Depression in infant monkeys separated from their mothers.

The mothers of four pigtail (Macaca nemestrina) infants living in a group were removed for 4 weeks. All infants reacted initially with agitation. Three of the four infants then became severely depressed. The depression lasted about a week and was strikingly similar to the "anaclitic depression" of human infants who lost their mothers. When they were reunited, all four dyads showed a marked and prolonged intensification of the mother-infant relationship.

Clinical improvement with fluoxetine therapy and noradrenergic function in patients with panic disorder.

BACKGROUND: Central noradrenergic (NA) dysregulation has provided a major theoretical framework for understanding the pathogenesis of panic disorder (PD). Using clonidine, an alpha 2-adrenergic receptor agonist, as a probe of NA function, we investigated the hypothesis that the antipanic efficacy of the selective serotonin reuptake inhibitors may be associated with normalization of a putatively dysregulated NA system. METHODS: We report further analyses on data from 17 subjects with PD and 16 healthy volunteers who underwent measurement of the plasma NA metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) immediately before and after oral clonidine administration. Thirteen patients with PD were rechallenged after 12 weeks during open fluoxetine hydrochloride treatment using the same clonidine paradigm; 13 healthy volunteers were rechallenged at 12 weeks, not having received treatment between challenges. RESULTS: Patients with PD, compared with healthy volunteers, have markedly elevated plasma MHPG volatility during the first clonidine challenge. Volatility describes the magnitude of within-subject plasma MHPG oscillatory activity as assessed by the root of the mean square successive difference. A greater degree of clinical global improvement was predicted by a greater magnitude of basal MHPG reduction with fluoxetine treatment. Antipanic response to fluoxetine was accompanied by a significant decrease of MHPG volatility to volunteer levels. Volunteer MHPG volatility remained unchanged from the first to second clonidine challenge. CONCLUSIONS: Further evidence is provided for the hypothesis of NA dysregulation in PD as reflected by elevations of within-subjects plasma MHPG volatility during clonidine challenge. Effective selective serotonin reuptake inhibitor-antipanic treatment in this clinical sample was paralleled by normalization of dysregulated NA function.

Cerebrospinal fluid concentrations of somatostatin and biogenic amines in grown primates reared by mothers exposed to manipulated foraging conditions.

BACKGROUND: In an earlier study, infant primates were nursed by mothers randomly assigned to variable foraging demand (VFD) or nonvariable foraging conditions (non-VFD). A group of grown VFD-reared subjects demonstrated elevations of cisternal cerebrospinal fluid (CSF) corticotropin-releasing factor concentrations and decreased CSF cortisol levels vs non-VFD counterparts. To further characterize neurobiological sequelae of disturbed early rearing, CSF concentrations of serotonin, dopamine, and norepinephrine metabolites (5-hydroxyindoleacetic acid, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol [MHPG], respectively) and of somatostatin were determined. METHODS: Second CSF taps were obtained from the previously studied cohort of 30 subjects and from 28 age-matched ad libitum-reared control subjects. Relevant assays were performed. RESULTS: All neurochemicals assayed except MHPG were elevated in the VFD-reared compared with non-VFD subjects. In the VFD group, statistically significant positive correlations between corticotropin-releasing factor and each neurochemical was found, except for MHPG. In the non-VFD subjects, no significant correlations with corticotropin-releasing factor were observed. No effect of age was evident. CONCLUSIONS: Reducing the predictability of maternal foraging demand during early rearing was associated with elevations of cisternal somatostatin and of serotonin and dopamine metabolite concentrations in grown offspring. The corticotropin-releasing factor elevations reported previously were positively correlated with all the elevated CSF parameters of the current study. The findings support the notion that adverse early rearing experiences in primates have longstanding and complex effects on a range of neurochemicals relevant to emotional regulation. Replication in prospective age-controlled studies is warranted.

Dose-response effects of oral yohimbine in unrestrained primates.

Six unrestrained bonnet macaques were each observed after oral administration of four dosages of yohimbine hydrochloride (0.10, 0.25, 0.50, and 0.75 mg/kg) and a placebo. Yohimbine significantly increased episodes of motoric activation and affective response interspersed with intervals of behavioral enervation. Yohimbine scores correlated closely with baseline levels; there was no dose-response relationship. Response to oral yohimbine differed in several ways from subcutaneous and intravenous sodium lactate infusions, including prominent enervative symptoms and the appearance of sexual arousal. In light of the appearance of cyclic enervative episodes, this study suggests limitations to primate models of panic disorder utilizing oral yohimbine.

Adverse early experiences affect noradrenergic and serotonergic functioning in adult primates.

It has been proposed that certain adverse early experiences may play a role in determining subsequent susceptibility to adult anxiety and affective disorders and this relationship may be the result of altered neurodevelopment of the noradrenergic and/or serotonergic systems. In this study of nonhuman primates, the predictability of foraging requirements for mothers during an early period of their infants' lives was manipulated. When the offspring were young adults, these early manipulations were related to differences in behavioral response to acute administration of two putative anxiety-provoking agents: the noradrenergic probe, yohimbine, and the serotonergic probe, mCPP. These long-term effects of the developmental environment on subsequent pharmacological responsivity suggest that both neuronal systems may be permanently altered by early experiential factors.

Variable foraging demand rearing: sustained elevations in cisternal cerebrospinal fluid corticotropin-releasing factor concentrations in adult primates.

BACKGROUND: The authors previously reported elevated cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations in juvenile primates nursed by mothers undergoing experimentally imposed unpredictable foraging conditions in comparison to normally reared controls. The purpose of the present study was to determine if these changes would endure into young adulthood. METHODS: Cisternal CSF samples were obtained from those unpredictably reared young adult primates who had been previously studied as juveniles and age-matched ad libitum normally reared controls. Samples were assayed for CSF CRF. RESULTS: Concentrations of CSF CRF were significantly elevated in the unpredictably reared sample in comparison to the ad libitum-reared control group. A significant positive correlation was noted between juvenile and young adult CSF CRF values within the unpredictably reared cohort. CONCLUSIONS: Disturbances of maternal-infant attachment processes have an enduring impact on primate CRF function into young adulthood. The CRF elevations following unpredictable maternal foraging conditions appear traitlike in nature.

Imipramine and alprazolam treatment of lactate-induced acute endogenous distress in nonhuman primates.

The authors studied the response of 10 macaque monkeys to administration of sodium lactate, a panicogenic agent used in human panic disorder research, after treatment with the tricyclic antidepressant imipramine, the triazolobenzodiazepine alprazolam, or placebo. Both drugs effectively blocked the lactate-induced acute endogenous distress responses that had been reliably observed in the monkeys before drug treatment. Only alprazolam significantly reduced the occurrence of conditioned situational anxiety responses observed in the home cage. The alprazolam monkeys appeared to be sedated compared to the imipramine and placebo groups, and tremor and temporary exacerbation of anxious behaviors were observed during alprazolam withdrawal.

Effects of sodium lactate infusion on cisternal lactate and carbon dioxide levels in nonhuman primates.

OBJECTIVE: To further the understanding of lactate-induced panic in patients with panic disorder, the authors examined cisternal lactate and carbon dioxide levels in nonhuman primates after infusions of sodium lactate comparable to those used in studies of human beings. METHOD: CSF and venous blood lactate, pH, PCO2, PO2, and bicarbonate were measured in five ketamine-anesthetized nonhuman primates, without mechanical ventilation, before and after they underwent infusions of sodium lactate. In addition, the same measurements were made for three of the five subjects who were given saline infusions. RESULTS: Despite the development of the characteristic peripheral biochemical effects of infused sodium lactate--increased lactate and bicarbonate levels and metabolic alkalosis--no increases in central lactate or carbon dioxide levels were observed. Saline infusions produced no biochemical effects on venous and cisternal measures. CONCLUSIONS: The results of this study are in keeping with previous findings of nonpermeability of the blood-brain barrier to anionic compounds such as lactate. They therefore support theories of lactate panic based on cognitive and/or brainstem misevaluation of peripheral somatic sensations.

Persistence of blunted human growth hormone response to clonidine in fluoxetine-treated patients with panic disorder.

OBJECTIVE: The authors determined the effects of antipanic treatment with fluoxetine on human growth hormone (GH) response to the alpha 2 agonist clonidine. METHOD: Seventeen patients with panic disorder and 15 healthy volunteers were challenged with clonidine. Thirteen of the patients and 12 of the volunteers were given a second challenge with clonidine 12 weeks later. The patients received open fluoxetine and the healthy subjects received no treatment between challenges. Subjects with high baseline human GH levels (greater than 2 ng/ml) at the first and second challenges were excluded from further analysis. RESULTS: The patients with panic disorder (N = 13 for the first challenge and N = 9 for the second) had significantly lower human GH responses to clonidine than the healthy subjects (N = 14 during the first challenge and N = 9 for the second) during both challenges, despite clinical improvement in eight of the nine patients at the time of the second challenge. CONCLUSIONS: Blunted secretion of human GH in response to clonidine in patients with panic disorder persists despite clinical recovery.

Behavioral effects of oral yohimbine in differentially reared nonhuman primates.

Eight unrestrained macaques were observed for 2 hours following either two oral doses of yohimbine (0.2 mg/kg and 2.0 mg/kg) or placebo administration. Four of the subjects were normally reared and four subjects had early maternal and social deprivation. In the normal subjects, yohimbine, at both doses, produced increased tension and enervation and decreased species-typical "normal" behaviors. In deprivation-reared subjects, low-dose yohimbine produced reductions in tension and enervation, and increases in "normal" behaviors. High doses of yohimbine diminished behavioral score differences between groups. The prominent increases in enervation observed in normally reared subjects suggests that yohimbine is not unequivocally anxiogenic. Moreover, early social deprivation may alter the pattern of response to yohimbine, perhaps as a result of aberrant neurodevelopment. This study reflects the role of experiential factors in determining patterns of affective response to putative anxiogenic agents.

Uncoupling of the noradrenergic-hypothalamic-pituitary-adrenal axis in panic disorder patients.

In this paper the authors examine the interrelationship of both the noradrenergic (NA) system and the hypothalamic-pituitary-adrenal (HPA) axis and its implications for panic disorder (PD). Seventeen PD patients and 16 healthy volunteers were challenged orally 12 weeks apart with the alpha 2-agonist clonidine (13 healthy volunteers and 12 patients repeated the challenge). Between challenges, PD patients were treated with fluoxetine, with 10 of 12 improving at least moderately. Both during the acute phase of the illness and during the phase of pharmacological improvement, patients demonstrated a greater percentage of reductions of plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and plasma cortisol during clonidine challenge. We used correlational matrices to examine the relationship between the NA system, as reflected by plasma MHPG, and the HPA axis, as reflected by plasma cortisol measures. Healthy volunteers exhibited multiple significant "couplings" between either baseline or maximal decrease (delta max) of plasma MHPG, with either baseline or delta max plasma cortisol measures both within the first and second challenges and between the first and second challenges. In contrast, PD patients demonstrated "uncoupling" of the NA system and the HPA axis, with no significant correlations observed between either baseline and/or maximal decrease (delta max) measures of MHPG with the same cortisol measures for either the first or second challenge. The same uncoupling was observed for NA/HPA correlations between the first and second challenges. These data suggest that the hyperresponsivity to clonidine in PD patients persists during fluoxetine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Primate models of separation-induced depression.

Nonhuman primates have been shown to demonstrate behavioral and physiologic reactions to social separation that suggest symptoms of clinical depression. Although care must be taken in the use of animal models of psychopathology, it can be argued that in the case of certain affective disorders, including depression, nonhuman primate response to separation meets the criteria for validity. A variety of social, environmental, and genetic factors can influence the separation response in terms of intensity and specific types of symptomatology, and through the use of experimental manipulations, the relative importance of these and other variables in mediating depressive reactions have been studied. The effects of catecholamine depleting drugs (such as AMPT) as well as therapeutic agents on separation-induced depression in monkeys are being studied in an effort to determine underlying mechanisms of depression and particularly how neurochemical factors may interact synergistically with environmental and psychosocial factors in determining severity and nature of depressive reactions to separation.

Primate models of anxiety. Longitudinal perspectives.

In summary, VFD subjects appear to have sustained long-term behavioral and biologic sequelae following disruption of normative maternal-infant attachment patterns. The sequelae are primarily manifest as stable anxiety or affective traits and, from a biologic perspective, are most analogous to recent data that have emerged from studies of patients with PTSD. Multiple abnormalities are observed of systems directly involved in affect regulation. Further studies are required to clarify the pathologic ontogeny of the VFD condition and its potential relevance to human psychopathology.

Automated recording of individual performance and hand preference during joystick-task acquisition in group-living bonnet macaques (Macaca radiata).

A microchip that provided a unique identification number was injected into each forearm of all 8 members of a bonnet macaque (Macaca radiata) social group. The group was then given computer-controlled joystick tasks of increasing difficulty. The identification number of the arm used on each trial was input into the computer and used to determine individual performance and hand preference in more than 23,000 trials. Three subjects reversed hand preference as task difficulty was increased over time. All subjects exhibited nearly exclusive use of a single hand on the most difficult task; 6 used the right hand, and 2 used the left. Daily patterns of joystick activity for the group members differed somewhat from that of our individually housed monkeys.

Assessment of attachment in differentially reared infant monkeys (Macaca radiata): response to separation and a novel environment.

To assess the developmental consequences of rearing environments for 12 infant bonnet macaques (Macaca radiata), infants from 2 environments, either low foraging demand (LFD) or variable foraging demand (VFD) for their mothers, were observed under 2 test conditions after the completion of the differential rearing treatment. One of the test conditions involved introduction of the rearing cohorts to a novel room; this was done in two series of four 1-hr sessions, a series before and a series after completion of the 2nd test condition. The 2nd test condition involved a 20.5-hr removal of each mother from the rearing cohort; this was repeated once a week for 3 weeks. The results of the novel room tests effectively differentiated rearing treatments in this study and suggested treatment group differences in attachment security. In contrast, the maternal separations failed to differentiate rearing treatments.

A nonhuman primate model of panic disorder.

In this article we report on the reliable production of several features of panic attacks following subcutaneous administration of sodium lactate to nonhuman primates. Unrestrained monkeys were evaluated by an observer without knowledge of the subjects' treatment with either sodium lactate or a dextrose control solution. The lactate produced temporally circumscribed episodes of agitation, wariness, and motor responses, normally elicited under stressful or threatening conditions. In an initial pharmacological intervention, we found that pretreatment with imipramine blocked the response to lactate. The further development of this model offers promise for the systematic examination of etiological factors in susceptibility to lactate induction of panic attacks, the physiological basis of the response, and new modes of treatment of panic disorder.

Growth hormone response to clonidine in adversely reared young adult primates: relationship to serial cerebrospinal fluid corticotropin-releasing factor concentrations.

A reduction of the growth hormone (GH) response to the alpha(2) adrenergic agonist clonidine is a neuroendocrine abnormality observed with reasonable consistency among human patients with mood and anxiety disorders. In previous primate studies, in comparison to predictably reared controls, monkeys exposed as infants to maternal variable foraging demand (VFD) rearing exhibited persistent elevations of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF), as well as other biological disturbances. As CRF has been demonstrated to inhibit GH release, the authors hypothesized that within VFD-reared subjects, animals with relatively high CRF concentrations would exhibit relatively diminished GH responses to clonidine. The current study examined the relationship between the GH response to clonidine in VFD-reared adult primates in relation to a range of both juvenile and follow-up CSF CRF concentrations. Nine bonnet macaques (Macaca radiata) were given ascending dosages of clonidine under ketamine anesthesia. Plasma samples for GH-like immunoreactivity were obtained throughout the session. A significant positive correlation was noted between juvenile CSF CRF concentrations and the levels of the neuropeptide observed in young adults. The mean of the serial CSF CRF concentrations exhibited a significant inverse relationship towards the GH response to clonidine in young adulthood, with relatively high CSF CRF associated with relatively attenuated GH responses to clonidine. These data raise the possibility that a reduced GH response to clonidine may inversely reflect trait-like increases of central nervous system (CNS) CRF activity.

Stress, peer affiliation, and transforming growth factor-beta1 in differentially reared primates.

A bidirectional regulatory interaction between the central nervous system and the immune system is largely provided by cytokines and their specific receptors, which are expressed by cells of both systems. Transforming growth factor-beta1 (TGF-beta1), produced by glial cells and lymphocytes and regulated by steroid hormones, is one such cytokine. In the current study, we examined the relationship between TGF-beta1 and peer affiliation in bonnet macaques (Macaca radiata) either reared normally or exposed as infants to conditions in which their mothers faced fluctuating requirements for food procurement (variable foraging demand [VFD]). Rearing under VFD conditions has been previously shown to produce dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in these animals. Serum levels of TGF-beta1 after exposure to a moderate stressor had no correlation with peer affiliation under baseline conditions (r=.07), but were highly correlated with affiliation after subsequent challenge with a fear stimulus (r=.62). Affiliation after the fear stimulus also was inversely correlated with baseline levels of affiliation (r=-.71). These data suggest that changes in peripheral TGF-beta1 may be reflective of latent behavioral and biochemical propensities possibly related to affect. Further examination of the effects of early adversity will improve our understanding of the relationship between the HPA axis and immune function.

Hypothalamic-pituitary-adrenal axis function and the metabolic syndrome X of obesity.

Obesity has negative health consequences related to fat distribution, particularly the central or visceral accumulation of fat. The major complications associated with visceral obesity, termed the "Metabolic Syndrome of Obesity," or "Syndrome X," are type II diabetes, hypertension, and dyslipidemia. As with certain mood disorders, the syndrome may be a consequence of neuroendocrine perturbations typically associated with chronic stress. Our work with bonnet macaque monkeys provides an animal model for the relationship between early stress, behavioral and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and Syndrome X. During their infant's first half-year, mothers face a variable foraging demand (VFD), in which ample food varies unpredictably in the difficulty of its acquisition, and the offspring show persistent abnormalities in systems known to modulate stress and affective regulation. Early work on the bonnet macaque noted the emergence of a sample of spontaneously obese subjects as they matured. Using the VFD model, the current study showed that there was a clear relationship between early cerebrospinal fluid corticotropin-releasing factor levels and subsequently measured body mass index, supporting the hypotheses regarding the interactive roles of early experience and HPA axis dysregulation in the ontogeny of both metabolic and mood disorders.

Glutamate-hypothalamic-pituitary-adrenal axis interactions: implications for mood and anxiety disorders.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a pathologic feature of certain mood and anxiety disorders that results in the increased production and secretion of corticotropin-releasing factor. There is increasing preclinical evidence that glutamate, an excitatory amino acid, plays an important role in the regulation of the HPA axis. Activation of glutamatergic projections to limbic structures such as the amygdala and brainstem structures such as the nucleus tractus solitarius is implicated in the stress response. There are laboratory and clinical suggestions that glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonists function as antidepressants, and that chronic antidepressant treatments have a significant impact on NMDA receptor function. Clinical investigations of glutamate antagonists in patients with mood and anxiety disorders are in their infancy, with a few reports suggesting the presence of mood-elevating properties. Ultimately, HPA axis modulators, serotonin-enhancing agents, and glutamate antagonists might serve to increase neurotropic factors in key brain regions for affective and anxiety regulation, providing a putative final common pathway.