William T. McKinney

Depressive Disorders: Toward a Unified Hypothesis Clinical, experimental, genetic, biochemical, and neurophysiological data are integrated

Our scientific understanding of psychiatric syndromes, including the phenomena of depression, has been hampered because of: (i) the use of metapsychological concepts that are difficult to test; (ii) methodological and linguistic barriers that prevent communication among psychoanalysts, behaviorists, experimental psychologists, and psychiatrists; and (iii) the reluctance of psychiatrists to accept animal models as possible approximations of certain aspects of human psychopathology. We have attempted to demonstrate that the animal models simulate some of the central features of clinical depression (for example, helplessness and object loss), thereby allowing one to rigorously investigate them from developmental, behavioral, and biochemical perspectives. The object loss model, as a concrete version of a metapsychological-psychoanalytic concept, has enabled primatologists to study the disruption of an attachment bond. The behavioral model accommodates this concept to a broader generalization: loss of reinforcement or loss of control over reinforcement. We have reviewed the evidence that these processes involve the diencephalic centers of reward or reinforcement, thereby permitting integration of the psychoanalytical and behavioral formulations with the biochemical hypotheses. Also, we have presented data strongly suggesting that the breaking of an attachment bond in the primate represents significant loss of reinforcement that induces helplessness and disrupts motivated behavior. Finally, we have argued that the depressive syndrome could be caused by interactions of genetic, chemical, developmental, and interpersonal factors, all of which impinge on the diencephalic centers of reinforcement.

Interactions of pharmacological agents which alter biogenic amine metabolism and depression: An analysis of contributing factors within a primate model of depression

The observation that the biogenic amine depleting agent, reserpine, could induce severe depression in a small proportion of the patients treated with it has proved to be seminal finding in what is now a much larger field of research relating the function brain biogenic amine systems to emotions and behavior. A review of the human reserpine literature suggests, however, that factors other than pharmacologically produced alterations in brain biogenic amine metabolism must have been critical determinants of the eventual mood alterations observed in conjunction with reserpine treatment. While some of these factors, such as previous history of depression, ongoing psychosocial and environmental stress, can be intuitively identified, there are practical as well as ethical problems involved in actually testing the relative contribution of these factors in precipitating human depression and thereby determining their importance in a quantitative fashion. In the present paper we have attempted to examine, in a nonhuman primate model of depression, the degree to which factors such as prior rearing condition, repeated peer separation, and housing environment can intact with the behavioral effects produced by biogenic amine depleting agents. Major emphasis will be placed on studies utilizing alpha-methyl-para-tyrosine, an inhibitor of tyrosine hydroxylase, to ostensively reduce levels of the catecholamine neurotransmitters norepinephrine and dopamine. The results of these studies provide quantitative estimates, in terms of dose-effect relationships, of the degree to which a number of factors can combine to produce despair-like behavior in rhesus monkeys. These data may be of practical importance in evaluating the contribution of similar factors to the precipitation of human depression. Analysis of some of the existing literature relating alterations in behavior to changes in biogenic amine metabolism in animals suggests that there are important differences between rodent and primate species. These differences, when fully established, may indicate that additional research examining the mechanisms whereby modest alterations in biogenic amine metabolism can interact with environmental and social stress is needed.

Hypersensitivity to d-amphetamine several years after early social deprivation in rhesus monkeys

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.

Corticotropin-releasing factor administered intraventricularly to rhesus monkeys ☆

Synthetic ovine corticotropin-releasing factor (CRF) administered intraventricularly (ICV) to rhesus monkeys resulted in endocrine and behavioral changes. At doses of 20 and 180 micrograms, CRF stimulated the pituitary-adrenal axis in four chair-restrained monkeys. These monkeys showed concomitant increases in arousal. To study these animals in a less restrictive setting, three of the monkeys later received CRF ICV (20 and 180 micrograms) in their home cages. At the 180-micrograms dose the monkeys exhibited a combination of huddling and lying down behavior. These behavioral effects did not seem to be due to alterations in blood pressure.

Cerebrospinal fluid measures of neurotransmitter changes associated with pharmacological alteration of the despair response to social separation in rhesus monkeys

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.

Effects of social deprivation in prepubescent rhesus monkeys: immunohistochemical analysis of the neurofilament protein triplet in the hippocampal formation

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.

Use of 6-hydroxydopamine to deplete brain catecholamines in the rhesus monkey: effects on urinary catecholamine metabolites and behavior

The purpose of this study was to determine: 1) whether 6-hydroxydopamine (6-OHDA), previously shown to deplete brain catecholamines (CA) in rodents, depletes brain CA in rhesus monkeys; 2) whether depletion of brain CA produces changes in behavior; and, 3) whether urinary output of 3-methoxy-4-hydroxyphenylglycol (MHPG) reflects brain norepinephrine (NE) depletions.Repeated intracerebroventricular (ICV) injection of 6-OHDA (N=20; 15.5–73.3 mg/subject) produced chronic changes in social behavior and, at higher dosages, reduced output of urinary MHPG. However, 4 weeks after the last ICV 6-OHDA injection, urinary MHPG excretion returned to baseline values and whole brain CA content was not reliably different from control.A single treatment with 6-OHDA microinjected into the substantia nigra (SN) (N=12; 120–240 μg/subject) produced chronic whole brain depletions of brain CA without depleting serotonin. Reductions in brain CA were associated with a specific set of motor behaviors, aphagia, and adipsia. SN 6-OHDA produced greater brain NE depletions than ICV 6-OHDA, but urinary MHPG output was not reduced. SN 6-OHDA treated subjects showed chronic changes in social behavior and were more sensitive to the operant response rate decreasing effects of alpha-methyl-para-tyrosine (AMPT) than control subjects. Subjects with the largest depletions of brain dopamine (DA) (>90%) were hypokinetic, rigid, and had a distal limb tremor.These results show that SN but not ICV injection of 6-OHDA can deplete brain CA in the rhesus monkey. The most prominent behavioral changes were characterized bydisturbances in motor function. Urinary MPHG output does not reflect depletions of brain NE in this species.

Social separation increases alcohol consumption in rhesus monkeys

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 behavioural (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.

Associated endocrine, physiological and behavioral changes in rhesus monkeys after intravenous corticotropin-releasing factor administration.

The intravenous (IV) administration of synthetic ovine corticotropin-releasing factor (CRF) (10 and 125 micrograms/kg) to chair restrained rhesus monkeys stimulated the pituitary-adrenal axis. At these doses, increases in plasma concentrations of adrenocorticotropic hormone (ACTH) and cortisol were associated with blood pressure decreases and behavioral effects. These data demonstrate that synthetic ovine CRF (10 and 125 micrograms/kg) administered IV to the rhesus monkey results in associated endocrine, physiological, and behavioral changes.

Evidence for heritability of biogenic amine levels in the cerebrospinal fluid of rhesus monkeys

Susceptibility to several human psychopathological disorders is under partial genetic influence, and many of these disorders have biological correlates that may form part of the basis of this vulnerability. In humans, alterations in cerebrospinal fluid (CSF) metabolite levels of the amine transmitters norepinephrine, dopamine, and serotonin have been associated with several forms of psychopathology, and altered levels of these metabolites have been found in healthy probands with a familial history of such illnesses. We report evidence for heritability of CSF levels of biogenic amine measures in rhesus monkeys, Macaca mulatta. In a pilot study of 54 monkeys with known pedigrees, significant differences among sire families were found for CSF levels of norepinephrine (p = 0.04), homovanillic acid (p = 0.02), and 5-hydroxyindoleacetic acid (p = 0.04). These data indicate that variation in bioaminergic measures is associated with pedigree, and that model systems incorporating both genetic and environmental factors can contribute to the understanding of the function of aminergic systems implicated in vulnerability to psychopathology.