Early Infant Predictors of Later Behavior and Adult Alcohol Consumption Type 1 alcoholics are typically thought to consume alcohol to self-medicate their anxiety and stress A principal measure of anxiety and fear in young macaques is distress vocals, most often exhibited by immature monkeys. Work in the laboratory by Dr. Becker correlated distress vocals obtained from infant PR and MR monkeys in year one (Y1?at about month 8) and juveniles in year two (Y2?at about month 18) of life under resting and stressful conditions. In Y1, the mean number of distress vocalizations measured during the initial acute phase of a one-week separation was positively correlated with distress vocals during the rest of the 5-day separation. Distress vocalizations that occurred early in the separation, during the acute phase in Y1 were positively correlated with those measured in Y2 but only for MR infants. Interindividual differences during the acute phase in Y1 in plasma cortisol were correlated with distress vocalizations, although more so for MR than PR monkeys. Given these findings, Dr. Becker began an investigation of neonatal infants to assess the developmental pathway of these vocalizations. Our results thus far show that vocalizations produced at 14 days of age are positively correlated with those at 30 days of age, and at day 30 is there a positive relationship between the amount of vocalizations produced and levels of plasma cortisol. Work this year will extend these findings to assess early distress vocals as predictors or alcohol consumption in the nonhuman primate. Characterization of other Species The bonnet macaque, while similar in size, is temperamentally the antithesis of rhesus macaque, showing placid, friendly gregarious interactions. They provide an excellent test to see if species temperament is related to alcohol consumption. In collaboration with Dr. Mark Laudenslager, we found that bonnet macaques were similar to the rhesus drinking modest levels of alcohol, but unlike the rhesus bonnets seldom showed aggression following alcohol intake. Biochemical Correlates of Behavior, Alcohol Intake, and Reproductive Outcome In last year?s report, we reported that males with low CSF 5-HIAA concentrations sired fewer offspring than males with high 5-HIAA and that this was not a result of differential reproductive potential (i.e., they did not differ in sperm characteristics). Studies by Dr. Newman of male macaques, demonstrated that monoamines other than serotonin may also play a role in this differential reproductive activity, with high CSF concentrations of the dopamine metabolite, HVA, predicting low offspring production, although this failed to reach a traditional level of significance. This type of study has largely been possible because of Dr. Newman?s recent discovery of new macaque genotypes that have made paternity testing more accurate, and his unique studies that estimate the rate of error in genotypes, as well as the cause for such errors. By conducting up to ten PCR replicates within a subset of the animals used for paternity testing, he has identified loci that tend to produce inconsistent genotypes that would not normally be detected with one or even two replicates. Using this same CSF HVA data, Dr Newman investigated the relationship of HVA with voluntary alcohol consumption, finding that independent of rearing, subjects with high HVA levels consumed more alcohol than those with low CSF HVA. Dr. Christina Barr began a series of studies investigating the LHPA axis it relationship to alcohol consumption. In sons of alcoholics, a blunted ACTH response is also observed, even prior to alcohol dependence and withdrawal. In her studies of rhesus macaques ACTH is blunted, but the degree of blunting appears to be 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, we have demonstrated a sex by rearing condition interaction, such that females exposed to early life stress demonstrate significantly elevated ACTH levels relative to non-stressed females and males. This effect remains after controlling for chronicity of exposure. In addition, the same pattern is observed after acute intravenous administration of alcohol. Dr. Barr has also continued our studies of intrinsic sensitivity to alcohol, serotonin, and aggression. Low CSF levels of 5-HIAA and decreased sensitivity to alcohol are independently associated with aggression following intravenous administration of alcohol. Because intoxicated animals would be less able to exhibit motor behaviors characteristic of highly aggressive animals, we also considered each of the behaviors (open mouth threat, bark, lunge, and head-bob) separately. When compared to monkeys that were heavily intoxicated, behaviors such as lunges were no more frequent in animals that showed minimal intoxication, suggesting that this difference in aggression is not simply a product of impaired motor skills. In our continued collaboration with NIMH and Drs. Gold and Habib, we administered the CRH 1 antagonist antalarmin to monkeys during a study of alcohol consumption. While it did not decrease overall alcohol consumption in all of the monkeys, it did decrease alcohol in the monkeys whose consumption was excessive. As a follow-up of our study in monkeys looking at the effect of central testosterone and aggression, we initiated a collaboration with ?sa Westrin and his colleagues at the Lund University Hospital in Sweden to assess the relationship between testosterone and behavior pathology. In general, the patients we studied had lower CSF testosterone levels than aggressive violent patients investigated in other studies. Surprisingly, patients with depression or dysthymia showed higher CSF testosterone levels than the rest. Among patients with axis II, cluster B personality disorders high testosterone was correlated with high irritability, and verbal aggression, and low social desirability. CSF testosterone levels were lower in patients who attempted suicide, possibly because of the stress experienced through a suicide attempt, although this needs to be investigated further.
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