Biomedical subjects

R L Hauger

Publications and source records attributed to R L Hauger.

At least 37 records · Page 2Linked to original sources

PubMed1999

Isolation and pharmacological characterization of two functional splice variants of corticotropin-releasing factor type 2 receptor from Tupaia belangeri.

From brain, heart and muscle tissue of the tree shrew (Tupaia belangeri), a higher order mammal, cDNA clones were isolated that encoded two functional splice variants of the corticotropin-releasing factor (CRF) type 2 receptor (CRF-R2). The first, full-length splice variant, amplified from brain and heart tissue, encoded a CRF receptor protein that is 410 amino acids in length and approximately 96% homologous to human CRF-R2alpha. The second, full-length splice variant, derived from skeletal muscle tissue, encoded a 437-amino acid CRF receptor protein that is approximately 92% homologous to human CRF-R2beta. Semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) amplifications and RNase protection analyses, showed that tree shrew CRF-R2alpha (tCRF-R2alpha) and tree shrew CRF-R2beta (tCRF-R2beta) were coexpressed in brain tissue but not in heart and skeletal muscle tissue. Finally, human embryonic kidney 293 (HEK293) cells stably transfected with tCRF-R2alpha and tCRF-R2beta were used to demonstrate that the CRF analogs urocortin and sauvagine bind with significantly greater affinity (21- to 140-fold) to these two CRF-R2 splice variants than do human/rat and ovine CRF analogs. In keeping with these results of our CRF binding studies, EC50 values were substantially lower for urocortin-and sauvagine-stimulated than for h/rCRF-and oCRF-stimulated cyclic AMP accumulation in HEK293 cells stably transfected with tCRF-R2alpha or tCRF-R2beta cDNAs. The tree shrew therefore constitutes an important animal model in which to investigate the role of CRF receptor subtypes in the stress response.

Amino Acid Sequence↗

PubMed1999

N-terminal splice variants of the type I PACAP receptor: isolation, characterization and ligand binding/selectivity determinants.

Three full-length cDNAs encoding functional splice variants of the pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1) were isolated from Y-79 retinoblastoma cells and human cerebellum. Although the third intracellular loops of the three splice variants were identical, their N-terminal extracellular domains differed. The first full-length PAC1 variant, PAC1normal (PAC1n), encoded the entire N-terminus, whereas the second variant named PAC1short (PAC1s) was deleted by 21 amino acids (residues 89-109). Finally, the third variant, named PAC1very short (PAC1vs), was deleted by 57 amino acids (residues 53-109). Using semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis, it was established that all three variants were expressed in neuronal tissues. Binding- and cAMP studies using human embryonic kidney 293 (HEK293) cells stably transfected with PAC1n, PAC1s and PAC1vs showed significant differences in the affinities and selectivities towards PACAP38, PACAP27 and VIP. PAC1n bound PACAP38 and PACAP27 with affinities in the low nanomolar range whereas VIP was bound with up to 400-fold lower affinity. PAC1vs preferentially bound PACAP38 (Ki=121 nM) and PACAP27 (Ki=129 nM) over VIP (Ki>1000 nM) but with 100-fold lower affinity than PAC1n. Surprisingly, PAC1s unselectively bound all three ligands with high affinity. These data indicate that residues 53-88 within the N-terminal domain of the PAC1 are important for high affinity ligand binding, whereas residues 89-109 determine the receptor's ligand selectivity.

Binding Sites↗

PubMed1999

The ligand-selective domains of corticotropin-releasing factor type 1 and type 2 receptor reside in different extracellular domains: generation of chimeric receptors with a novel ligand-selective profile.

The nonselective human corticotropin-releasing factor (hCRF) receptor 1 (hCRFR1) and the ligand-selective Xenopus CRFR1 (xCRFR1), xCRFR2, and hCRFR2alpha were compared. To understand the interactions of hCRF, ovine CRF (oCRF), rat urocortin (rUcn), and sauvagine, ligands with different affinities for type 1 and type 2 CRFRs, chimeric and mutant receptors of hCRFR1, xCRFR1, hCRFR2alpha, and xCRFR2 were constructed. In cyclic AMP stimulation and CRF-binding assays, it was established that different extracellular regions of CRFR1 and CRFR2 conferred their ligand selectivities. The ligand selectivity of xCRFR1 resided in five N-terminal amino acids, whereas the N-terminus of both CRFR2 proteins did not contribute to their ligand selectivities. Chimeric receptors in which the first extracellular domain of hCRFR1 replaced that of hCRFR2alpha or xCRFR2 showed a similar pharmacological profile to the two parental CRFR2 molecules. Chimeric receptors carrying the N-terminal domain of xCRFR1 linked to hCRFR2alpha or xCRFR2 displayed a novel pharmacological profile. hCRF, rUcn, and sauvagine were bound with high affinity, whereas oCRF was bound with low affinity. Furthermore, when three or five residues of xCRFR1 (Gln76, Gly81, Val83, His88, Leu89; or Gln76, Gly81, Val83) were introduced into receptor chimeras carrying the N-terminus of hCRFR1 linked to xCRFR2, the same novel pharmacology was observed. These data indicate a compensation mechanism of two differentially selecting regions located in different domains of both xCRFR1 and CRFR2.

Amphibian Proteins↗

PubMed1998

Prolactin response to D-fenfluramine in outpatients with major depression.

There is much indirect evidence of serotonin abnormalities in patients with major depression. Unfortunately, previous reports of serotonin challenge studies in depressed patients have yielded conflicting results. In order to test the serotonin hypothesis of depression, the authors compared 20 outpatients with major depressive disorder to 20 normal control subjects using prolactin response to D-fenfluramine as a measure of central serotonergic (5-HT) functioning. Patients were free of histories of suicidal behavior and had no Axis II disorders. There were no significant differences in prolactin responses between depressed patients and control subjects to challenge with D-fenfluramine at a dose of 0.5 mg/kg. The possible implications of these findings are discussed with respect to theories regarding biological vulnerabilities to major depression.

Adult↗

PubMed1998

Cerebrospinal fluid vasopressin levels: correlates with aggression and serotonin function in personality-disordered subjects.

BACKGROUND: Animal studies suggest that central vasopressin plays a facilitatory role in aggressive behavior. To examine this possibility in humans, the relationship between cerebrospinal fluid (CSF) arginine vasopressin (AVP) and indices of aggression and central serotonin system function was examined in personality-disordered subjects. METHODS: We used CSF (AVP), CSF 5-hydroxyindoleacetic acid, and the prolactin response to d-fenfluramine challenge (PRL[d-FEN]) as central indices of vasopressin and serotonergic system function, respectively, in 26 subjects who met the DSM-IV criteria for personality disorder. Measures of aggression and impulsivity included the Life History of Aggression assessment and the Barratt Impulsiveness Scales. RESULTS: The CSF AVP level was correlated directly with life history of general aggression and aggression against persons and inversely with PRL[d-FEN] responses (but not with CSF 5-hydroxyindoleacetic acid), which in turn was correlated inversely with these 2 measures of life history of aggression. The positive relationship between CSF AVP and life history of aggression remained even when the variance associated with PRL[d-FEN] responses in these subjects was accounted for. CONCLUSION: Central AVP may play a role in enhancing, while serotonin plays a role in inhibiting, aggressive behavior in personality-disordered individuals. In addition to the possibility of central AVP and serotonin interacting to influence human aggression, central AVP may also influence human aggressive behavior through a mechanism independent of central serotonin in personality-disordered subjects.

Adult↗

PubMed1998

Plasma neuropeptide Y (NPY) increases in humans in response to the alpha 2 antagonist yohimbine.

Previous studies have shown that the intravenous administration of yohimbine, an alpha 2 antagonist, increases norepinephrine turnover and has related anxiogenic effects in humans. We herein report that yohimbine also increases plasma neuropeptide Y (NPY) in healthy human subjects. This finding is consistent with previous reports in animals, but contrasts with a previously reported study in humans. NPY is a 36 amino acid peptide neurotransmitter located in sympathetic and nonsympathetic nerve fibers, as well as in brain structures such as the locus coeruleus, where it is colocalized with norepinephrine. NPY has been shown to inhibit locus coeruleus neuronal firing, decrease norepinephrine release, and increase postsynaptic noradrenergic signal transduction. When administered centrally, NPY also has anxiolytic properties. This study therefore suggests that yohimbine challenge may be useful in assessing NPY and noradrenergic system interactions in neuropsychiatric disorders such as panic disorder or post traumatic stress disorder in which noradrenergic system dysfunction has been observed.

Adrenergic alpha-Antagonists↗

PubMed1998

Cortisol levels during human aging predict hippocampal atrophy and memory deficits.

Elevated glucocorticoid levels produce hippocampal dysfunction and correlate with individual deficits in spatial learning in aged rats. Previously we related persistent cortisol increases to memory impairments in elderly humans studied over five years. Here we demonstrate that aged humans with significant prolonged cortisol elevations showed reduced hippocampal volume and deficits in hippocampus-dependent memory tasks compared to normal-cortisol controls. Moreover, the degree of hippocampal atrophy correlated strongly with both the degree of cortisol elevation over time and current basal cortisol levels. Therefore, basal cortisol elevation may cause hippocampal damage and impair hippocampus-dependent learning and memory in humans.

Aged↗

PubMed1997

Serotonin function and antiaggressive response to fluoxetine: a pilot study.

BACKGROUND: The reported inverse relationship between indices of central serotonin (5-HT) function and indices of impulsive aggression in human subjects suggests the possibility that enhancement of 5-HT activity will reduce impulsive aggressive behavior. Although evidence for this hypothesis is emerging, the relationship between baseline central 5-HT system function and antiaggressive responses to treatment with 5-HT agents has not yet been examined in human subjects. METHODS: In this pilot study, we examined the relationship between: a) pretreatment prolactin responses to d-fenfluramine (PRL[d-FEN]) challenge; and b) antiaggressive responses to 12 weeks of treatment with either fluoxetine or placebo in 15 impulsively aggressive personality disordered subjects as observed in a 12-week, double-blind, placebo-controlled trial. RESULTS: Among all subjects there were positive correlations between the pretreatment PRL[d-FEN] response and the percent improvement in Overt Aggression Scale-Modified scores for "Aggression" and "Irritability." These correlations were present in the fluoxetine (n = 10), but not in the placebo (n = 5), treated subjects. CONCLUSIONS: These data suggest the possibility that the antiaggressive response to fluoxetine is directly, rather than inversely, dependent on the responsiveness of central 5-HT synapses in the brain of impulsive aggressive personality disordered subjects.

Adolescent↗

PubMed1997

Longitudinal analysis of multiple indicators of health decline among spousal caregivers.

The hazards for experiencing major health events were studied longitudinally among 150 spousal caregivers of Alzheimer's disease (AD) patients and 46 married control participants. Based on longitudinal assessments from one to six years, the hazards of reaching any of three health events (extended physical illness or disability > 1 month, unhealthy medical rating from a nurse interview, or hospitalization) were not significantly different in a group comparison of caregivers to controls (Cox proportional hazards assumption, p > .05). However, there was a trend [X2(1, N = 107) = 3.13, p = .08] for caregivers to have a greater hazard for serious illness. Among caregivers only, a greater hazard for reaching at least one of these health events was associated with providing more activities of daily living (ADL) assistance [X2(1, N = 125) = 3.83, p = .05] but not with problem behaviors of the AD patient (p > .05). These results suggest that providing extensive ADL assistance may have health implications for spousal AD caregivers, while caregiving, per se, does not. Furthermore, these physical health impacts of caregiving may be best characterized using multidimensional assessments. Contrary to our guiding hypothesis, caregivers encountering more problem behaviors of their AD spouse were less likely to be hospitalized, X2(1, N = 145) = 5.88, p = .02. This finding may reflect a reluctance by caregivers to schedule necessary medical care when their spouses are most problematic, and this may have further long-term health implications for caregivers.

Activities of Daily Living↗

PubMed1997

Responses to alpha 2-adrenoceptor blockade by idazoxan in healthy male and female volunteers.

Seven male and five female volunteers underwent double-blind infusions of the alpha 2-adrenoceptor antagonist idazoxan (100 and 200 micrograms/mg) and placebo in random order. Blood pressure, plasma norepinephrine, growth hormone and subjective responses were measured. The higher dose of idazoxan produced increases in blood pressure, norepinephrine and growth hormone and slight increases in anxiety. Both subject age and sex appeared to influence the magnitude of responses.

Adrenergic alpha-2 Receptor Antagonists↗

PubMed1997

Regulation of corticotropin-releasing factor receptor function in human Y-79 retinoblastoma cells: rapid and reversible homologous desensitization but prolonged recovery.

Homologous receptor desensitization is an important regulatory response to continuous activation by agonist that involves the uncoupling of a receptor from its G protein. When human retinoblastoma Y-79 cells expressing corticotropin-releasing factor (CRF) receptors were preincubated with CRF for 10 min-4 h, a time-dependent reduction in both the peak and sensitivity of CRF-stimulated intracellular cyclic AMP (cAMP) accumulation developed with a t1/2 of 38 min and an EC50 of 6-7 nM CRF. CRF receptor desensitization was slowly reversible after a 4-h CRF preincubation with a t1/2 of 13 h and a full restoration of cAMP responsiveness to CRF at 24 h following the removal of 10 nM CRF. Because the ability of vasoactive intestinal peptide, forskolin, or (-)-isoproterenol to stimulate cAMP accumulation was not diminished in Y-79 cells desensitized with 10 nM CRF, the observed desensitization was considered to be a specific homologous action of CRF. CRF receptor desensitization was markedly attenuated by CRF receptor antagonists, which alone did not produce any appreciable reduction in CRF-stimulated cAMP accumulation. Although recent reports have demonstrated a rapid decline in steady-state levels of CRF receptor type 1 (CRF-R1) mRNA in anterior pituitary cells during several hours of exposure to CRF, there was no observed reduction in CRF-R1 mRNA levels when Y-79 cells were preincubated with 10 nM CRF for 10 min-24 h despite a rapid time- and concentration-dependent loss of CRF receptors from the retinoblastoma cell surface.

Adenylyl Cyclases↗

PubMed1997

Central serotonin activity and aggression: inverse relationship with prolactin response to d-fenfluramine, but not CSF 5-HIAA concentration, in human subjects.

OBJECTIVE: This study compared the nature and magnitude of the relationship between aggression and CSF 5-hydroxyindoleacetic acid (5-HIAA) concentration with that between aggression and the prolactin response to d-fenfluramine challenge in human subjects. METHOD: The Life History of Aggression assessment scores of 24 subjects with personality disorders were compared with their lumbar CSF 5-HIAA concentrations and with their prolactin responses to d-fenfluramine challenge. RESULTS: Aggression was significantly and inversely correlated with prolactin responses to d-fenfluramine challenge but not with lumbar CSF 5-HIAA concentrations in these subjects. CONCLUSIONS: Prolactin response to d-fenfluramine may be more sensitive than lumbar CSF 5-HIAA concentration in detecting a relationship between aggression and central serotonin activity in noncriminally violent human subjects.

Adult↗

PubMed1997

Stress-induced declarative memory impairment in healthy elderly subjects: relationship to cortisol reactivity.

A group of 14 healthy elderly subjects was submitted to a nonstressful (attentional task) and a stressful (public speaking task) condition. Declarative (conscious recollection of learned information) and nondeclarative (retrieved information without conscious or explicit access) memory as well as salivary cortisol levels were measured before and after each condition. The results showed that the stressful condition significantly decreased declarative memory performance, whereas the nonstressful condition did not. Nondeclarative memory performance was not affected by either condition. Further analyses separating the subjects into responders and nonresponders in terms of stress-induced cortisol changes revealed a very different pattern of cortisol secretion and declarative memory performance in both populations. We showed that the responders presented increased cortisol levels 60 min before the actual stressor, whereas the nonresponders presented increased cortisol levels 25 min before the actual stressor. Although the responders did not differ from the nonresponders in declarative memory performance before and after the nonstressful condition, they presented a lower declarative memory performance when measured before and after the stressful condition. The early increase in cortisol levels observed in the responder group suggests that the anticipation of the stress, rather than the actual stressor per se, may have played a more significant role in the stress-induced declarative memory deficits observed in this subgroup. Together, these results show that the cortisol response to anticipation of stress and/or to stress in the elderly specifically affects those memory functions that are dependent on hippocampal activity. They also suggest that an altered cortisol responsivity to acute and/or chronic stress, with its detrimental effects on memory, could be an important factor explaining the genesis of memory deficits in aged populations.

Aged↗

PubMed1996

Relationship of prolactin response to d-fenfluramine to behavioral and questionnaire assessments of aggression in personality-disordered men.

Prolactin (PRL) responses to acute challenge with the serotonin (5-HT) releaser/uptake inhibitor, d-fenfluramine (PRL[d-FEN]), were correlated with three different measures of aggression in 14 male personality-disordered subjects. Consistent with previous work, PRL[d-FEN] responses were inversely correlated with scores on the Buss-Durkee Hostility Inventory-Assault scale (BDHI-Assault) and with the Brown-Goodwin Aggression-Revised (BGA-R) Aggression scale. In addition, PRL[d-FEN] responses were inversely correlated with a direct laboratory measure of aggressive behavior (Point-Subtraction Aggression Paradigm: PSAP). Although all measures of aggression correlated with PRL[d-FEN] response, differences among the intercorrelations of these measures were found. Specifically, BGA-R Aggression scores correlated with both BDHI-Assault and PSAP scores, but no relation was found between BDHI-Assault and PSAP scores. The results suggest that central 5-HT function may be associated with both self-report and behavioral measures of aggressive behavior, which may represent somewhat separate aspects of aggressive behavior.

Adult↗

PubMed1996

Plasma neuropeptide Y in anxiety disorders: findings in panic disorder and social phobia.

The demonstration in preclinical studies that centrally administered neuropeptide Y (NPY) has anxiolytic effects had led to speculation that NPY may play a role in human anxiety disorders. We therefore decided to study plasma NPY levels in 22 patients with DSM-III-R anxiety disorders (11 with panic disorder and 11 with social phobia, generalized type) and 12 never psychiatrically ill comparison subjects. Under resting conditions, plasma NPY levels did not differ among the three diagnostic groups. Following hand immersion in ice water, plasma NE levels--but not NPY levels--increased immediately, but there were no significant differential diagnostic effects. These results are convergent with prior reports of normal sympathetic nerve activity in patients with anxiety disorders.

Adult↗

PubMed1996

Hormonal responses to d- and d,l-fenfluramine in healthy human subjects.

Two different doses of d-fenfluramine HCl and d,l-fenfluramine HCl (0.5 mg/kg and 1.0 mg/kg) were administered to 11 healthy male volunteers to compare the neuroendocrine responses to these two forms of fenfluramine in human subjects. Prolactin (PRL) responses to d- and d,l-fenfluramine were significantly greater than those to placebo and were equivalent at both dose levels. Adrenocortiatrophic-releasing hormone (ACTH) and cortisol (CORT) responses to d-fenfluramine at both dose levels were also significantly greater than those to placebo. In contrast, the higher dose of d,l-fenfluramine was associated only with a significant CORT response in comparison to placebo. PRL responses to d-fenfluramine were higher than the PRL response to d,l-fenfluramine at either dose level. The PRL response to d-fenfluramine at 0.5 mg/kg was very highly correlated with the PRL responses to d,l-fenfluramine at 1.0 mg/kg (r = 0.97, n = 10). Homovanillic acid (HVA) were not altered by either d, or d,l-fenfluramine at either dose in a subsample of subjects (n = 4). ACTH/CORT responses to d- and d,l-fenfluramine were modestly intercorrelated. These data suggest that the PRL response evoked by d-fenfluramine is quantitatively very similar to that evoked by d,l-fenfluramine.

Adrenocorticotropic Hormone↗

PubMed1995

Time course of the corticosteroid-dopaminergic interaction during metyrapone and dexamethasone administration.

Recent studies performed with depressed patients and normal subjects suggest that corticosteroids may alter dopaminergic activity. We measured the time course of the interaction between corticosteroid and plasma homovanillic acid (HVA) levels in 10 young healthy subjects after the administration of 2 mg of dexamethasone in session 1 and after the administration of 4.5 g of metyrapone in session 2. Plasma levels of adrenocorticotropic hormone (ACTH), 11-desoxycortisol, cortisol, HVA, and prolactin (PRL) were measured at 08:00, 09:00, 12:00, 15:00, and 16:00 h on a baseline day and during both drug-administration sessions. Dexamethasone administration resulted in a significant decrease in plasma levels of ACTH, 11-desoxycortisol, and cortisol at all time points and to a significant decrease in PRL secretion in the early morning. Plasma HVA levels were unchanged after dexamethasone administration. Metyrapone administration resulted in a significant decrease in cortisol levels and a significant increase in ACTH and 11-desoxycortisol levels. Plasma HVA levels were significantly increased in the early morning, while PRL levels were unaltered. These results are discussed in relation to the neurochemical and behavioral changes associated with steroid administration and interpreted with regard to a possible association between HVA and PRL in the effects of corticosteroids on dopaminergic activity.

Adrenocorticotropic Hormone↗

PubMed1995

Physiological responses to d-fenfluramine and ipsapirone challenge correlate with indices of aggression in males with personality disorder.

Hormonal responses to challenge with the 5-HT2A/2C probe d-fenfluramine and hormonal and thermal responses to challenge with the 5-HT1A probe ipsapirone were correlated with self-report and historical assessments of aggression in a pilot sample of eight male personality-disordered individuals. Prolactin responses to d-fenfluramine and cortisol responses to ipsapirone challenge were inversely correlated with self-reported assaultiveness. Thermal responses to ipsapirone were inversely correlated with a historical assessment of aggression. Since none of these physiological indices of 5-HT system function were intercorrelated, it is possible that simultaneous assessment of these 5-HT indices may yield a more comprehensive assessment of the relationship between central 5-HT system function and aggressive behavior in humans.

Adult↗