar tras la naturaleza compulsiva de la administración de la droga en los adictos o en su incapacidad para controlar las ansias de consumir cuando se encuentran expuestos a la droga. En adictos a cocaína, los estudios de neuroimagen muestran un descenso de la actividad dopaminérgica (estimada por la densidad de receptores D2) en la corteza orbitofrontal y en la región anterior de la circunvolución del cíngulo. La dopamina tiene una función inhibitoria, que al perderse podría redundar en un exceso de actividad en dichas áreas. Asimismo, parecen existir cambios a nivel de circuitos dopaminérgicos mesocorticales.
Nenhum comentário:
Postar um comentário