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.

Genetic factors

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 GABA_A 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 GABA_A 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-HT_1B and 5-HT_2A 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

Childhood stress

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-HT_1A receptors in the hippocampus and dentate gyrus, decreased 5-HT_2A receptor density in the hippocampus and amygdala, and decreased density of 5-HT transporters in the medial prefrontal cortex.^100-103

Gene-environment interaction

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

Clinical implications

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.

References:

References1. Goodman A. Neurobiology of addiction: an integrative review. Biochem Pharmacol. 2008;75:266-322.
2. Kendler KS. “A gene for . . .”: the nature of gene action in psychiatric disorders. Am J Psychiatry. 2005;162:1243-1252.
3. Uhl GR, Liu QR, Naiman D. Substance abuse vulnerability loci: converging genome scanning data. Trends Genet. 2002;18:420-425.
4. Comings DE, Gade-Andavolu R, Gonzalez N, et al. The additive effect of neurotransmitter genes in pathological gambling. Clin Genet. 2001;60:107-116.
5. Vanyukov MM, Tarter RE, Kirisci L, et al. Liability to substance use disorders, 1: common mechanisms and manifestations. Neurosci Biobehav Rev. 2003;27: 507-515.
6. Slutske WS, Eisen S, True WR, et al. Common genetic vulnerability for pathological gambling and alcohol dependence in men. Arch Gen Psychiatry. 2000;57:666-673.
7. Comings DE, Gade R, Wu S, et al. Studies of the potential role of the dopamine D₁ receptor gene in addictive behaviors. Mol Psychiatry. 1997;2:44-56.
8. Cohen MX, Young J, Baek JM, et al. Individual differences in extraversion and dopamine genetics predict neural reward responses. Brain ResCogn Brain Res. 2005;25:851-861.
9. Bowirrat A, Oscar-Berman M. Relationship between dopaminergic neurotransmission, alcoholism, and reward deficiency syndrome. Am J Med Genet B NeuroPsychiatr Genet. 2005;132B:29-37.
10. Kirsch P, Reuter M, Mier D, et al. Imaging gene-substance interactions: the effect of the DRD₂ TaqIA polymorphism and the dopamine agonist bromocriptine on the brain activation during the anticipation of reward. Neurosci Lett. 2006;405:196-201.
11. Köhnke MD, Kolb W, Köhnke AM, et al. DBH*444G/A polymorphism of the dopamine-betα-hydroxylase gene is associated with alcoholism but not with severe alcohol withdrawal symptoms. J Neural Transm. 2006;113:869-876.
12. Weinshenker D, Miller NS, Blizinsky K, et al. Mice with chronic norepinephrine deficiency resemble amphetamine-sensitized animals. Proc Natl Acad Sci U S A. 2002;99:13873-13877.
13. Kreek MJ, Nielsen DA, Butelman ER, et al. Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nat Neurosci. 2005;8:1450-1457.
14. Ibañez A, Perez de Castro I, Fernandez-Piqueras J, et al. Pathological gambling and DNA polymorphic markers at MAO-A and MAOB genes. Mol Psychiatry. 2000;5:105-109.
15. Oswald LM, Wand GS. Opioids and alcoholism. Physiol Behav. 2004;81:339-358.
16. Xuei X, Dick D, Flury-Wetherill L, et al. Association of the kappα-opioid system with alcohol dependence. Mol Psychiatr. 2006;11:1016-1024.
17. Kreek MJ, Bart G, Lilly C, et al. Pharmacogenetics and human molecular genetics of opiate and cocaine addictions and their treatments. Pharmacol Rev. 2005;57:1-26.
18. Nomura A, Ujike H, Tanaka Y, et al. Genetic variant of prodynorphin gene is risk factor for methamphetamine dependence. Neurosci Lett. 2006;400: 158-162.
19. Schmidt LG, Samochowiec J, Finckh U, et al. Association of a CB1 cannabinoid receptor gene (CNR1) polymorphism with severe alcohol dependence. Drug Alcohol Depend. 2002;65:221-224.
20. Comings DE, Muhleman D, Gade R, et al. Cannabinoid receptor gene (CNR1): association with IV drug use. Mol Psychiatry. 1997;2:161-168.
21. Zhang PW, Ishiguro H, Ohtsuki T, et al. Human cannabinoid receptor 1: 5’ exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse. Mol Psychiatry. 2004;9:916-931.
22. Goudriaan AE, Oosterlaan J, de Beurs E, Van den Brink W. Pathological gambling: a comprehensive review of biobehavioral findings. Neurosci Biobehav Rev. 2004;28:123-141.
23. Serretti A, Calati R, Mandelli L, De Ronchi D. Serotonin transporter gene variants and behavior: a comprehensive review. Curr Drug Targets. 2006;7:1659-1669.
24. Steiger H, Bruce KR. Phenotypes, endophenotypes, and genotypes in bulimia spectrum eating disorders. Can J Psychiatry. 2007;52:220-227
25. Hariri AR, Holmes A. Genetics of emotional regulation: the role of the serotonin transporter in neural function. Trends Cog Sci. 2006;10:182-191.
26. Pezawas L, Meyer-Lindenberg A, Drabant EM, et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci. 2005;8: 828-834.
27. Cheng CY, Hong CJ, Yud YW, et al. Brain-derived neurotrophic factor (Val66Met) genetic polymorphism is associated with substance abuse in males. Brain ResMol Brain Res. 2005;140:86-90.
28. Hashimoto K, Koizumi H, Nakazato M, et al. Role of brain-derived neurotrophic factor in eating disorders: recent findings and its pathophysiological implications. Prog Neuro-Psychopharmacol Biol Psychiatry. 2005;29:499-504.
29. Liu QR, Walther D, Drgon T, et al. Human brain derived neurotrophic factor (BDNF) genes, splicing patterns, and assessments of associations with substance abuse and Parkinson’s disease. Am J Med Genet B. 2005;134B:93-103
30. Gratacòs M, González JR, Mercader JP, et al. Brain-derived neurotrophic factor Val66Met and psychiatric disorders: metα-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry. 2007;61:911-922.
31. Monteleone P, Zanardini R, Tortorella A, et al. The 196G/A (val66met) polymorphism of the BDNF gene is significantly associated with binge eating behavior in women with bulimia nervosa or binge eating disorder. Neurosci Lett. 2006;406:133-137.
32. Uhl GR, Liu QR, Walther D, et al. Polysubstance abuse–vulnerability genes: genome scans for association, using 1,004 subjects and 1,494 single-nucleotide polymorphisms. Am J Hum Genet. 2001;69: 1290-1300.
33. Mottagui-Tabar S, Prince JA, Wahlestedt C, et al. A novel single nucleotide polymorphism of the neuropeptide Y (NPY) gene associated with alcohol dependence. Alcohol Clin Exp Res. 2005;29:702-707.
34. Pandey SC, Zhang H, Roy A, Xu T. Deficits in amygdaloid cAMP-responsive element-binding protein signaling play a role in genetic predisposition to anxiety and alcoholism. J Clin Invest. 2005;115:2762-2773.
35. Belfer I, Hipp H, McKnight C, et al. Association of galanin haplotypes with alcoholism and anxiety in two ethnically distinct populations. Mol Psychiatry. 2006;11:301-311.
36. Lobo DS, Kennedy JL. The genetics of gambling and behavioral addictions. CNS Spectr. 2006;11:931-939.
37. Laucht M, Becker K, Blomeyer D, Schmidt MH. Novelty seeking involved in mediating the association between the dopamine D₄ receptor gene exon III polymorphism and heavy drinking in male adolescents: results from a high-risk community sample. Biol Psychiatry. 2007;61:87-92.
38. McGeary JE, Esposito-Smythers C, Spirito A, Monti PM. Associations of the dopamine D₄ receptor gene VNTR polymorphism with drug use in adolescent psychiatric inpatients. Pharmacol Biochem Behav. 2007;86:401-406.
39. Li T, Xu K, Deng H, et al. Association analysis of the dopamine D₄ gene exon III VNTR and heroin abuse in Chinese subjects. Mol Psychiatry. 1997;2:413-416.
40. Shao C, Li Y, Jiang K, et al. Dopamine D₄ receptor polymorphism modulates cue-elicited heroin craving in Chinese. Psychopharmacology (Berl). 2006;186: 185-190.
41. Lusher J, Ebersole L, Ball D. Dopamine D₄ receptor gene and severity of dependence. Addict Biol. 2000;5:471-474.
42. Levitan RD, Masellis M, Basile VS, et al. The dopamine-4 receptor gene associated with binge eating and weight gain in women with seasonal affective disorder: an evolutionary perspective. Biol Psychiatry. 2004;56:665-669.
43. Sobik L, Hutchison K, Craighead L. Cue-elicited craving for food: a fresh approach to the study of binge eating. Appetite. 2005;44:253-261.
44. Lowe N, Kirley A, Hawi Z, et al. Joint analysis of the DRD₅ marker concludes association with attention-deficit/hyperactivity disorder confined to the predominantly inattentive and combined subtypes. Am J Hum Genet. 2004;74:348-356.
45. Bau CHD, Almeida S, Costa FT, et al. DRD₄ and DAT1 as modifying genes in alcoholism: interaction with novelty seeking on level of alcohol consumption. Mol Psychiatry. 2001;6:7-9.
46. Soyka M, Preuss UV, Hesselbrock V, et al. GABα-A2 receptor subunit gene (GABRA2) polymorphisms and risk for alcohol dependence. J Psychiatr Res. 2008;42:184-191.
47. Agrawal A, Edenberg HJ, Foroud T, et al. Association of GABRA2 with drug dependence in the collaborative study of the genetics of alcoholism sample. Behav Genet. 2006;36:640-650.
48. Dick DM, Agrawal A, Schuckit MA, et al. Marital status, alcohol dependence, and GABRA2: evidence for gene-environment correlation and interaction. J Stud Alcohol. 2006;67:185-194
49. Edenberg HJ, Foroud T. The genetics of alcoholism: identifying specific genes through family studies. Addict Biol. 2006;11:386-396.
50. Lappalainen J, Long JC, Eggert M, et al. Linkage of antisocial alcoholism to the serotonin 5-HT_1B receptor gene in 2 populations. Arch Gen Psychiatry. 1998;55:989-994.
51. O’Connor TG, Heron J, Golding J, et al. Maternal antenatal anxiety and children’s behavioural/emotional problems at 4 years. Report from the Avon Longitudinal Study of Parents and Children. Br J Psychiatry. 2002;180:502-508.
52. Van den Bergh BR, Marcoen A. High antenatal maternal anxiety is related to ADHD symptoms, externalizing problems, and anxiety in 8- and 9-year-olds. Child Dev. 2004;75:1085-1097.
53. O’Connor TG, Ben-Shlomo Y, Heron J, et al. Prenatal anxiety predicts individual differences in cortisol in pre-adolescent children. Biol Psychiatry. 2005;58:211-217.
54. Huizink AC, Mulder EJ, Buitelaar JK. Prenatal stress and risk for psychopathology: specific effects or induction of general susceptibility? Psychol Bull. 2004;130:115-142.
55. Kalinichev M, Easterling KW, Holtzman SG. Long-lasting changes in morphine-induced locomotor sensitization and tolerance in Long-Evans mother rats as a result of periodic postpartum separation from the litter: a novel model of increased vulnerability to drug abuse? Neuropsychopharmacology. 2003;28:317-328.
56. Pryce CR, Feldon J. Long-term neurobehavioural impact of the postnatal environment in rats: manipulations, effects and mediating mechanisms. Neurosci Biobehav Rev. 2003;27:57-71.
57. Sørensen HJ, Mortensen EL, Reinisch JM, Mednick SA. Early weaning and hospitalization with alcohol-related diagnoses in adult life. Am J Psychiatry. 2006;163:704-709.
58. Lyons DM, Afarian H, Schatzberg AF, et al. Experience-dependent asymmetric variation in primate prefrontal morphology. Behav Brain Res. 2002;136:51-59.
59. Ploj K, Roman E, Nylander I. Long-term effects of maternal separation on ethanol intake and brain opioid and dopamine receptors in male Wistar rats. Neuroscience. 2003;121:787-799.
60. Cruz FC, Quadros IM, Planeta Cda S, Micsek KA. Maternal separation stress in male mice: long-term increases in alcohol intake. Psychopharmacology (Berl). 2008;201:459-468.
61. Kosten TA, Zhang XY, Kehoe P. Neurochemical and behavioral responses to cocaine in adult male rats with neonatal isolation experience. J Pharmacol Exp Ther. 2005;314:661-667.
62. Moffett MC, Vicentic A, Kozel M, et al. Maternal separation alters drug intake patterns in adulthood in rats. Biochem Pharmacol. 2007;73:321-330.
63. Vazquez V, Penit-Soria J, Claudette Durand C, et al. Maternal deprivation increases vulnerability to morphine dependence and disturbs the enkephalinergic system in adulthood [published correction appears in J Neurosci. 2005;25:6024]. J Neurosci. 2005;25:4453-4462.
64. Ryu V, Lee JH, Yoo SB, et al. Sustained hyperphagia in adolescent rats that experienced neonatal maternal separation. Int J Obes (Lond). 2008;32:1355-1362.
65. Fries AB, Ziegler TE, Kurian JR, et al. Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. Proc Natl Acad Sci U S A. 2005;102:17237-17240.
66. Colvert E, Rutter M, Kreppner J, et al. Do theory of mind and executive function deficits underlie the adverse outcomes associated with profound early deprivation? Findings from the English and Romanian adoptees study. J Abnorm Child Psychol. 2008;36: 1057-1068.
67. Stevens SE, Sonugα-Barke EJ, Kreppner JM, et al. Inattention/overactivity following early severe institutional deprivation: presentation and associations in early adolescence. J Abnorm Child Psychol. 2008;36: 385-398.
68. Burton C, Lovic V, Fleming AS. Early adversity alters attention and locomotion in adult Sprague-Dawley rats. Behav Neurosci. 2006;120:665-675.
69. Marais L, van Rensburg SJ, van Zyl JM, et al. Maternal separation of rat pups increases the risk of developing depressive-like behavior after subsequent chronic stress by altering corticosterone and neurotrophin levels in the hippocampus. Neurosci Res. 2008;61:106-112.
70. Caldji C, Diorio J, Meaney MJ. Variations in maternal care in infancy regulate the development of stress reactivity. Biol Psychiatry. 2000;48:1164-1174.
71. Holmes A, le Guisquet AM, Vogel E, et al. Early life genetic, epigenetic and environmental factors shaping emotionality in rodents. Neurosci Biobehav Rev. 2005;29:1335-1346.
72. Aisa B, Tordera R, Lasheras B, et al. Effects of maternal separation on hypothalamic-pituitary-adrenal responses, cognition and vulnerability to stress in adult female rats. Neuroscience. 2008;154:1218-1226.
73. Ladd CO, Huot RL, Thrivikraman KV, et al. Long-term adaptations in glucocorticoid receptor and mineralocorticoid receptor mRNA and negative feedback on the hypothalamo-pituitary-adrenal axis following neonatal maternal separation. Biol Psychiatry. 2004;55:367-375.
74. Plotsky PM, Thrivikraman KV, Nemeroff CB, et al. Long-term consequences of neonatal rearing on central corticotropin-releasing factor systems in adult male rat offspring. Neuropsychopharmacology. 2005;30:2192-2204.
75. Kendler KS, Bulik, CM, Silberg J, et al. Childhood sexual abuse and adult psychiatric and substance use disorders in women: an epidemiological and cotwin control analysis. Arch Gen Psychiatry. 2000;57:953-959.
76. Schuck AM, Widom CS. Childhood victimization and alcohol symptoms in females: causal inferences and hypothesized mediators. Child Abuse Negl. 2001;25:1069-1092.
77. Johnson JG, Cohen P, Kasen S, Brook JS. Childhood adversities associated with risk for eating disorders or weight problems during adolescence or early adulthood. Am J Psychiatry. 2002;159:394-400.
78. Heim C, Meinlschmidt G, Nemeroff CB. Neurobiology of early-life stress. Psych Ann. 2003;33:1-10.
79. Dong M, Anda RF, Felitti VJ, et al. The interrelatedness of multiple forms of childhood abuse, neglect, and household dysfunction. Child Abuse Negl. 2004;28:771-784.
80. Mullen PE, Martin JL, Anderson JC, et al. The long-term impact of the physical, emotional, and sexual abuse of children: a community study. Child Abuse Negl. 1996;20:7-21.
81. Fergusson DM, Mullen PE. Childhood Sexual Abuse: An Evidence Based Perspective. Developmental Clinical Psychology and Psychiatry Series. Vol. 40. Thousand Oaks, CA: Sage; 1999.
82. Bulik CM, Prescott CA, Kendler KS. Features of childhood sexual abuse and the development of psychiatric and substance use disorders. Br J Psychiatry. 2001;179:444-449.
83. Magariños AM, McEwen BS, Flügge G, Fuchs E. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J Neurosci. 1996;16:3534-3540.
84. Uno H, Tarara R, Else JG, et al. Hippocampal damage associated with prolonged and fatal stress in primates. J Neurosci. 1989;9:1705-1711.
85. Gould E, Tanapat P, McEwen BS, et al. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Pro Natl Acad Sci U S A. 1998;95:3168-3171.
86. Ressler KJ, Nemeroff CB. Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety. 2000;12(suppl 1):2-19.
87. Heim C, Plotsky PM, Nemeroff CB. Importance of studying the contributions of early adverse experience to neurobiological findings in depression. Neuropsychopharmacology. 2004;29:641-648.
88. Sapolsky RM, Uno H, Rebert CS, Finch CE. Hippocampal damage associated with prolonged glucocorticoid exposure in primates. J Neurosci. 1990;10: 2897-2902.
89. Roy M, Sapolsky RM. The exacerbation of hippocampal excitotoxicity by glucocorticoids is not mediated by apoptosis. Neuroendocrinology. 2003;77: 24-31.
90. Bock J, Gruss M, Becker S, Braun K. Experience-induced changes of dendritic spine densities in the prefrontal and sensory cortex: correlation with developmental time windows. Cereb Cortex. 2005;15:802-808.
91. De Bellis MD, Keshavan MS, Spencer S, Hall J. N-acetylaspartate concentration in the anterior cingulate of maltreated children and adolescents with PTSD. Am J Psychiatry. 2000;157:1175-1177.
92. de Geus EJ, van’t Ent D, Wolfensberger SP, et al. Intrapair differences in hippocampal volume in monozygotic twins discordant for the risk for anxiety and depression. Biol Psychiatry. 2007;61:1062-1071.
93. Marinelli M, Piazza PV. Interaction between glucocorticoid hormones, stress and psychostimulant drugs. Eur J Neurosci. 2002;16:387-394.
94. de Wit H. Priming effects with drugs and other reinforcers. Exp Clin Psychopharmacol. 1996;4:5-10.
95. Sinha R, Catapano D, O’Malley S. Stress-induced craving and stress response in cocaine dependent individuals. Psychopharmacology (Berl). 1999;142: 343-351.
96. Sinha R. How does stress increase risk of drug abuse and relapse? Psychopharmacology. 2001;158: 343-359.
97. Sinha R, Fuse T, Aubin LR, O’Malley SS. Psychological stress, drug-related cues and cocaine craving. Psychopharmacology (Berl). 2000;152:140-148.
98. Heim C, Newport DJ, Heit S, et al. Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA. 2000; 284:592-597.
99. Pruessner JC, Champagne F, Meaney MJ, Dagher H. Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride. J Neurosci. 2004;24:2825-2831.
100. Petty F, Kramer G, Wilson L. Prevention of learned helplessness: in vivo correlation with cortical serotonin. Pharmacol Biochem Behav. 1992;43:361-367.
101. Watanabe Y, Sakai RR, McEwen BS, Mendelson S. Stress and antidepressant effects on hippocampal and cortical 5-HT1A and 5-HT2 receptors and transport sites for serotonin. Brain Res. 1993;615:87-94.
102. McKittrick CR, Blanchard DC, Blanchard RJ, et al. Serotonin receptor binding in a colony model of chronic social stress. Biol Psychiatry. 1995;37:383-393.
103. Wu J, Kramer GL, Kram M, et al. Serotonin and learned helplessness: a regional study of 5-HT1A, 5-HT_2A receptors and the serotonin transport site in rat brain. J Psychiatr Res. 1999;33:17-22.
104. Nilsson KW, Sjöberg RL, Damberg M, et al. Role of the serotonin transporter gene and family function in adolescent alcohol consumption. Alcohol Clin Exp Res. 2005;29:564-570.
105. Kaufman J, Yang BZ, Douglas-Palumberi H, et al. Genetic and environmental predictors of early alcohol use. Biol Psychiatry. 2007;61:1228-1234.
106. Covault J, Tennen H, Armeli S, et al. Interactive effects of the serotonin transporter 5-HTTLPR polymorphism and stressful life events on college student drinking and drug use. Biol Psychiatry. 2007;61:609-616.
107. Laucht M, Skowronek MH, Becker K, et al. Interacting effects of the dopamine transporter gene and psychosocial adversity on attention-deficit/hyperactivity disorder symptoms among 15-year-olds from a high-risk community sample. Arch Gen Psychiatry. 2007;64:585-590.
108. Tarter RE, Kirisci L, Habeych M, et al. Neurobehavior disinhibition in childhood predisposes boys to substance use disorder by young adulthood: direct and mediated etiologic pathways. Drug Alcohol Depend. 2004;73:121-132.
109. Goodman A. Addiction: definition and implications. Br J Addict. 1990;85:1403-1408
110. Goodman A. Sexual addiction. In Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Baltimore: Lippincott Williams & Wilkins; 2009:2111-2127.
111. Goodman A. Sexual addiction: nosology, diagnosis, etiology, and treatment. In: Lowinson JH, Ruiz P, Millman RB, Langrod JG, eds. Substance Abuse: A Comprehensive Textbook. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2004:504-539.