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Original Article |

Cerebrospinal Fluid Concentrations of Somatostatin and Biogenic Amines in Grown Primates Reared by Mothers Exposed to Manipulated Foraging Conditions FREE

Jeremy D. Coplan, MD; Ronald C. Trost, PhD; Michael J. Owens, PhD; Thomas B. Cooper, MA; Jack M. Gorman, MD; Charles B. Nemeroff, MD, PhD; Leonard A. Rosenblum, PhD
[+] Author Affiliations

From the Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY (Drs Coplan and Gorman and Mr Cooper); The Department of Psychiatry and Primate Behavior Laboratory, SUNY Health Sciences Center at Brooklyn, Brooklyn, NY (Drs Coplan, Trost, and Rosenblum); and the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Ga (Drs Owens and Nemeroff).


Arch Gen Psychiatry. 1998;55(5):473-477. doi:10.1001/archpsyc.55.5.473.
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Published online

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.

THE PIVOTAL role of adverse early life experiences in the pathogenesis of adult psychopathological symptoms has long been recognized in both psychoanalytic circles1 and systematic epidemiologic studies.2,3 Primate infants, human and nonhuman, display a relatively extended period of dependence on their mothers during development. Relatively subtle disruptions during critical "windows" of maternal-infant affective interaction may come to symbolize a threat to survival, with long-term behavioral and biological (mal)adaptions.4

To study the potential effects of such early disruptions, 3 different foraging paradigms were implemented so that accessibility to food could be mechanically manipulated while the primate mother was nursing her infant.5 In the first paradigm, mothers were exposed to consistently low foraging demand conditions (LFD); ie, food was readily obtained with little time or effort required. The second paradigm involved consistently high foraging demand conditions (HFD). For the third paradigm, referred to as variable foraging demand (VFD), foraging was alternated between low and high demand every 2 weeks. Several reports47 have indicated that VFD-reared primate infants show stable behavioral patterns reminiscent of anxiety in human children.

Cisternal taps on adolescent primate subjects indicated that cerebrospinal fluid (CSF) concentrations of the stress-related neuropeptide corticotropin-releasing factor (CRF) were elevated in VFD subjects in comparison with both HFD and LFD groups. The latter 2 groups were indistinguishable from each other.8 Despite high levels of CRF in CSF, VFD-reared subjects exhibited lower CSF cortisol levels. High levels of CRF in CSF9 in the context of a suppressed hypothalamic-pituitary-adrenal axis10 strikingly resembles the biochemical profile reported in human posttraumatic stress disorder.

In the identical subjects, we assayed the peptide somatostatin (SOM), whose release is stimulated by CRF11 and which exerts a putative inhibitory influence on the hypothalamic-pituitary-adrenal axis.12 In addition, we examined the metabolites of serotonin, dopamine, and norepinephrine: 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenethyleneglycol (MHPG), respectively. Serotonin neurons participate in the regulation of CRF,13 and our previous work also suggested VFD behavioral hyposensitivity to the serotonin agonist m-CPP.14 We examined levels of MHPG in CSF, in light of the important stimulatory role of CRF on the noradrenergic locus coeruleus,15 as well as our previous observations of behavioral sensitivity to the α2 autoreceptor antagonist yohimbine in adult VFD subjects.14 We analyzed levels of HVA in CSF to explore if the documented CRF and dopamine interaction found in rodents16 was evident in VFD-reared animals.

Thirty bonnet macaques (Macaca radiata) served as subjects for the study. For 12 to 14 weeks beginning when the infants were approximately 17 weeks of age, 15 of the subjects (10 male and 5 female) were raised under VFD conditions, 8 (5 male and 3 female) under HFD conditions, and 7 (4 male and 3 female) under LFD conditions. The mean age at the time of the cisternal CSF sampling in the VFD subjects was 4 years, with all HFD and LFD subjects born within a few weeks of each other. As the VFD subjects were significantly younger than the subjects of the other 2 groups, the role of age in CSF studies was explored in a separate control group of 28 monkeys. These subjects were reared by their mothers in laboratory breeding groups under stable ad libitum conditions, generally comparable with LFD. These additional animals had a mean age of 30 months (minimum, 15 months; maximum, 52 months; SD, 10.3 months), spanning the age range of the differentially reared groups. The age range of the animals at the time of CSF sampling corresponded to that of peripubertal to young adult phases of human development.

Rearing treatment was preceded by habituation to the rearing paradigm, in which infants were required to remain within a nursery enclosed by contact-permissive mesh within their mothers' pens. A full range of mother-infant behavioral patterns was permitted by the design. Following habituation to the nursery paradigm, differential treatment began. For the HFD mothers, this consisted of 12 weeks in which they were required to dig through clean wood-chip bedding to obtain their daily food ration. For the LFD mothers, abundant food items could simply be picked up from the pen floor during this same 12-week period. For the VFD mothers, foraging demand varied between low and high in 2-week blocks during the 12-week rearing period, beginning with 2 weeks of low demand. The low-demand blocks were identical to the LFD condition. During the high-demand blocks, 4 mothers were required to dig for their food as in the HFD condition, whereas 11 mothers were required to perform a joystick-video task described previously7 to earn 190-mg banana-flavored food pellets. Mothers were trained on the joystick task prior to nursing. Four infants of this latter group of 11 mothers were not housed in the nursery enclosure. Water was constantly available to all mothers. All infants had free access to food and water in an area inaccessible to the mothers. Weekly body weight measurements and health checks revealed normal growth and health in both mothers and infants of all groups, consistent with the developmental norms of the bonnet macaque determined in this laboratory during a 30-year period. Mothers did not receive differential amounts of food throughout the experimental period. Infants were weaned at age 6 months or older and were completely separated from their mothers at 1 year of age, subsequently living in stable combined (VFD and non-VFD) peer groups until the current studies.6,7

Approval was obtained for all studies from the Institutional Animal Care and Use Committee of both SUNY-Health Sciences Center at Brooklyn and Columbia University, New York, NY. The CSF sampling commenced with the administration of ketamine (10 mg/kg) within 2 minutes after the subject's entrance into a squeeze cage. The suboccipital area was prepared with 2% povidone iodine solution. The animal was placed in a strictly symmetrical sitting position and the neck was fully flexed to expose a small triangular depression directly below the occiput and superficial to the cisterna magna. A 24-gauge,34-in needle with a 3-mL syringe was advanced perpendicular to the surface. Once the dura had been penetrated, 1.5 mL of CSF were slowly withdrawn and stored at −70°C until analysis. All CSF sampling was performed between 10:15 AM and 11:30 AM to avoid diurnal confounds. Several hundred taps using this dosage of ketamine have been carried out without any evidence of short- or long-term difficulty. Animals were observed until they were fully recovered following the tap and did not appear to be in pain or distress during or after the procedure.

Levels of SOM in CSF were determined using radioimmunoassay techniques described in detail by Nemeroff and colleagues17 from the same CSF sample from which CRF was obtained. A second CSF sample was obtained under identical conditions several weeks later, from which CSF cortisol measures were taken,8 and provided CSF for 5-HIAA, HVA, and MHPG assays by the Department of Analytic Psychopharmacology, New York State Psychiatric Institute, New York City.

The 5-HIAA and HVA levels were determined using gas chromatography linked to a mass spectrometer according to the method described by Fri et al.18 The assay is routinely performed using a gas chromatograph/mass spectrometer with a direct capillary inlet with simultaneous ion monitoring in the electron impact mode. Within- and between-run coefficients of variation were less than 5% and less than 7% for each compound.

Cerebrospinal fluid MHPG was measured by gas chromatography/mass spectometry operated in the simultaneous ion monitoring mode using deuterated MHPG as an internal standard. The method is essentially the same as that of Jimerson et al.19 Within- and between-run coefficients of variation were 4.6% and 5.1%, respectively. Laboratory personnel conducting the biochemical assays were blind to the subjects' rearing status.

For all CSF measures assayed, the LFD group scores were statistically indistinguishable from those of the HFD group (the highest P value obtained comparing them was for 5-HIAA (t=0.9; df=8; P =.4) and so the LFD and HFD scores were combined into a single non-VFD group of 15 subjects for all subsequent comparisons. The occurrence of taps that were bloody or of insufficient quantity meant that the full complement of values was not available for each measure (available sample sizes for each parameter are indicated in Table 1). To avoid undue influence produced by extreme outliers, it was decided to exclude from analysis any subject's data with a value of 2 SD from the group mean. Using this cutoff, only 3 (3%) of 106 total observations fulfill outlier status. Following assessment of experimental rearing effects, we determined the potential role of age at testing through the use of the age control group. A previously employed age control analysis8 was to be performed on the differentially reared groups if (1) a significant Pearson correlation was evident between age and the CSF parameter or (2) analysis of variance (ANOVA) revealed age, sex, or age × sex effects.

Table Graphic Jump LocationMean Concentrations in Cerebrospinal Fluid (CSF) Somatostatin (SOM) and Biogenic Amines in Differently Reared Primate Groups*

Pearson correlations between neurochemical parameters and CRF and cortisol measures, which have been separately reported,8 were performed in the differentially reared groups. Group comparisons of correlations used the Fisher r-to-z transformation. Outlier scores on any particular measure may represent measurement artifacts, selective anomalies, or abnormalities that are reflected across more than one neurochemical system. To assess the latter possibility, and in contrast to the group analysis, individual outliers were included in the correlational analyses. When, however, examination revealed undue influence of any particular outlier score(s), the nonparametric Spearman correlation coefficient was used to determine the final significance. The control (ad libitum) group was analyzed similarly.

Significance level was set at an α value of P<.05, 2 tailed.

REARING EFFECTS

Levels of SOM, 5-HIAA, and HVA, but not MHPG, were each significantly elevated in VFD as compared with non-VFD subjects (Table 1). Analyses of the control group scores for SOM, 5-HIAA, HVA, and MHPG revealed no significant age effects, sex effects, or sex × age effects. Levels of HVA showed the strongest, but nonsignificant, relationship with age (Pearson r=−0.32, df=27; P=.1).

Because of the study design, it was difficult to determine if the changes observed in the VFD-reared subjects were due to the specific nature of maternal foraging demand and/or the joystick task. We therefore compared by 1-way ANOVA the 3 VFD-reared groups based on maternal foraging demand (digging with mesh, video task with mesh, and video task without mesh). There were no significant differences between the 3 groups for all parameters, including CRF and cortisol. We then compared only the offspring of the 4 mothers who were assigned to the variable digging paradigm with the non-VFD group. Levels of CRF (t=3; df=16; P=.009) and 5-HIAA (t=2.4; df=10; P=.04) were elevated, while cortisol levels were decreased (t=2.7; df=17; P<.02) in the digging VFD group in comparison with the non-VFD group. Thus, even when subjects who were video-reared are excluded, abnormal biochemistry in the VFD group is observed.

CORRELATIONS WITH CRF IN CSF

Strong positive correlations of CRF and SOM (r=0.74; df=10; P=.009), 5-HIAA (r=0.72; df=14; P=.002), and HVA (r=0.80; df=14; P<.001) were recorded for the VFD group. One VFD outlier subject who demonstrated unusually low 5-HIAA levels had correspondingly low CRF values. Follow-up Spearman rank order correlational analysis revealed that this outlier did not account for the CRF and 5-HIAA relationship in the VFD group (t=2.7; r=0.6; P<.02).

In the non-VFD group, the overall Pearson correlation of CRF and SOM was significant (r=0.65; df=13; P=.01) but appeared dependent on an outlier subject who showed high levels on both measures. Spearman rank order correlation for this relationship was not significant (n=14; t=1.3; P=.23). There was no significant relationship between CRF levels and measures of either 5-HIAA or HVA in the non-VFD group (r=−0.17; df=10; P=.6; and r=−0.04; df=14; P=.9, respectively). The Fisher r-to-z transformation test revealed that the correlations between CRF and both 5-HIAA and HVA levels were significantly stronger in VFD than in non-VFD subjects (χ2=5.2; df=1; P<.02; and χ2=7.8; df=1; P<.006, respectively). Because heterogeneity of variance could have accounted for the group correlational differences, the Levene homogeneity of variance test was performed and showed none of the differentially reared groups' parameters to exhibit significant differences in variances in comparison with non-VFD subjects. No significant correlations involving CRF in the ad libitum–reared control group were observed.

CORRELATIONS EXCLUDING CRF IN CSF

In the VFD group, HVA correlated with 5-HIAA (r=0.63; df=14; P=.01) and MHPG (r=0.57; df=14; P<.03); in the non-VFD group, HVA correlated with MHPG. Unlike CRF, CSF cortisol did correlate with MHPG in both the VFD (r=0.70; df=14; P=.003) and non-VFD (r=0.63; df=10; P=.04) rearing groups.

In the control group, 1 subject with outlier 5-HIAA levels and 1 subject with outlier SOM levels were excluded. Levels of HVA correlated with those of 5-HIAA (r=0.4; df=26; P<.03). A counterintuitive positive cortisol and SOM correlation (r=0.4; df=26; P<.03) was observed.

The current report extends previous findings of long-term neurobiological sequelae following disturbances of early rearing in the nonhuman primate.2024 We previously reported elevated CRF and decreased cortisol concentrations in the CSF of a group of bonnet macaques raised under VFD conditions.8 The current study demonstrated elevations of SOM, 5-HIAA, and HVA in the same group of primates, in comparison with predictably reared counterparts. No group differences for MHPG levels were noted. The lack of significant age effects in a separate control cohort suggests that the SOM, HVA, or 5-HIAA group differences were not likely due to age artifact. Nevertheless, the lack of an age-matched control group and the lack of homogeneity of the mode of VFD-rearing limits the generalizability of the findings.

Elevated levels of SOM, HVA, and 5-HIAA are positively correlated with previously reported CRF elevations.8 It is worth noting that the average relationships between measures also appeared to hold for the 3 "outlier" subjects, who generally showed extreme scores on more than 1 defining variable. Levels of MHPG correlated positively with levels of cortisol in the CSF of both groups, but did not correlate with CRF levels, consistent with the documented functional links between the noradrenergic system and the hypothalamic-pituitary-adrenal axis25 and also supporting the view that CRF in CSF is of extrahypothalamic origin.13 Although future cisternal studies should include parallel blood sampling, we believe that CSF cortisol values are likely reflective of adrenal secretory activity. In both primates26 and humans,27 steroids, unlike peptides, equilibrate rapidly across the blood-brain barrier.

The complex and ostensibly coordinated chemical alterations observed in the VFD may be CRF-driven and have resulted from disturbance of optimal maternal-infant interaction. Another untested possibility is the excessive passage of glucocorticoids to the infant when lactation occurs during periods of stress.28 Further developmentally adjusted, strategic behavioral and pharmacological interventions involving specific neurochemical systems are warranted.

Accepted for publication October 31, 1997.

This research was supported in part by National Institute of Mental Health (NIMH) grants MH 42545 and MH 15965, NIMH Research Scientist Award MH-00416 (Dr Gorman), and clinical training grant MH-18641 and NIMH Research Scientist Development Award MH-01039 (Dr Coplan).

We acknowledge the contributions of Michael W. Andrews and Steven Friedman to the fundamental work associated with the current material. We also acknowledge the expert technical assistance of Siobhan Noland, BSc, Antoinette Rookard, LATG, and Douglas Rosenblum.

Reprints: Jeremy D. Coplan, MD, New York State Psychiatric Institute, Columbia University, 722 W 168th St, Box 13, New York, NY 10032.

Freud  S Project for a scientific psychology (1886-1899). Complete Psychological Works of Sigmund Freud London, England Hogarth Press Ltd1966;281- 343
Brown  GW Life events and affective disorder: replications and limitations. Psychosom Med. 1993;55248- 259
Kendler  KSNeale  MCKessler  RCHeath  ACEaves  LJ The genetic epidemiology of phobias in women: the inter-relationship of agoraphobia, social phobia, situational phobia and simple phobia. Arch Gen Psychiatry. 1992;49267- 272
Rosenblum  LAPaully  GS The effects of varying environmental demands on maternal and infant behavior. Child Dev. 1984;55305- 314
Andrews  MWRosenblum  LA Relationship between foraging and affiliative social referencing in primates. Fa  JESouthwick  CHeds.Ecology and Behavior of Food-Enhanced Primate Group New York, NY Alan R Liss Inc1988;247- 268
Andrews  MWRosenblum  LA Attachment in monkey infants raised in variable and low-demand environments. Child Dev. 1991;62686- 693
Andrews  MWRosenblum  LA Developmental consequences of altered dyadic coping patterns in bonnet macaques. Roeder  JThierry  BAnderson  JRHerrenschmidt  Neds.Current Primatology Social Development. Learning and Behaviour Strasbourg, France Universitié Louis Pasteur1994;265- 271
Coplan  JDAndrews  MWRosenblum  LAOwens  MJGorman  JMNemeroff  CB Increased cerebrospinal fluid CRF concentrations in adult non-human primates previously exposed to adverse experiences as infants. Proc Natl Acad Sci U S A. 1996;931619- 1623
Bremner  JDLicinio  JDarnell  AKrystal  JOwens  MJSouthwick  SMNemeroff  CBCharney  DS Elevated CSF corticotropin releasing-factor concentrations in chronic posttraumatic stress disorder. Am J Psychiatry. 1997;154624- 629
Yehuda  RBoisoneau  DLowy  MTGiller  EL  Jr Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic disorder. Arch Gen Psychiatry. 1995;52583- 593
Kling  MARubinow  DRDoran  ARRoy  ADavis  CLCalabrese  JRNieman  LKPost  PMChrousos  GPGold  PW Cerebrospinal fluid immunoreactive somatostatin concentrations in patients with Cushing's disease and major depression: relationship to indices of corticotropin-releasing hormone and cortisol secretion. Neuroendocrinology. 1993;5779- 88
Vescsei  LWiderlöv  E Brain and CSF somatostatin concentrations in patients with psychiatric or neurological illness: an overview. Acta Psychiatr Scand. 1988;78657- 667
Nemeroff  CB New vistas in neuropeptide research in neuropsychiatry: focus on corticotropin-releasing factor. Neuropsychopharmacology. 1992;669- 75
Rosenblum  LACoplan  JDFriedman  SBassoff  TBGorman  JM Adverse early experiences affect noradrenergic and serotonergic functioning in adult primates. Biol Psychiatry. 1994;35221- 227
Butler  PDWeiss  JMStout  JCNemeroff  CB Corticotropin-releasing factor produces fear-enhancing and behavioral activating effects following infusion into the locus coeruleus. J Neurosci. 1990;10176- 183
Thind  KKGoldsmith  PC Corticotropin-releasing factor neurons innervate dopamine neurons in the periventricular hypothalamus of juvenile macaques: synaptic evidence for a possible companion neurotransmitter. Neuroendocrinology. 1989;50351- 358
Widerlöv  EBissette  GNemeroff  CB Monoamine metabolites, corticotropin releasing factor and somatostatin as CSF markers in depressed patients. J Affect Disord. 1988;1499- 107
Fri  CGWiesel  FASedvall  G Simultaneous quantification of homovanillic acid and 5-hydroxyindoleacetic acid in cerebrospinal fluid by mass fragmentography. Life Sci. 1974;142469- 2480
Jimerson  DCMarkey  SPOliver  JAKopin  IJ Simultaneous measurement of plasma 4-hydroxy-3 methoxyphenylethylene glycol and 3, 4-dihydroxyphenylethylene glycol by gas chromatography mass spectrometry. Biomed Mass Spectrom. 1981;8256- 259
Kraemer  GWEbert  MHSchmidt  DEMcKinney  WT A longitudinal study of the effect of different social rearing conditions on cerebrospinal fluid norepinephrine and biogenic amine metabolites in rhesus monkeys. Neuropsychopharmacology. 1989;2175- 189
Higley  JDThompson  WWChampoux  MGoldman  DHasert  MFKraemer  GWScanlan  JMSuomi  SJLinnoila  M Paternal and maternal genetic and environmental contributions to cerebrospinal fluid monoamine metabolites in rhesus monkeys (Macaca mulatta). Arch Gen Psychiatry. 1993;50615- 623
Clarke  ASKammerer  CMGeorge  KPKupfer  DJMcKinney  WTSpence  MAKraemer  GW Evidence for heritability of biogenic amine levels in the cerebrospinal fluid of rhesus monkeys. Biol Psychiatry. 1995;38572- 577
Coplan  JDRosenblum  LAFriedman  SBassoff  TGorman  JM Effects of oral yohimbine administration in differentially reared nonhuman primates. Neuropsychopharmacology. 1992;631- 37
Coplan  JDRosenblum  LAGorman  JM Primate models of anxiety: longitudinal perspectives. Psychiatr Clin North Am. 1995;18727- 743
Coplan  JDPine  DPapp  LARosenblum  LACooper  TGorman  JM Noradrenergic/HPA axis uncoupling in panic disorder. Neuropsychopharmacology. 1995;1365- 73
Kalin  NHCohen  RMMurphy  DL Circadian variation in the CSF cortisol concentration of the rhesus monkey. Life Sci. 1980;261485- 1487
Schwarz  SPohl  P Steroid hormones and steroid hormone binding globulins in cerebrospinal fluid studied in individuals with intact and with disturbed blood-cerebrospinal fluid barrier. Neuroendocrinology. 1992;55174- 182
Plotsky  PMEisler  JAThrivikraman  KVAnand  KJSMeaney  MJ Early experience as a factor in sculpting the developing brain.  Paper presented at: 35th Annual Meeting of the American College of Neuro-psychopharmacology December 10, 1996 San Juan, Puerto Rico

Figures

Tables

Table Graphic Jump LocationMean Concentrations in Cerebrospinal Fluid (CSF) Somatostatin (SOM) and Biogenic Amines in Differently Reared Primate Groups*

References

Freud  S Project for a scientific psychology (1886-1899). Complete Psychological Works of Sigmund Freud London, England Hogarth Press Ltd1966;281- 343
Brown  GW Life events and affective disorder: replications and limitations. Psychosom Med. 1993;55248- 259
Kendler  KSNeale  MCKessler  RCHeath  ACEaves  LJ The genetic epidemiology of phobias in women: the inter-relationship of agoraphobia, social phobia, situational phobia and simple phobia. Arch Gen Psychiatry. 1992;49267- 272
Rosenblum  LAPaully  GS The effects of varying environmental demands on maternal and infant behavior. Child Dev. 1984;55305- 314
Andrews  MWRosenblum  LA Relationship between foraging and affiliative social referencing in primates. Fa  JESouthwick  CHeds.Ecology and Behavior of Food-Enhanced Primate Group New York, NY Alan R Liss Inc1988;247- 268
Andrews  MWRosenblum  LA Attachment in monkey infants raised in variable and low-demand environments. Child Dev. 1991;62686- 693
Andrews  MWRosenblum  LA Developmental consequences of altered dyadic coping patterns in bonnet macaques. Roeder  JThierry  BAnderson  JRHerrenschmidt  Neds.Current Primatology Social Development. Learning and Behaviour Strasbourg, France Universitié Louis Pasteur1994;265- 271
Coplan  JDAndrews  MWRosenblum  LAOwens  MJGorman  JMNemeroff  CB Increased cerebrospinal fluid CRF concentrations in adult non-human primates previously exposed to adverse experiences as infants. Proc Natl Acad Sci U S A. 1996;931619- 1623
Bremner  JDLicinio  JDarnell  AKrystal  JOwens  MJSouthwick  SMNemeroff  CBCharney  DS Elevated CSF corticotropin releasing-factor concentrations in chronic posttraumatic stress disorder. Am J Psychiatry. 1997;154624- 629
Yehuda  RBoisoneau  DLowy  MTGiller  EL  Jr Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic disorder. Arch Gen Psychiatry. 1995;52583- 593
Kling  MARubinow  DRDoran  ARRoy  ADavis  CLCalabrese  JRNieman  LKPost  PMChrousos  GPGold  PW Cerebrospinal fluid immunoreactive somatostatin concentrations in patients with Cushing's disease and major depression: relationship to indices of corticotropin-releasing hormone and cortisol secretion. Neuroendocrinology. 1993;5779- 88
Vescsei  LWiderlöv  E Brain and CSF somatostatin concentrations in patients with psychiatric or neurological illness: an overview. Acta Psychiatr Scand. 1988;78657- 667
Nemeroff  CB New vistas in neuropeptide research in neuropsychiatry: focus on corticotropin-releasing factor. Neuropsychopharmacology. 1992;669- 75
Rosenblum  LACoplan  JDFriedman  SBassoff  TBGorman  JM Adverse early experiences affect noradrenergic and serotonergic functioning in adult primates. Biol Psychiatry. 1994;35221- 227
Butler  PDWeiss  JMStout  JCNemeroff  CB Corticotropin-releasing factor produces fear-enhancing and behavioral activating effects following infusion into the locus coeruleus. J Neurosci. 1990;10176- 183
Thind  KKGoldsmith  PC Corticotropin-releasing factor neurons innervate dopamine neurons in the periventricular hypothalamus of juvenile macaques: synaptic evidence for a possible companion neurotransmitter. Neuroendocrinology. 1989;50351- 358
Widerlöv  EBissette  GNemeroff  CB Monoamine metabolites, corticotropin releasing factor and somatostatin as CSF markers in depressed patients. J Affect Disord. 1988;1499- 107
Fri  CGWiesel  FASedvall  G Simultaneous quantification of homovanillic acid and 5-hydroxyindoleacetic acid in cerebrospinal fluid by mass fragmentography. Life Sci. 1974;142469- 2480
Jimerson  DCMarkey  SPOliver  JAKopin  IJ Simultaneous measurement of plasma 4-hydroxy-3 methoxyphenylethylene glycol and 3, 4-dihydroxyphenylethylene glycol by gas chromatography mass spectrometry. Biomed Mass Spectrom. 1981;8256- 259
Kraemer  GWEbert  MHSchmidt  DEMcKinney  WT A longitudinal study of the effect of different social rearing conditions on cerebrospinal fluid norepinephrine and biogenic amine metabolites in rhesus monkeys. Neuropsychopharmacology. 1989;2175- 189
Higley  JDThompson  WWChampoux  MGoldman  DHasert  MFKraemer  GWScanlan  JMSuomi  SJLinnoila  M Paternal and maternal genetic and environmental contributions to cerebrospinal fluid monoamine metabolites in rhesus monkeys (Macaca mulatta). Arch Gen Psychiatry. 1993;50615- 623
Clarke  ASKammerer  CMGeorge  KPKupfer  DJMcKinney  WTSpence  MAKraemer  GW Evidence for heritability of biogenic amine levels in the cerebrospinal fluid of rhesus monkeys. Biol Psychiatry. 1995;38572- 577
Coplan  JDRosenblum  LAFriedman  SBassoff  TGorman  JM Effects of oral yohimbine administration in differentially reared nonhuman primates. Neuropsychopharmacology. 1992;631- 37
Coplan  JDRosenblum  LAGorman  JM Primate models of anxiety: longitudinal perspectives. Psychiatr Clin North Am. 1995;18727- 743
Coplan  JDPine  DPapp  LARosenblum  LACooper  TGorman  JM Noradrenergic/HPA axis uncoupling in panic disorder. Neuropsychopharmacology. 1995;1365- 73
Kalin  NHCohen  RMMurphy  DL Circadian variation in the CSF cortisol concentration of the rhesus monkey. Life Sci. 1980;261485- 1487
Schwarz  SPohl  P Steroid hormones and steroid hormone binding globulins in cerebrospinal fluid studied in individuals with intact and with disturbed blood-cerebrospinal fluid barrier. Neuroendocrinology. 1992;55174- 182
Plotsky  PMEisler  JAThrivikraman  KVAnand  KJSMeaney  MJ Early experience as a factor in sculpting the developing brain.  Paper presented at: 35th Annual Meeting of the American College of Neuro-psychopharmacology December 10, 1996 San Juan, Puerto Rico

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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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