These data suggest a potential interaction between serotonin transporter gene variation and early experience in vulnerability to alcoholism.

In a variety of species, development of attachment to a caregiver is crucial for infant survival and partly mediated by the endogenous opioids. Functional mu-opioid receptor gene polymorphisms are present in humans (OPRM1 A118G) and rhesus macaques (OPRM1 C77G). We hypothesized that rhesus infants carrying a gain-of-function OPRM1 77G allele would experience increased reward during maternal contact and would, therefore, display increased measures of attachment. We collected behavioral data from rhesus macaques (n ‫؍‬ 97) during early infancy and at 6 months of age, across four cycles of maternal separation (4 days) and reunion (3 days). Animals were genotyped for the OPRM1 C77G polymorphism, and the effects of this allele on attachmentrelated behaviors were analyzed. Infants carrying the G allele exhibited higher levels of attachment behavior during early infancy. During prolonged periods of maternal separation, although infant macaques homozygous for the C allele exhibited decreases in their levels of distress vocalization with repeated separation, this response persisted in G allele carriers. The OPRM1 77G allele also affected social preference during reunion. C/G infants spent increasing amounts of time in social contact with their mothers as a function of repeated separation and were less likely to interact with other individuals in the social group, a pattern not observed among infants with the C/C genotype. These findings suggest a role for OPRM1 variation in the expression of attachment behavior in human subjects, especially as a function of separation from the caregiver.genetic ͉ rhesus macaque ͉ mother-infant bond ͉ C77G ͉ A118G

A polymorphism in the human serotonin transporter gene promoter (5-HTTLPR) is associated with anxiety and increased risk for developing depression in the face of adversity. Here, we report that among infant rhesus macaques, an orthologous polymorphism (rh5-HTTLPR) interacts with adversity in the form of peer rearing to influence adrenocorticotropic hormone (ACTH) response to stress and, further, that this interaction is sexually dichotomous. ACTH responses to separation are higher in l͞s than in l͞l males. In females, however, it is only among those with a history of adversity that the s allele is associated with increased ACTH responses to stress. Of interest, peer-reared animals, in particular females carrying the s allele, also exhibit lower cortisol responses to stress, a pattern that has been recognized in association with certain stress-related neuropsychiatric disorders. By extension, our findings suggest the intriguing possibility that human females carrying the 5-HTTLPR s allele could be more vulnerable to the effects of early adversity. This interactive effect may underlie the increased incidence of certain stress-related disorders in women.

This study investigated the effects of early exposure to variable parenting style and infant abuse on cerebrospinal fluid (CSF) concentrations of monoamine metabolites and examined the role of monoaminergic function in the intergenerational transmission of infant abuse in rhesus monkeys (Macaca mulatta). Forty-three infants reared by their biological mothers and 15 infants that were cross-fostered at birth and reared by unrelated mothers were followed longitudinally through their first 3 years of life or longer. Approximately half of the infants were reared by abusive mothers and half by nonabusive controls. Abused infants did not differ from controls in CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), or 3-methoxy-4-hydroxyphenylgycol (MHPG). Abused infants, however, were exposed to higher rates of maternal rejection, and highly rejected infants had lower CSF 5-HIAA and HVA than low-rejection infants. The abused females who became abusive mothers in adulthood had lower CSF 5-HIAA than the abused females who did not. A similar trend was also observed among the cross-fostered females, suggesting that low serotonergic function resulting from early exposure to high rates of maternal rejection plays a role in the intergenerational transmission of infant abuse.

These findings demonstrate that the rhesus macaques' equivalent of the OPRM1A118G variant is associated with increased alcohol response, consumption, and preference. Our results reveal effects of the OPRM1C77G genotype to be male-restricted or more marked among male macaques. This is of interest, given the fact that early-onset type II alcoholism is more common among men and that, among addicted individuals, men are more responsive to mu-opioid receptor blockade.

These findings suggest that low CSF 5-HIAA concentrations quantified early in life is a powerful biological predictor of future excessive aggression, risk taking, and premature death among nonhuman primate males.

Thirteen group-living rhesus macaque females that were crossfostered shortly after birth were followed longitudinally until they gave birth for the first time. Their maternal behavior was compared to the behavior of both their foster and their biological mothers, and analyzed in relation to the cerebrospinal fluid (CSF) concentrations of serotonin, dopamine, and norepinephrine metabolites (5-HIAA, HVA, and MHPG) measured in their second year of life. Crossfostered females were similar to their foster mothers in their rates of maternal rejection and grooming, whereas their contact-making behavior was more similar to that of their biological mothers. Crossfostered females with lower CSF concentrations of 5-HIAA exhibited higher rates of maternal rejection than females with higher CSF 5-HIAA. In a related article (Maestripieri et al., 2006), we reported that rhesus infants reared by highly rejecting mothers had lower CSF 5-HIAA in their first 3 years of life. Taken together, these findings suggest that early social experience and experience-related long-term changes in serotonergic function may play a role in the intergenerational transmission of maternal rejection from mothers to daughters. ß 2007 Wiley Periodicals, Inc. Dev Psychobiol 49: 165-171, 2007.

Corticotropin-releasing factor (CRF), encoded by the CRH gene, is a key integrator of stress responses, and, as such, CRH gene variation may contribute to individual differences in susceptibility to stressrelated pathology. In rhesus macaques, a single nucleotide polymorphism (SNP) is found within the CRH promoter (؊248C3 T). Here, we assessed whether this variant influenced stress responding and, because increased CRF system activity drives alcohol drinking in rodents, we examined whether it predicted voluntary alcohol consumption as a function of prior stress exposure. Using a hypothalamic nuclear extract, we showed that the ؊248 T allele resulted in increased DNA protein interactions relative to the C allele. In vitro, the T allele resulted in CRH promoter activity that was higher following both stimulation with forskolin and treatment with dexamethasone. Endocrine and behavioral responses to social separation stress (release of ACTH and cortisol, and suppression of environmental exploration, respectively) were higher among carriers of the T allele, particularly among those exposed to early adversity in the form of peer rearing. We also found that T allele carriers with a history of early life adversity consumed more alcohol in a limited-access paradigm. Our data suggest that CRH promoter variation that confers increased stress reactivity increases the risk for alcohol use disorders in stress-exposed individuals.corticotropin-releasing factor ͉ CRH promoter C orticotropin-releasing factor (CRF or CRH), encoded by the CRH gene, is a key integrator of stress adaptation. In response to stress, extrahypothalamic and hypothalamic CRF systems act in concert to mount adaptive behavioral, autonomic, and endocrine responses (1). In the adrenal gland, secretion of glucocorticoids is stimulated by adrenocorticotropic hormone (ACTH), which is released from adenohypophyseal corticotrophs in response to CRF (2). Glucocorticoids then interact with specific cytosolic receptors (glucocorticoid receptors, or GR) in central and peripheral tissues (3), enabling lifepreserving adaptation to stress. In parallel, release of CRF from extrahypothalamic brain regions, such as the locus coeruleus, BNST, and amygdala, mediate autonomic and behavioral responses to stress (4) that underlie vigilance, fear, and emotionality (5-7).The CRF system is critical for survival, but chronic overactivity can lead to stress-related pathologies (8-10). Dysregulation of this system has been linked to a variety of stress-related psychiatric disorders, including depression, PTSD, and alcohol dependence (11)(12)(13)(14). Studies in both non-primate and primate species have shown that an up-regulated CRF system can produce anxiety-and/or depression-like phenotypes (15-18), and rodent studies show that it leads to escalated alcohol drinking (19)(20)(21)(22)(23). Based on these findings, CRF1 antagonists have been proposed for the treatment of stress-related disorders, including alcohol dependence (24, 25). Genetic variation that drives further recruitment o...