Saul M. Schanberg

METABOLISM OF NORMETANEPHRINE-H3 IN RAT BRAIN—IDENTIFICATION OF CONJUGATED 3-METHOXY-4-HYDROPHENYLGLYCOL AS THE MAJOR METABOLITE

Abstract Normetanephrine-H 3 injected into the cisterna magna of rats is rapidly metabolized and disappears from brain with an initial half-life of about 12 min. Monoamine oxidase inhibition prevents almost completely the conversion of normetanephrine-H 3 to other metabolites and markedly diminishes the rate of disappearance of radioactivity from brain ( T 1 2 = 2·4 hr ) . These data show that normetanephrine is normally metabolized primarily by monoamine oxidase and that unaltered normetanephrine does not readily pass out of the brain. Free 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3-methoxy-4-hydroxymandelic acid (VMA) formed from intracisternally injected normetanephrine-H 3 represent only a small fraction of the radioactivity in brain. The major metabolite was identified as the sulfate conjugate of MHPG. After intracisternal administration of norepinephrine-H 3 , 3-methoxy-4-hydroxyphenylglycol sulfate (MHPG-SO 4 ) was also found to be the major metabolite present in brain. These findings suggest that deamination, reduction, and subsequent conjugation with sulfate is the primary route of metabolism of normetanephrine in rat brain and that norepinephrine is also metabolized to this sulfate conjugate.

NEUROENDOCRINE, CARDIOVASCULAR, AND EMOTIONAL RESPONSES OF HOSTILE MEN : THE ROLE OF INTERPERSONAL CHALLENGE

Objective We examined the effects of hostility and harassment on neuroendocrine, cardiovascular, and emotional responses in 52 healthy white men. Methods Subjects were preselected on the basis of scores in the top and bottom quartiles (above 23 and below 15, respectively) on the Cook and Medley Hostility (Ho) scale. Subjects participated in a solvable anagram task. Thirty subjects were harassed by the technician during the task. Results Harassed subjects with high Ho scores exhibited enhanced and prolonged blood pressures, heart rate, forearm blood flow, forearm vascular resistance, norepinephrine, testosterone, and cortisol responses relative to low-Ho subjects in the harassed condition and high and low-Ho subjects in the nonharassed condition. Heightened physiological reactivity in high-Ho subjects was correlated with arousal of negative affects. Conclusions The findings are consistent with the general hypothesis that high hostile men show excessive behaviorally-induced cardiovascular and neuroendocrine responsivity to interpersonal challenging situations. Moreover, in high-Ho men, the stress-induced cardiovascular and neuroendocrine hyperreactivity is associated with the arousal of negative affects such as anger.

Serotonin-Related Gene Polymorphisms and Central Nervous System Serotonin Function *

Central nervous system (CNS) serotonergic function affects a wide range of biological and behavioral functions affecting health and disease. Our objective in this study was to determine whether functional polymorphisms of the genes that encode for the serotonin transporter promoter (5HTTLPR) and monoamine oxidase A (MAOA-uVNTR) are associated with CNS serotonin turnover—indexed by cerebrospinal fluid levels of 5-hydroxyindoleacetic acid (5-HIAA)—in a community sample of healthy adults. Subjects were 165 community volunteers without current medical or psychiatric illness, stratified with respect to ethnicity, gender, and socioeconomic status who underwent inpatient evaluation in the General Clinical Research Center of a university medical center. A significant ethnicity×genotype interaction (P=0.008) indicated that, compared to the long/long and long/short genotypes, the 5HTTLPR short/short genotype was associated with higher CSF 5-HIAA levels in African Americans, but with lower levels in Caucasians. A gender×genotype interaction (P=0.04) indicated that 5HTTLPR short/short genotype was associated with higher 5-HIAA levels in women but with lower levels in men. MAOA-uVNTR 3.5 and 4 repeat alleles were associated with higher 5-HIAA (P=0.03) levels in men, but were unrelated to 5-HIAA levels in women. These findings suggest that effects of serotonin-related gene polymorphisms on CNS serotonergic function vary as a function of both ethnicity and gender. Further research will be required to determine the mechanism(s) underlying these differential effects. In the meanwhile, both ethnicity and gender should be taken into account in research evaluating effects of these and related polymorphisms on CNS serotonergic function, as well as the broad range of biological and behavioral functions that are regulated by CNS serotonergic function.

Massage Reduces Anxiety in Child and Adolescent Psychiatric Patients

A 30-minute back massage was given daily for a 5-day period to 52 hospitalized depressed and adjustment disorder children and adolescents. Compared with a control group who viewed relaxing videotapes, the massaged subjects were less depressed and anxious and had lower saliva cortisol levels after the massage. In addition, nurses rated the subjects as being less anxious and more cooperative on the last day of the study, and nighttime sleep increased over this period. Finally, urinary cortisol and norepinephrine levels decreased, but only for the depressed subjects.

CORTISOL DECREASES AND SEROTONIN AND DOPAMINE INCREASE FOLLOWING MASSAGE THERAPY

In this article the positive effects of massage therapy on biochemistry are reviewed including decreased levels of cortisol and increased levels of serotonin and dopamine. The research reviewed includes studies on depression (including sex abuse and eating disorder studies), pain syndrome studies, research on auto-immune conditions (including asthma and chronic fatigue), immune studies (including HIV and breast cancer), and studies on the reduction of stress on the job, the stress of aging, and pregnancy stress. In studies in which cortisol was assayed either in saliva or in urine, significant decreases were noted in cortisol levels (averaging decreases 31%). In studies in which the activating neurotransmitters (serotonin and dopamine) were assayed in urine, an average increase of 28% was noted for serotonin and an average increase of 31% was noted for dopamine. These studies combined suggest the stress-alleviating effects (decreased cortisol) and the activating effects (increased serotonin and dopamine) of massage therapy on a variety of medical conditions and stressful experiences.

RESPONSES TO MATERNAL SEPARATION : MECHANISMS AND MEDIATORS

Clinical studies indicate the predominance of psychosocial factors (nurturing environment) in the genesis of the Maternal Deprivation Syndrome. Consequences of disrupting mother‐infant interactions range from marked suppression of certain neuroendocrine and physiological systems after short periods of maternal deprivation to retardation of growth and behavioral development after chronic periods. We have shown that maternal separation initiates a complex adaptive biobehavioral response in preweaning rat pups that includes (1) a decrease in the synthesis of ornithine decarboxylase, an obligatory enzyme for normal cell growth and development, (2) a reduction in DNA synthesis, an index of cell multiplication, (3) abnormal patterns of neuroendocrine secretion, and (4) a suppression of cell responses to growth hormone, prolactin and insulin, three major trophic hormones. This unique pattern of adaptation to maternal separation is not related to food or temperature changes but results from a lack of a specific type of tactile stimulation of the pup by the mother. Recently, we have shown that in the absence of “nurturing touch” the brain initiates the suppression of ornithine decarboxylase gene transcription by interfering with the cells ability to transduce the activating signal induced by the growth promoting hormones. Studies indicate that central endorphinergic pathways may mediate this action. This is accomplished by the downregulation of specific Immediate Early Genes (c‐myc and max) that normally promote the synthesis of this critical growth‐regulatory enzyme. These studies of short‐term maternal separation not only demonstrated that maternal care is a critical regulator of pup physiology and biobehavioral development but that there are marked similarities between this animal model of maternal separation and the delay in growth and development observed in children with the deprivation syndrome or in touch‐deprived premature human neonates. Our identification of a specific type of nurturing touch as a neonatal growth requirement led us to test supplemental tactile stimulation in isolated very‐premature human babies. The result of our intervention with massage was dramatic. Infants not only showed marked gains in weight and behavioral development, but also a significant enhancement in sympatho‐adrenal maturation. We suggest that animal models of maternal deprivation can be used to understand the integrative processing of appropriate sensory input, CNS function and end‐organ physiology required to maintain normal development.

AROMATHERAPY POSITIVELY AFFECTS MOOD, EEG PATTERNS OF ALERTNESS AND MATH COMPUTATIONS*

EEG activity, alertness, and mood were assessed in 40 adults given 3 minutes of aromatherapy using two aromas, lavender (considered a relaxing odor) or rosemary (considered a stimulating odor). Participants were also given simple math computations before and after the therapy. The lavender group showed increased beta power, suggesting increased drowsiness, they had less depressed mood (POMS) and reported feeling more relaxed and performed the math computations faster and more accurately following aromatherapy. The rosemary group, on the other hand, showed decreased frontal alpha and beta power, suggesting increased alertness. They also had lower state anxiety scores, reported feeling more relaxed and alert and they were only faster, not more accurate, at completing the math computations after the aromatherapy session.

Maternal psychological distress, prenatal cortisol, and fetal weight.

Objective: The objective of this study was to examine the effects of maternal psychological distress on estimated fetal weight during midgestation and explore the maternal hypothalamic–pituitary axis and sympathoadrenal dysregulation as potential risk factors for these effects. Methods: Fetal ultrasound biometry measurements and maternal sociodemographic characteristics, emotional distress symptoms, and first morning urine samples were collected during a clinical ultrasound examination for a cross-sectional sample of 98 women who were between 16 and 29 weeks pregnant. Fetal weight was estimated from ultrasound biometry measurements; maternal emotional distress was assessed using the daily hassles (stress), Center for Epidemiologic Studies–Depression (depression), and State-Trait Anxiety Inventory (anxiety) scales; and urine samples were assayed for cortisol and norepinephrine levels. Results: Correlation analyses revealed that both maternal psychological (daily hassles, depression, and anxiety) and biochemical (cortisol and norepinephrine) variables were negatively related to fetal biometry measurements and estimated fetal weight. A structural equation model further revealed that when the independent variance of maternal sociodemographic, psychological distress, and biochemistry measures were accounted for, prenatal cortisol was the only significant predictor of fetal weight. Conclusions: Women exhibiting psychological distress during pregnancy exhibit elevated cortisol levels during midgestation that are in turn related to lower fetal weight. CRH = corticotropin-releasing hormone; HPA = hypothalamic–pituitary axis; IGFBP1 = insulin-like growth factor binding protein 1; eFW = estimated fetal weight; BPD = biparietal diameter; AC = abdominal circumference; FL = femur length; HC = head circumference; SES = socioeconomic status; SEM = structural equation model; CFI = comparative fit index; RMSEA = root mean square error of approximation.

Sensory deprivation stress and supplemental stimulation in the rat pup and preterm human neonate

This article reviews the literature and presents data from our laboratories on sensory deprivation stress and supplemental stimulation of the rat pup and the preterm neonate. The data suggest that the effects of maternal deprivation in the rat pup (suppression of growth hormone release and protein synthesis) are regulated by a specific form of tactile stimulation: only brush stroking of maternally deprived rat pups returned growth parameters to normal; other forms of stimulation, including kinesthetic and vestibular stimulation, were ineffective in restoring normal functions. Other data are presented demonstrating that very small preterm neonates given tactile-kinesthetic stimulation gain more weight per day, spend more time awake and active, and show more mature habituation, orientation, motor, and range of state behaviors on the Brazelton assessment.

Prepartum, Postpartum, and Chronic Depression Effects on Newborns

Abstract In order to assess the effects of the onset and chronicity of maternal depression on neonatal physiology, eighty pregnant women were assessed for depression during mid-pregnancy (M gestational age = 25.9 weeks) and shortly after delivery. The women were classified as reporting depressive symptoms 1) only during the prepartum assessment; 2) only during the postpartum assessment; 3) during both the prepartum and postpartum assessments; or 4) reporting no depressive symptoms at either the prepartum or the postpartum assessment. Maternal mood and biochemistry were assessed during pregnancy, and the EEG and biochemical characteristics of their 1-week-old infants were assessed shortly after birth. As predicted, the newborns of the mothers with prepartum and postpartum depressive symptoms had elevated cortisol and norepinephrine levels, lower dopamine levels, and greater relative right frontal EEG asymmetry. The infants in the prepartum group also showed greater relative right frontal EEG asymmetry and higher norepinephrine levels. These data suggest that effects on newborn physiology depend more on prepartum than postpartum maternal depression but may also depend on the duration of the depressive symptoms.