The Neurobiological Development of Addiction
The Neurobiological Development of Addiction
Self-administration of drugs of abuse often causes changes in the brain that potentiate the development or intensification of addiction. However, an addictive disorder does not develop in every person who uses alcohol or abuses an illicit drug. Whether exposure to a substance of abuse leads to addiction depends on the antecedent properties of the brain.
Research indicates that a shared biological vulnerability underlies various psychoactive substance dependencies. The realm of addictions has expanded to include pathological gambling, bulimia, and hypersexuality.1 The underlying vulnerability that these disorders share is termed “the addictive process.” Currently, the addictive process is believed to involve impairments in 3 interrelated sets of functions: motivation-reward, affect regulation, and behavioral inhibition. The addictive process is not what makes cocaine, ice cream, or sex pleasurable for people in general; rather, it is what makes the drive for cocaine or ice cream or sex so much more inexorable for those who have an addictive disorder characterized by cocaine use, binge eating, or engaging in some abnormal form of sexual behavior.
The development of an addictive disorder is shaped by 2 sets of factors: those that concern the underlying addictive process, and those that relate to the selection of a particular substance or behavior as the one that is preferred for addictive use. Whereas the type of behavior that is exhibited addictively is the most readily noticeable manifestation of an addictive disorder, the addictive process is the component that leads to pathological behavior (ie, characterized by impaired control and harmful consequences).
This overview focuses on factors that can apply to addictive disorders in general. The etiological schema that guides the organization of the reviewed findings is the diathesis-stress model. Genetic predispositions interact with adverse experiences in critical phases of development to result in a phenotype that is neurobiologically vulnerable to the effects of stress later in life. This vulnerability increases the risk that further exposure to stress will lead to the development of an addictive disorder.
Researchers generally believe that predisposition to an addictive disorder results from the interaction of multiple genes.2 A large number of genes contribute to the risk for substance addiction or pathological gambling, but no single gene displays such a large magnitude of effect that it alone accounts for a major fraction of the genetic influence.3,4 Meanwhile, most of the genetic liability to develop any one psychoactive substance use disorder is shared among the substances, as distinct from liability that is specific to a particular substance or class of substances.5 Along similar lines, the genetic risk for alcohol dependence accounts for much of the risk for pathological gambling,6 and genes that increase the risk for pathological gambling increase the risk for other impulsive-compulsive and addictive behaviors.4
Genetic variants (polymorphisms) that are associated with the development of one or more addictive disorders can be grouped according to their involvement in motivation-reward, affect regulation, or behavioral inhibition.
Motivation-reward. The homozygous 11 genotype of the dopamine D1 receptor is associated with increased risk of alcohol use, cigarette smoking, use of illicit drugs, gambling, compulsive shopping, and compulsive eating.7 The Taq A1 allele of the D2 receptor gene predicts alcoholism, cigarette smoking, addictive use of psychoactive substances, pathological gambling, and exaggerated reward value of food.8,9 The Taq A1 allele is associated with reduced D2 receptor density, hypersensitive presynaptic D2 receptors, and decreased general responsiveness of the reward system to rewarding stimuli, along with heightened responsiveness after events that increase intrasynaptic dopamine in the reward system.10 Such an increased reward effect could promote the development of an addictive disorder by intensifying motivation to repeat behaviors that increase intrasynaptic dopamine in the reward system. Behaviors that do so include self-administration of a substance of abuse, eating (especially sweets), gambling, and engaging in sexual behavior.
Addictive disorders are also associated with variants of genes that code for 3 enzymes that act on dopamine: dopamine β-hydroxylase (DBH), catechol-O-methyl transferase (COMT), and monoamine oxidase (MAO). Alcoholics have elevated frequencies of the A allele of the gene that encodes DBH, and cocaine abusers with low-activity DBH haplotypes have increased sensitivity to cocaine-induced euphoria.11,12 The Val(158) allele of the COMT gene is associated with alcoholism, methamphetamine use, heroin addiction, and polysubstance abuse.13 Pathological gambling is associated with allelic variants in both MAO-A and MAO-B genes.14
Variants of the genes that code for μ-opioid receptors and K-opioid receptors occur more frequently in alcoholics than in nonalcoholic controls, and variants of the gene that codes for the K-opioid ligand prodynorphin occur more frequently in alcoholics, cocaine users, and methamphetamine addicts than in controls.15-18 Polymorphisms of the gene for the cannabinoid CB1 receptor are associated with increased risk for addiction to alcohol, cocaine, amphetamines, cannabis, and multiple other substances.19-21