Overview Over the past decade, systematic studies from our laboratory using adolescent rhesus macaques have shown that social stress increases alcohol consumption and that during nonstressful periods, interindividual rates of alcohol consumption are positively correlated with interindividual trait-like anxiety and hypothalamic-pituitary-adrenal (HPA) axis output. HPA Axis and Alcohol To date, studies from our laboratory have shown that the strongest predictor of excessive alcohol intake is the response of the HPA Axis, with high levels of cortisol being highly predictive of alcohol intake. Dr. Christina Barr began a series of studies investigating the HPA axis and its relationship to alcohol consumption. Sons of alcoholics studied prior to alcohol dependence and withdrawal show a blunted ACTH response. In alcohol-naive macaques, a low ACTH response to intravenous alcohol is predictive of high voluntary alcohol consumption. ACTH levels are also blunted, with the degree of blunting dependent on the duration of the daily exposure (i.e., the number of days for which an animal was given access to alcohol) rather than the amount consumed each day. When the roles of early life stress and sex are considered, she found a sex-by-rearing condition interaction, such that parentally-deprived females demonstrated significantly elevated ACTH levels relative to non-stressed females and males. This effect remains even after controlling for chronicity of exposure. In addition, following acute intravenous administration of alcohol, this same sex-by-rearing condition interaction effect on ACTH is observed. While social separation from an attachment source is a potent stressor for infants with an exaggerated HPA response predicting high alcohol intake, few studies have examined the adult response to a social separation from their offspring. Plasma was taken from mothers during social separation from their infants. While the infant showed a potent HPA response, contrary to classical belief, mothers showed evidence of reduced stress when separated from their infants, showing lower plasma levels of cortisol and ACTH following chronic separation relative to baseline. Moreover, when the infant was returned, ACTH and cortisol levels returned to the significantly higher levels seen at baseline. Interestingly in the home cage, mothers with their first infant showed the highest ACTH levels, and the greatest decrease in ACTH levels during separation from their infants. These findings were exaggerated in primiparous mothers when compared to multiparous mothers. Such findings suggest that contrary to our expectations, mothers, particularly mothers of first infants, show a reduction in stress when their infants are removed from them. In our continued collaboration with NIMH and Drs. Gold and his colleagues, we exposed a group of mother-reared and a group of maternally-deprived, peer-reared male infant rhesus macaques to four consecutive, four-day social separations and monitored the changes in their cerebrospinal fluid (CSF) CRH and NPY. All infants showed progressive elevations in the CSF CRH with repeated separation. Conversely, the changes in CSF NPY concentrations diminished over repeated separations, and there was a negative correlation between the two neuropeptides. The higher CRH responses in the peer-reared infants were paralleled by increased locomotion, self-directed behavior, vocalization and behavioral withdrawal. These findings are consistent with clinical data and suggest that reciprocal changes in CRH and NPY in the brain may be implicated in the behavioral changes induced by exposure to early life adversity in primates. In a previous report, we investigated the antianxiety effects of Antalarmin, a specific CRH-1 receptor antagonist, showing that it reduced anxiety during an intruder challenge in adult males. Social separation is a potent stressor for rhesus monkeys that is thought to induce despair-like psychopathology. Given the potent HPA response to social separation and the HPA relationship to depression in humans, we sought to investigate the hormonal responses to chronic administration of Antalarmin during social separation in young monkeys. Among the behaviors assessed, environmental exploration, a behavior inhibited by stress and seldom found in monkeys exhibiting depression-like despair, was increased during Antalarmin administration. ACTH, cortisol, epinephrine, and norepinephrine were all increased during social separation and were not attenuated by Antalarmin. Such findings suggest that oral chronic administration of a specific CRH-1 receptor antagonist to rhesus monkeys does not blunt the sympathoadrenal response to stress but it does facilitate adjustment to the stress, increasing environmental exploration, a behavior that is normally suppressed during stressful events. HPA Functioning and Alcohol Studies reported by Dr. Barr in our report last year showed that acute intravenous administration of ethanol produced increases in both ACTH and cortisol relative to placebo-injected animals. In studies this year, we investigated the effect of long-term consumption patterns on HPA response. Animals were given access to a 8.4% ethanol solution for six weeks, 5 days a week for one hour each day. Blood was drawn for analysis both prior to initiation and following discontinuation of the drinking paradigm for determination of plasma levels of ACTH and cortisol. There was no difference in the levels of ACTH and cortisol after chronic oral ethanol intake and one week following discontinuation of the alcohol solution (withdrawal). Although acute exposure to ethanol produces increases in HPA-axis activity in our colony of animals, there were no significant changes in it after chronic, voluntary intake. Continued Investigation of Long-Term Access to Alcohol During the past year, we began a series of studies designed to investigate of situational and temperamental variables affecting alcohol intake. While studies show that stress can increase alcohol intake, further analysis of day-to-day drinking patterns in subjects that are allowed constant, 7-days week alcohol intake, showed that when there was a possibility that the subjects might require an active coping response (e.g., during days of home cage aggression or on days when they were captured), rates of alcohol decreased, a finding consistent with studies reviewed by Pohorecky in her comprehensive review of the effects of stress on alcohol intake.