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A series of neuroanatomic analyses have been undertaken to identify potential neuropathological changes seen in monkeys exposed to early social deprivation, which leads to psychopathology, inappropriate responses to stress and appetitive disorders. The animals used in this study were either socially reared or maternal- and peer-deprived. Within this framework, the distribution and density of noradrenergic (and adrenergic) varicosities was assessed in the hypothalamic paraventricular nucleus of rhesus monkeys using dopamine-beta-hydroxylase immunohistochemistry combined with laser scanning microscopy. Quantitative analysis of dopamine-beta-hydroxylase-immunoreactive varicosity density within magnocellular and parvicellular regions revealed no significant differences between rearing conditions, suggesting that this chemically identified afferent input to the paraventricular nucleus was not affected by the early environmental insult of social deprivation. The apparent lack of vulnerability of the paraventricular nucleus to differential rearing conditions contrasts with the neuropathological changes observed in several discrete brain regions.

Social deprivation during early postnatal life has profound and long-lasting effects on the behavior of primates, including prolonged and exaggerated responses to stress as well as impaired performance on a variety of learning tasks. Although the cellular changes that underlie such alterations in behavior are unknown, environmentally induced psychopathology may involve morphologic or biochemical changes in select neuronal populations. The hippocampal formation of both socially deprived and socially reared prepubescent rhesus monkeys was selected for immunocytochemical investigation because of its association with the behavioral stress response and learning. Immunocytochemical analysis using antibodies specific for the neurofilament protein triplet was performed since these proteins are modified within degenerating neurons in a variety of neurodegenerative disorders. Results from optical density measurements indicate an increase in the intensity of non-phosphorylated neurofilament protein immunoreactivity in the dentate gyrus granule cell layer of socially deprived monkeys in comparison with that of socially reared animals, suggesting that early social deprivation may result in an increase in the amount of non-phosphorylated neurofilament protein in these cells. This phenotypic difference in dentate granule cells between differentially reared monkeys supports the notion that specific subpopulations of neurons in brain regions that subserve complex behaviors may undergo long-term modifications induced by environmental conditions. Furthermore, the data suggest that constitutive chemical components related to structural integrity may be as susceptible to early environmental manipulations as the more traditionally viewed measures of cellular perturbations, such as neurotransmitter dynamics, cell density and the establishment of connectivity. The observed modifications may serve as an anatomical substrate for behavioral abnormalities that persist in later life.

Social separation is a risk factor for major depressions that can be modeled in nonhuman primates. Changes in central monoamine neurotransmission are also likely to be involved in major depression. This study examined the relationship between separation-induced depressive-like behavior and central monoamine neurotransmitter changes in rhesus monkeys. Measures of cerebrospinal fluid (CSF) norepinephrine (NE), 5-hydroxyindoleacetic acid (5HIAA), and homovanillic acid (HVA) were used to assess the neurobiological impact of social separation and drug treatments alone or in combination. alpha-Methyl-p-tyrosine exacerbated, and fusaric acid ameliorated, the depressive-like response to separation. Probenecid-induced accumulations of HVA and 5HIAA reflected changes in behavior, but were not consistently affected by drug treatment. In contrast, pretreatment CSF NE was comparatively stable across repeated sampling, and drug-induced changes in this measure were correlated with changes in behavior. Low CSF NE, whether drug-induced or naturally occurring, was associated with a more severe depressive-like response to separation.

Four rhesus monkeys were reared for the first eight months of life in total social isolation. One animal died during this period; the three remaining subjects were treated with diazepam in an isolation chamber, in their home cages, and in a playroom testing situation. Diazepam significantly decreased the self-disturbance behaviors of two subjects, and there was even the appearance of some social behaviors, although they were limited and not of the same quality as in nonisolated subjects. The authors discuss the implications of the data for understanding the significance of the social isolation syndrome in monkeys as a model for human psychoses.

Two groups of young rhesus monkeys were subjected to repetitive peer separations, a procedure that has been shown to produce depressivelike reactions in infant monkeys. Midway through the procedure one group was treated with the antidepressant imipramine hydrochloride, the other with a saline placebo. In comparison with placebo treatment, the imipramine treatment yielded significant behavioral improvement in a form and with a time course similar to that seen when the drug is given clinically to human depressives. We discuss the implications of the findings.

Social deprivation of rhesus monkeys in infancy results in increased sensitivity to psychotic-like behavioral effects of low doses of d-amphetamine given 2-3 years later. These behavioral effects are associated with increased levels of CSF norepinephrine. These data suggest that social developmental factors could be partially responsible for variation in neurochemical responses and long-lasting differential sensitivity of primates to the psychosis-inducing effects of d-amphetamine.

This study used 16 socially reared juvenile rhesus monkeys as subjects to test the hypothesis that social separation promotes alcohol consumption in this species. In the first part of the study, 12 monkeys were intermittently separated from their social groups, while 4 were separated before the beginning of the study and remained continuously separated. Refrigerated water or aspartame-sweetened water (vehicle) containing 6% alcohol (w/v) were presented after 4.5 h of fluid deprivation. Intermittently separated monkeys drank more alcohol during separation than when they were socially housed, and more than the continuously separated monkeys. Stable individual differences in consumption rate developed over repeated separations. These differences were not correlated with consumption of refrigerated water or vehicle, or with differential behavioral (locomotor) responses to social separation. This suggested that some monkeys were predisposed to drink more alcohol than others. The second part of the study determined whether established alcohol/vehicle consumption rates for all 16 monkeys were altered when the monkeys were not water deprived, and then when water and the vehicle were available at the same time as alcohol/vehicle. Among monkeys that drank the most (mean of 2.4 g/kg/h) and the least (mean of 0.8 g/kg/h), alcohol consumption was not affected. These results, combined with previous reports, suggest a neurobiological linkage between genetically based social attachment mechanisms, social stressors, and vulnerability to alcohol abuse and addiction in primates.