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 alcohol(Drug information on alcohol)ism, 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(Drug information on 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(Drug information on morphine), or excess food.58-64