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.
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
Affect regulation. The gene that encodes the serotonin (5-HT) transporter protein has a variant site (5-HTTLPR, for 5-HT transporter-linked polymorphic region) that is characterized by 2 alleles, 1 short (s) and the other long (l). The s allele, and especially the homozygous ss genotype, is associated with alcoholism, heroin addiction, cigarette smoking, pathological gambling, bulimia, and binge eating disorder.22-24 It is associated also with affective instability, anxiety-related personality traits, and heightened sensitivity to mild stressors.23,25,26
The A allele of the gene that encodes brain-derived neurotrophic factor is associated with alcoholism, methamphetamine abuse, heroin abuse, tobacco smoking, and all subtypes of eating disorder.27-30 It is specifically associated with binge eating behavior, a phenotypic trait that occurs in both bulimia and binge-eating disorder.31 The long allele of another brain-derived neurotrophic factor gene variant, in the gene’s promoter region, is associated with vulnerability to polysubstance abuse.32
Alcoholism is associated with 3 polymorphisms of the gene that codes for neuropeptide Y (NPY) and with 2 haplotypes of the galanin gene.33-35 The mediating link in both cases is thought to be impaired regulation of anxiety.
Behavioral inhibition. Whereas dopamine D1, D2, and D3 receptors play central roles in the motivation-reward system, dopamine D4 and D5 receptors are involved primarily in behavioral inhibition and attentional processing. The long allele of a polymorphism in the D4 receptor gene is associated with impulsive personality traits and is a risk factor for adolescent alcohol abuse, adolescent “hard drug” use, heroin use, cue-elicited heroin craving, greater severity of alcohol and opiate addiction, pathological gambling, binge eating, and cue-elicited craving for food.36-43
The common 148 bp variant of the D5 receptor gene is correlated with substance abuse and also with attention-deficit/hyperactivity disorder (ADHD) and novelty seeking.5,44 By itself, the 10-repeat allele of the dopamine transporter (DAT) gene DAT1 is not associated with increased consumption of alcohol. But the correlation between novelty seeking and increased alcohol consumption is significantly greater with this allele than with the normal genotype.45
Studies have reported associations between variants of the gene GABRA2, which encodes the α-2 subunit of the GABAA receptor, with alcoholism and addictive use of cannabis as well as one or more other illicit drugs.46-48 Risk alleles of this gene are also associated with conduct disorder in children and with antisocial personality disorder in adults.46 Polymorphisms of the gene that encodes the α-3 subunit of the GABAA receptor are associated with alcoholism.49
Although impaired behavioral inhibition or impulsivity is a key feature of addiction, research has linked variants of genes that code for 5-HT1B and 5-HT2A receptors with greater impulsivity among persons with alcoholism and bulimia, respectively, but not with greater prevalence of any addictive disorder per se.24,50 In at least some instances, genotypic variations seem to map onto disorder-relevant intermediate phenotypes (ie, trait-level variations) within a population that is affected by a particular disorder more closely than they map onto gross phenotypes, such as the disorders themselves.
Maternal gestational stress
Prospective naturalistic studies with human subjects have found maternal gestational stress to be associated with high affective/behavioral reactivity, negative affect, difficulty being consoled, and disinhibitory traits.51,52 The most pervasive neurobiological effect of maternal gestational stress is dysregulation of the offspring’s hypothalamic-pituitary- adrenal (HPA) axis, which results in elevated baseline cortisol levels and exaggerated cortisol responses to stress. A longitudinal study found that the intensity of the mother’s anxiety during gestation was positively correlated with the elevation of the child’s awakening cortisol levels at age 10 years.53 Elevated basal cortisol and cortisol hyperresponsiveness constitute a vulnerability to addictive disorders, as well as to affective disorders, anxiety disorders, and personality disorders. The consensus among investigators is that exposure to maternal gestational stress results in a general susceptibility to psychopathology, rather than a direct effect on a specific form of psychopathology.54
Deficient infant caregiving
Considerable development of the human brain occurs after birth, particularly during the first two years of life, and is highly responsive to conditions in the environment. Epidemiological, clinical, and preclinical data indicate that exposure to adverse environments during infancy may engender an overreactive stress response system that leads to subsequent impairments in affect regulation, motivation-reward, and behavioral inhibition. These impairments constitute a vulnerability to develop an addictive disorder. For mammals, the most important aspect of an infant’s environment is the infant’s mother (or substitute primary caregiver).55,56
A prospective study with human subjects found a 1.47-fold elevated risk of being hospitalized in a psychiatric unit with an alcohol-related diagnosis among offspring who had been weaned at age one month or earlier, compared with offspring who had been breast-fed for more than one month.57 Extending this finding, animal studies (which can be controlled in ways that would be unacceptable in research with human subjects) indicate that deficient infant caregiving is associated with a higher risk of developing addictive patterns of self-administering or consuming alcohol, cocaine, morphine, or excess food.58-64
Children who spend their infancy in institutional settings where adequate individual caregiving is unavailable are at increased risk for subsequent impairments in affect regulation and behavioral inhibition, which, in turn, contribute to an addictive diathesis. The neuropeptides oxytocin and arginine vasopressin are associated with social bonding, stress regulation, and emotional reactivity. Adopted children who had resided in orphanages for an average of 16.6 months (range, 7 to 42 months) immediately after birth had lower levels of arginine vasopressin than children reared in families. Oxytocin levels of children with families increased after physical contact with their mothers; in contrast, children in the orphanage did not show this response.65 These findings suggest that a deficiency of maternal care during infancy disrupts the normal development of the oxytocin and arginine vasopressin systems, thereby interfering with the development of both affect regulation and social relationships.
In a separate orphanage study, children who were adopted from deprived institutional settings before age 43 months were found to display high degrees of inattention and overactivity at 6 and 11 years of age. They were found also to demonstrate deficits in executive functions of planning, inhibition, set-shifting, working memory, generativity, and action monitoring, which were most severe in children who had experienced more than 6 months of institutional maternal deprivation.66,67 Similarly, controlled preclinical studies have found deficient infant caregiving to be associated with intensified reactivity to acute stressors, increased anxiety-like and depression-like behaviors, decreased social interaction, and increased impulsive behavior.56,68-72 While deficient infant caregiving has been correlated with a broad range of neurobiological abnormalities, the most widely reported are hypersensitivity of the HPA and noradrenergic stress response systems.70-74
A large body of research reports strong associations between adverse childhood experiences and subsequent development of substance use disorders. A study of female monozygotic twins who were discordant for childhood sexual abuse reported that the twin who had been exposed to sexual abuse had a substantially increased risk for alcoholism and other drug addictions.75 A prospective study followed substantiated cases of child abuse and neglect (and demographically matched controls) into young adulthood, and found support for the hypothesis that childhood victimization plays a causal role in the development of alcohol abuse symptoms.76
Similar associations between a range of childhood adversities, especially sexual abuse, and bulimia or other problems with eating or weight have been documented as well.77 However, these associations are less specific than they seem to be. Adverse childhood experiences often coexist and are interrelated,78,79 and abuse of all types is more likely to occur in disturbed families.80 Moreover, childhood sexual abuse appears to increase the risk of a number of psychiatric disorders, rather than being selectively associated with any particular disorder.81,82
Children who have been sexually or physically abused manifest abnormal baseline and stressor-responsive cortisol levels (either abnormally elevated or abnormally flat). Childhood abuse may initially sensitize the stress response system, thus rendering persons who were abused during childhood particularly vulnerable to stress and increasing their risk for stress-related disorders. This vulnerability may result in hypersecretion of corticotropin-releasing hormone whenever they are stressed. A lack of feedback inhibition may also increase the discharge of central corticotropin-releasing hormone.65
Stress and disorders that are related to chronic stress tend to increase dendritic atrophy, accelerate neuronal degeneration, and subvert neuronal regeneration in the hippocampus and hippocampal and prefrontal cortex.83-85 Mediating factors may include chronically elevated levels of glucocorticoid, decreased expression of brain-derived neurotrophic factor, stunted sprouting of serotonergic axons from insufficient availability of brain-derived neurotrophic factor, glial cell loss, and decreased arborization and density of noradrenergic axons.86 In the developing brain, elevated levels of catecholamines and cortisol may lead to structural deviations or deficits through accelerated loss of neurons, delays in myelination, abnormalities in developmentally appropriate synaptic pruning, and inhibition of neurogenesis.87 Sustained glucocorticoid exposure truncates and impairs neurogenesis in the hippocampal and prefrontal cortex.88-90 Reduced baseline and hyporesponsive cortisol levels also can cause neuronal damage.
Together, these processes feed the downward spiral by potentiating hippocampal and cortical atrophy. Neuronal degeneration in the hippocampus and the prefrontal cortex diminishes the capacity of these regions to modulate or inhibit amygdalar stress or fear pathways and the HPA axis, and also undermines hippocampal negative feedback control over cortisol release. Evidence of neuronal loss in the anterior cingulate cortex has been reported in children, adolescents, and nonhuman primates with histories of adverse experiences early in life.91 In addition, adult survivors of early abuse have been found to have changes in hippocampal structure and function.92 Thus, these stress-induced processes may lead to compromised executive function, impaired affect regulation, and a greater incidence of impulsive behaviors.
Most studies of drug self-administration have reported increases in responding after repeated or prolonged exposure to stress levels of glucocorticoids, which enhance drug response by selectively facilitating dopamine transmission in the nucleus accumbens shell.93 During chronic stress, repeated increases in glucocorticoid and dopamine result in sensitization of the reward system. This sensitized state, which can persist after the end of the stress, renders the subject more responsive to pleasurable substances and behaviors that trigger release of mesolimbic dopamine and consequently more vulnerable to develop an addictive disorder.
Acute re-exposure to the self-administered drug and exposure to stressors, or simply the presentation of stress-related imagery, have been identified as potent stimuli for provoking relapse to drug-seeking.94-97 In addition to the frequency and intensity of stressor exposures, a person’s vulnerability to stress-induced reinstatement of drug-seeking, and thus to relapse, depends on the sensitivity of his or her HPA axis and the responsiveness of the mesolimbic dopaminergic system, which tends to be positively correlated with baseline glucocorticoid levels. Elevated baseline cortisol levels and higher increases of cortisol in response to stressors are common sequelae of adverse childhood events (and also, as noted earlier, of maternal gestational stress and deficient infant caregiving).
On exposure to a standardized (laboratory) psychosocial stressor, women with a history of childhood sexual or physical abuse demonstrated markedly increased pituitary-adrenal and autonomic responses. The mean adrenocorticotropic hormone response was highest in women with a history of childhood abuse and current major depression. Moreover, women with a history of childhood abuse and current major depression showed significantly increased cortisol responses to psychosocial stress.98 These findings suggest that HPA axis hyperreactivity, probably caused by hypersecretion of corticotropin-releasing hormone, is a persistent consequence of childhood abuse that may contribute to the diathesis for addiction and other psychiatric disorders in adulthood.
A study screened 120 healthy college students for quality of parental care during childhood.99 Five from the top end of the distribution and 5 from the bottom end were invited to participate in a positron emission tomography study during which they were asked to complete a stressful psychosocial task. The scans indicated that the psychosocial stressor elicited a significant release of dopamine in the ventral striatum of those in the low, but not the high, parental care group. The low parental care group also showed higher baseline cortisol levels and higher increases of cortisol during the stressful task. The magnitude of the cortisol response to stress was highly correlated with the magnitude of the ventral striatum dopamine response.99 These findings suggest that the chronic stress of neglectful or abusive parental care during childhood results in an HPA axis that is hypersensitive to psychosocial stressors and a midbrain that is hyperresponsive to triggers of dopamine release-conditions that are highly conducive to the development of addictive disorders.
Chronic stress is also associated with changes in the serotonergic system: reduced release of 5-HT in the frontal cortex, decreased binding of 5-HT1A receptors in the hippocampus and dentate gyrus, decreased 5-HT2A receptor density in the hippocampus and amygdala, and decreased density of 5-HT transporters in the medial prefrontal cortex.100-103
Genetic and environmental factors in human brain development interact through dynamic, nonlinear processes and are, to a large degree, interdependent. Thus far, few studies that investigate specific genetic- environmental interactions in the development of addictive disorders have been published. The following section offers a window into the process and is not intended as an overview.
5-HTTLPR. A Swedish study found that adolescents (aged 16 to 19) who had the heterozygous 5-HTTLPR l/s genotype and came from families with neutral or poor family relations had a 12- to 14-fold increased risk for high intoxication frequency, compared with both heterozygous adolescents who had a good relationship with their families and homozygous adolescents (l/l or s/s) who showed no increased risk despite deleterious family relations.104
Similarly, a prospective longitudinal study of abused or neglected children reported that alcohol use in preadolescence or early adolescence (which is associated with a 40% risk for alcoholism) was predicted by childhood maltreatment, by the 5-HTTLPR s/l genotype, and by environmental interaction.105
A third study found the 5-HTTLPR s-allele to be associated with increased use of alcohol and other drugs among college students who have had multiple negative life events. Individuals homozygous for the s allele who experienced multiple negative life events in the preceding year reported more frequent and heavier alcohol consumption, stronger urges to consume alcohol, and greater use of other nonprescribed drugs. Use of alcohol and other drugs was unaffected by past-year negative life events in individuals who were homozygous for the l allele. Heterozygous subjects showed drinking outcomes that were intermediate between the 2 homozygous groups.106
These studies suggest that the interactive effects of life stress and 5-HTTLPR reflect the influence of the 5-HTTLPR genotype on affective reactivity to life stressors. Interestingly, the genotype with the strongest interactive effect was the heterozygous l/s genotype in the first 2 studies,104,105 and the homozygous ss genotype in the third.106 Perhaps affective reactivity to childhood stressors is most robustly boosted by the l/s genotype, while affective reactivity to young adult stressors is most robustly boosted by the s/s genotype.
GABRA2. Analyses of data from the Collaborative Study of the Genetics of Alcoholism (COGA) sample provide evidence of both gene-environment correlation and gene-environment interaction with GABRA2, marital status, and alcoholism. Both variants at GABRA2 and marital status contributed independently to the development of alcoholism in the COGA sample. The risk allele at GABRA2 was also related to a decreased likelihood of marrying and an increased likelihood of divorce, which appeared to be mediated by personality characteristics. In addition, differential risk of developing alcoholism was associated with the GABRA2 genotype according to marital status. The risk of a carrier of the GABRA2 variant developing alcoholism was significantly higher when the carrier was single or divorced than when he was married.49
DAT1. Adolescents (age 15) who were homozygous for either of 2 variants of the DAT1 gene and who grew up in psychosocially adverse familial conditions were found to exhibit significantly more impulsivity, hyperactivity, and inattention than did adolescents with other genotypes or those with the same genotypes who grew up in less adverse family conditions.107 Variants of DAT1 had no significant main effects on these ADHD-like traits, which suggests that the DAT1 risk operates through its effect on susceptibility to risk environments. These findings are relevant to the development of addictive disorders because “neurobehavior disinhibition” (these same ADHD-like traits plus affect dysregulation) at ages 10 through 12 and 16 was found to differentiate boys at high average risk for a substance use disorder (SUD) from boys at low average risk. In addition, the neurobehavior disinhibition trait score mediated the association between both father’s and mother’s lifetime SUD and the son’s SUD.108
This overview concludes with a glance at the implications of the reviewed findings that are relevant to clinical psychiatry.
Diagnosis. A wealth of neuroscience research has converged to provide a neurobiological foundation for the theory that all addictive disorders share an underlying biological vulnerability. This neurobiological understanding complements the clinical and theoretical arguments for defining addiction as a chronic condition in which a behavior that can function both to produce pleasure and to reduce painful affects is used in a pattern that is characterized by 2 key features: recurrent failure to control the behavior, and continuation of the behavior despite significant harmful consequences.109,110
The critical diagnostic issue with respect to addictive disorders is not so much the specific name that designates the disorders or the superordinate category that includes them but rather that they are recognized to be disorders and are grouped together in the same category. Recognizing them to be addictive disorders identifies them as medical syndromes rather than moral failings. It directs attention and energy toward treatment, collaborative fostering of health, and prophylaxis, rather than toward exhortation, punishment, and fostering of guilt and shame. Grouping the conditions together directs clinicians to look for comorbid addictive disorders in patients’ past and current histories, and in their family histories. It also alerts clinicians to the possibility that as one addictive disorder becomes stable or enters remission, a comorbid addictive disorder might flare up, or addictive patterns of engaging in another behavior might emerge for the first time.
Treatment. If the various disorders that fit the definition of addiction share an underlying biological process, then a treatment approach, modality, technique, or agent that is effective with one of the addictive disorders has a better-than-average likelihood of being effective with one or more of the other addictive disorders. The treatment of one addictive disorder could potentially benefit from the lessons learned in treating other addictive disorders.
An implication for treatment that relates more specifically to the developmental issues that were discussed here concerns the potential value of psychodynamic psychotherapy in addressing addiction-prone impairments that are related to maternal deprivation or pathogenic caregiving during infancy or to traumatic experiences during childhood. In the envisioned treatment system, psychodynamic psychotherapy would not replace psychiatric medication or cognitive-behavioral therapies but would complement them, and each treatment modality would enhance the efficacy of the other two.110,111
Prevention. A theme that weaves through the preceding discussion is that stress and the associated increase in glucocorticoid levels at any phase of development can potentiate an addictive process. A corollary of this theme is that interventions at any phase of development that reduce stress or (better yet) prevent it from arising are likely to lower the probability that an addictive disorder will develop. The section on maternal gestational stress suggests that, from a public health perspective, the program for prevention of addictive disorders with the highest rate of return on investment could be providing psychiatric care and social support for pregnant women.
This overview of the neurobiological development of addiction indicates that the addiction diathesis develops as a result of some combination of genetic, prenatal, infancy, and childhood factors. Symptomatic expression of an addictive disorder is then initiated in response to stress in (most typically) adolescence or young adulthood. Drug addiction is not caused by exposure to drugs, any more than pathological gambling is caused by exposure to gambling. A scientific, empirically based understanding of how addiction develops suggests that reduction and prevention of drug addiction would be more likely to result if the resources that currently are allocated to the “war on drugs” were instead invested in treatment, research, and targeted social support.
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