Depressive disorders: toward a unified hypothesis.

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.

Effects of chlorpromazine on the vertical chamber syndrome in rhesus monkeys.

In an attempt at social rehabilitation, chlorporomazine was given to three groups of rhesus monkeys that had been confined to the vertical chambers apparatus early in their development. Previous studies have shown that such periods of deprivation produce severe deficits in social behavior. There were no substantial beneficial effects of chlorpromazine treatment; however, there was a notable amount of spontaneous improvement seen in all three groups. We discuss these data in terms of their implications for the use of the vertical chamber as a tool in experimental research of psychopathological disorder.

Overview of recent research in depression. Integration of ten conceptual models into a comprehensive clinical frame.

Disciplinary fragmentation and nosological and semantic controversies have obscured the impressive advances made in the area of depressive disorders during the past decade. This article is an attempt to translate data derived from psychodynamic, sociobehavioral, and neurobiologic research into a clinically meaningful framework. We review ten models of depression with special emphasis on newer models supported by empirical and experimental studies, and present a new model, which incorporates and synthesizes findings from different schools. Depressive illness is conceptualized as the feedback interaction of three sets of variables at chemical, experiential, and behavioral levels with the diencephalon serving as the field of action.

Effects of imipramine treatment of separation-induced social disorders in rhesus monkeys.

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.

Mother-infant separation in rhesus monkeys as a model of human depression. A reconsideration.

Nineteen rhesus monkeys between the ages of 5.9 and 8.5 months were separated from their mothers in five different studies. While in two of the studies, data indicated behavioral responses roughly parallel to Bowlby's protest-despair response to maternal separations, data across all five studies were sufficiently variable to bring this technique into serious question as a reliable and predictable animal model for neurobiologic and rehabilitative studies.

Biogenic amine activity in response to fluoxetine and desipramine in differentially reared rhesus monkeys.

BACKGROUND: It has been hypothesized that adverse early experience may be a mechanism by which children become vulnerable to later psychopathology via alteration of neurochemical or hormonal systems associated with such disorders. Such effects may in turn affect later responses to pharmacologic agents that act on these systems. METHODS: In this study, 18 mother-reared (MR) and 18 peer-reared (PR) rhesus monkeys experienced six 1-week separations from cagemates interspersed with 1-week reunions, while housed in like-reared groups of 3. Within rearing groups, equal numbers of animals received either fluoxetine (2 mg/kg), desipramine (5 mg/kg) or placebo delivered daily beginning 4 weeks before the first separation. Levels of norepinephrine (NE), the NE metabolite MHPG, the dopamine metabolites DOPAC and HVA, and the serotonin metabolite 5HIAA were measured in CSF samples collected approximately every 2 to 3 weeks during these procedures. RESULTS: Following treatment, DMI increased NE and decreased MHPG in the DMI-treated groups, while 5HIAA was decreased in the fluoxetine-treated groups following treatment. The increase in NE was followed by a sharp decline over the course of treatment, which was accompanied by an increase in MHPG. The rearing groups did not show a differential response to the drug treatments, and the separation manipulation itself had few effects. The mother-reared group showed higher levels of NE and DOPAC over all samples and higher levels of HVA in most samples. CONCLUSIONS: These rearing effects on biogenic amine activity were observed even in the presence of pharmacologic treatments that effectively altered the activity of these systems, and are consistent with previous findings from the same subject. The higher NE values observed in mother-reared infants over separations and reunions may have been due to higher basal levels of NE than peer-reared monkeys or to greater responsiveness to the stress of repeated social disruption or both. These findings agree with other primate studies showing that rearing differences persist beyond the infancy period and add to growing evidence of the important influence of the early social environment on neurobiologic development in primates.

Rearing experience and biogenic amine activity in infant rhesus monkeys.

In this report we present evidence that early social experience influences aspects of the function of brain biogenic amine systems, most notably the noradrenergic system. Biogenic amine activity was studied in mother- vs. peer-reared monkey infants over the first 6 months of life and in response to two housing transitions. Norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) levels in cerebrospinal fluid (CSF) were measured. Peer-reared monkeys showed significantly higher CSF levels of norepinephrine and MHPG than mother-reared animals over early development, but showed an attentuated NE response to separation and group formation compared to mother-reared animals. Peer-reared monkeys showed a greater developmental decline in 5-HIAA levels than mother-reared monkeys. There were no rearing effects for DOPAC or HVA over early development; however, peer-reared monkeys showed significantly lower HVA and DOPAC concentrations at 6-8 months of age. The results add to evidence for the influence of primate mothers on the psychobiological development of central nervous system neurotransmitter systems in their infants, and suggest that the noradrenergic system is among the more sensitive of these to early experience.

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.

Animal models of schizophrenia.

The authors review some general issues concerning the development and use of animal models of schizophrenia and present a summary of the criteria necessary for validating models. They also describe some of the major attempts at creating animal models of schizophrenia, including drug and nondrug methods. They comment on the etiologic, phenomenologic, and treatment relevance of the various systems and suggest approaches that might produce improved animal models of schizophrenia.

Diazepam treatment of socially isolated monkeys.

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.

A longitudinal study of the effect of different social rearing conditions on cerebrospinal fluid norepinephrine and biogenic amine metabolites in rhesus monkeys.

The purpose of this study was to determine whether disruption of early social attachment alters the activity of brain biogenic amine systems in rhesus monkeys (Macaca mulatta). Male rhesus monkey infants were deprived of maternal interaction, peer interaction, or both, during the first 22 months of life. Cerebrospinal fluid (CSF) was collected under rigorously controlled conditions approximately every month and assayed for levels of norepinephrine (NE), its major metabolite, and the metabolites of dopamine and serotonin. Mother-Deprived infants had lower levels of CSF NE than Mother-Reared infants. Mother-Deprived infants also failed to develop the same pattern of intercorrelations between compounds and month-to-month stability in levels of neurotransmitter and metabolites in CSF as the Mother-Reared infants. Finally, there were changes in CSF NE levels associated with social separation and social group formation. The brain NE system appears to be sensitive to changes in the social environment. Its level of activity, as reflected in levels of NE in CSF, appears to depend on both the prevailing social environment and the prior rearing environment.

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 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.

Mutual antagonism of behavioral effects of TRH and thiobarbiturate on an operant task in rhesus monkeys.

Similar excitatory or depressant response rate dependent effects on monkeys responding on a variable interval reinforcement schedule were observed following intravenous administration of either thyrotropin releasing hormone (TRH) or thiobarbiturate. However, these agents were mutally antagonistic when given together even though the response rate altering effects of each agent were in the same direction. These findings establish an additional behavioral effect of exogenously administered TRH in primates and suggest that barbiturates might alter behavior in part through an interaction with brain TRH receptive mechanisms.

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.

Effects of alcohol on cerebrospinal fluid norepinephrine in rhesus monkeys.

Alcohol (1-3 g/kg) significantly increased the concentration of cerebrospinal fluid (CSF) norepinephrine (NE) in rhesus monkeys. This effect is consistent with the previously demonstrated activational and possible antidepressant effect of low doses of alcohol. The greatest increase was observed in subjects with low baseline levels of CSF NE. Individual differences in activation or euphoria could be related to differential increases in CSF NE following alcohol consumption.

Effects of alcohol on the despair response to peer separation in rhesus monkeys.

In humans, alcoholism and depression are often interrelated. This study examines the effects of alcohol on peer separation-induced despair in rhesus monkeys, a proposed nonhuman primate model of depression. Alcohol, at three different dose levels, or placebo was administered to rhesus monkeys undergoing repeated peer separation. Low-dose alcohol (1 g/kg/day) decreased separation-induced despair, whereas high-dose alcohol (3 g/kg/day) exacerbated the despair response as compared to placebo. This biphasic effect of alcohol on the despair response may be analogous to similar effects of alcohol on depression in humans.

Long-term chlorpromazine in rhesus monkeys: production of dyskinesias and changes in social behavior.

The daily administration of chlorpromazine (CPZ) in doses of 8--40 mg/kg over 113 weeks to four rhesus monkeys produced dyskinesias and alterations in social behavior. General activity and social interactions were reduced by CPZ treatment but social aggression was elevated during initial drug administration. These behaviors returned to normal when treatment was discontinued. Dyskinesias appeared during CPZ treatment, and two striking ones, gravel mouth and hand gesture, persisted for 12 weeks after drug withdrawal. These results indicate that dyskinesias which share major features of human tardive dyskinesia can be produced in nonhuman primates by long-term CPZ treatment.

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 microgram/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) (greater than 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 by disturbances in motor function. Urinary MPHG output does not reflect depletions of brain NE in this species.

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.

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.