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(Drug information on 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(Drug information on 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