Biomedical subjects

H Akil

Publications and source records attributed to H Akil.

At least 37 records · Page 2Linked to original sources

PubMed2001

Sturgeon orphanin, a molecular "fossil" that bridges the gap between the opioids and orphanin FQ/nociceptin.

The elucidation of the cDNA sequence for sturgeon proorphanin provides a unique window for interpreting the evolutionary history of the opioid/orphanin gene family. The molecular "fossil" status of this precursor can be seen in several ancestral sequence characteristics that point to its origin as a duplication of either a prodynorphin- or proenkephalin-like gene. The sturgeon proorphanin cDNA encodes a precursor protein of 194 residues, and the orphanin heptadecapeptide itself binds not only the opioid receptor-like 1 (ORL1) receptor but also the classical (mu, kappa, and delta) opioid receptors with near equal affinity. Allowing for this broad receptor specificity are several amino acid substitutions at key positions in the heptadecapeptide sequence, relative to its mammalian orthologs, that have been linked by amino acid scans and site-directed mutagenic studies to the exclusion of mammalian orphanin FQ/nociceptin from classic opioid ligands (i.e. F1Y and L14W). The unique receptor binding profile of sturgeon orphanin not only provides insight into the evolutionary history of the opioid and opioid-related peptides but also provides an ideal context in which to investigate the underlying mechanisms by which novel and often divergent physiological functions arise in receptor-ligand systems.

Amino Acid Sequence↗

PubMed2001

Norepinephrine-induced CRH and AVP gene transcription within the hypothalamus: differential regulation by corticosterone.

We have previously demonstrated that microinjection of norepinephrine (NE) into the paraventricular nucleus of the hypothalamus (PVN) of conscious rats elicits a marked increase in CRH gene transcription, indicated by CRH hnRNA levels, without changing AVP hnRNA levels. We hypothesized that this differential response is due to differential sensitivity of AVP and CRH gene transcription to the inhibitory effects of the NE-induced rise in corticosterone. In the current study, we used animals that had been adrenalectomized and implanted with a subcutaneous corticosterone pellet (ADX/B) which prevented the NE-induced rise in corticosterone levels. NE (50 nmol) or artificial CSF was injected into the PVN of conscious rats, which had undergone either sham-operation (SHAM) or ADX/B 1 week earlier. CRH and AVP hnRNA levels were semi-quantitated by in situ hybridization using intron-specific riboprobes. In both SHAM and ADX/B animals, CRH hnRNA levels were significantly elevated at the 15 min time-point and returned to basal levels by 120 min. At 15 min, the magnitude of the CRH hnRNA response was only slightly greater in the ADX/B group than SHAM. In contrast, changes in medial parvocellular PVN AVP hnRNA levels in the ADX/B group were significantly greater than the changes observed in the SHAM group, at both the 15 and 120 min time-points. These results suggest that corticosterone has a greater impact on the transcriptional regulation of AVP than CRH, suggesting important differences and distinct roles of these secretagogues in the regulation of the hypothalamic-pituitary-adrenal axis.

Adrenalectomy↗

PubMed2001

Environmental novelty differentially affects c-fos mRNA expression induced by amphetamine or cocaine in subregions of the bed nucleus of the stria terminalis and amygdala.

The environmental context in which amphetamine or cocaine are administered modulates both their acute psychomotor activating effects and their ability to induce sensitization. Here we report that environmental context differentially affects patterns of amphetamine- and cocaine-induced c-fos mRNA expression in the bed nucleus of the stria terminalis (BST) and amygdala of male rats. In the medial amygdala and medial posterior BST, exposure to novelty resulted in a marked increase in c-fos mRNA. Amphetamine given at home did not induce c-fos mRNA, and when given in the novel environment, did not increase levels beyond that observed for novelty alone. In the basolateral and lateral amygdala, amphetamine or cocaine at home or exposure to novelty induced c-fos mRNA. When amphetamine or cocaine was given in a novel environment the c-fos mRNA response was significantly enhanced. In the central nucleus of the amygdala (CEA) and oval subnucleus of the BST (BSTov), amphetamine administration at home produced a robust increase in c-fos mRNA expression, whereas exposure to novelty had little effect. In contrast to other brain regions examined, the c-fos mRNA response to amphetamine in a novel versus home environment was significantly smaller. In both "home" and "novel" amphetamine groups, c-fos mRNA in the BSTov and CEA was predominantly expressed in enkephalin-containing cells; coexpression with corticotropin-releasing hormone was rare. These data suggest that the context in which psychostimulants are given powerfully and differentially alters the response of limbic structures that have been functionally implicated in drug reinforcement and emotional behaviors.

Amphetamine↗

PubMed2001

Effects of contextual or olfactory cues previously paired with morphine withdrawal on behavior and pain sensitivity in the rat.

RATIONALE: Pavlovian conditioning processes have been accorded an important role in maintaining persistent opiate administration. At least one locus for this contribution is during opiate withdrawal. These experiments studied the contribution of Pavlovian conditioning processes to morphine withdrawal. OBJECTIVES: To determine whether exposure to a distinctive context or odor paired with morphine withdrawal would provoke a withdrawal syndrome, defensive behaviors (e.g., freezing) and pain modulatory (e.g., hypoalgesia) responses similar to those produced by exposure to stimuli signaling other sources of aversive stimulation (e.g., footshock), or whether both withdrawal and fear-like responses would be provoked. METHODS: Rats were used in four experiments to study the effects on defensive behavior and pain sensitivity of naloxone-precipitated morphine withdrawal or exposure to a distinctive context or odor previously paired with such withdrawal. RESULTS: Injection of 2.5 mg/kg naloxone in morphine-dependent rats precipitated a withdrawal syndrome characterized by whole body shaking, diarrhea, ptosis, and postural abnormalities (experiment 1). Exposure to either a distinctive context (experiment 2) or odor (experiments 3) previously paired with morphine withdrawal provoked the species-typical defense response of freezing but not signs of withdrawal. Exposure to an odor previously paired with morphine withdrawal also provoked hypoalgesia in the formalin test, which was mediated by activity at opioid receptors (experiment 4). CONCLUSIONS: These results show that opiate withdrawal supports the conditioning of defensive and hypoalgesic responses consistent with the arousal of a fear motivational system. The emergence of fear in these experiments, and the relationship between the freezing observed here and the learned avoidance and suppression observed in other withdrawal conditioning preparations, is discussed with reference to dual representation accounts of Pavlovian conditioning.

Analgesics, Opioid↗

PubMed2001

Nociceptin/orphanin FQ regulates neuroendocrine function of the limbic-hypothalamic-pituitary-adrenal axis.

We examined the effects of the neuropeptide nociceptin/orphanin FQ on activity of the limbic-hypothalamic-pituitary-adrenal axis (also known as the stress axis) in rats. This axis regulates important metabolic functions, and initiates critical neuroendocrine responses that cope with environmental threats and challenges to homeostatic functioning. Disregulation of the limbic-hypothalamic-pituitary-adrenal axis is associated with impaired physical and psychological health. In the present experiments, rats were treated with intracerebroventricular injections of nociceptin/orphanin FQ in the presence or absence of acute stressors. Plasma adrenocorticotrophic hormone and corticosterone concentrations were assayed 15 or 30min after injections. In the rats that were not exposed to stress, nociceptin/orphanin FQ produced dose-orderly elevations of circulating adrenocorticotrophic hormone and corticosterone concentrations. These effects were also found after administration of the nociceptin/orphanin FQ analogues, des-Phe orphanin FQ and [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin((1-13))NH(2). In rats that were exposed to the mild stress of a novel environment, nociceptin/orphanin FQ administration enhanced the stress-induced elevations of plasma adrenocorticotrophic hormone concentrations and prolonged the stress-induced elevations of plasma corticosterone concentrations. In rats that were exposed to restraint stress, nociceptin/orphanin FQ administration did not augment the stress-induced elevations in plasma hormones, perhaps because of a ceiling effect. We conclude that administration of nociceptin/orphanin FQ activates neuroendocrine activity of the limbic-hypothalamic-pituitary-adrenal axis even in the absence of a stressor, and may delay the shutdown of these physiological responses after exposure to acute mild stress. In light of the known functions of this axis, it appears that nociceptin/orphanin FQ participates in the regulation of important metabolic functions, and may be implicated in physiological responses to stress. This interaction between nociceptin/orphanin FQ and the limbic-hypothalamic-pituitary-adrenal axis implicates nociceptin/orphanin FQ in important aspects of physiological and psychological well-being.

Adrenocorticotropic Hormone↗

PubMed2001

Individual differences in novelty-seeking behavior in rats: a c-fos study.

Novelty-seeking personality traits have been implicated in substance abuse and psychiatric disorders in humans. Novelty-seeking behaviors are also observed in rats, and individual rats exhibit substantial differences in expression of these behaviors. Thus, some rats exhibit low reactivity to novelty and high anxiety-like behavior and are termed low responders, while others are hyperresponsive to novelty and exhibit low anxiety-like behavior and are termed high responders. While we and others had shown differences in patterns of gene expression in high and low responding animals at rest, no studies have described their brain activation following an anxiety test. We report here that a 5-min exposure to an anxiogenic stressor induced distinct patterns of c-fos expression in the brains of high and low responding rats. When compared to low responders, high responding rats showed low expression of c-fos mRNA in the CA1 area of the hippocampus, but high c-fos mRNA levels in the olfactory area, the orbital cortex, the cingulate cortex, the dorsal striatum and the paraventricular nucleus of the hypothalamus. Given that c-fos is a trans-acting factor, we suggest that the short- and long-term consequences of the exposure to the anxiogenic stressor may also be quantitatively and anatomically different in these two groups of animals. Thus, these c-fos results demonstrate how experience may further exaggerate individual differences. Animals that differ in emotional reactivity not only exhibit basal differences in gene expression, but also react to novelty with different molecular responses, further increasing the neuronal differences between them.

Animals↗

PubMed2001

Expression of orphanin FQ and the opioid receptor-like (ORL1) receptor in the developing human and rat brain.

The orphanin peptide system, although structurally similar to the endogenous opioid family of peptides and receptors, has been established as a distinct neurochemical entity. The distribution of the opioid receptor-like (ORL1) receptor and its endogenous ligand orphanin FQ (OFQ) in the central nervous system of the adult rat has been recently reported, and although diffusely disseminated throughout the brain, this neuropeptide system is particularly expressed within stress and pain circuitry. Little is known concerning the normal expression of the orphanin system during gestation, nor how opiate or stress exposure may influence its development. Using in situ hybridization techniques, the present study was undertaken to determine the normal pattern of expression of ORL1 mRNA in the human and rat brain at various developmental stages. Rat embryos, postnatal rat brains and postmortem human brains were collected, frozen and cut into 15 microm coronal sections. In situ hybridization was performed using riboprobes generated from cDNA containing representative human and rat ORL1 and OFQ sequences. Both ORL1 and OFQ mRNA is detected as early as E12 in the cortical plate, basal forebrain, brainstem and spinal cord. Expression for both ORL1 and OFQ is strongest during the early postnatal period, remaining strong in the spinal cord, brainstem, ventral forebrain, and neocortex into the adult. Human ORL1 and OFQ expression is observed at 16 weeks gestation, remaining relatively unchanged up to 36 weeks. The influence of early orphanin expression on maturation of stress and pain circuitry in the developing brain remains unknown.

Age Factors↗

PubMed2001

Amphetamine and cocaine induce different patterns of c-fos mRNA expression in the striatum and subthalamic nucleus depending on environmental context.

In the dorsal striatum, there are two major populations of medium spiny projection neurons. One population is positive for dynorphin mRNA (DYN+), and these cells project preferentially to the substantia nigra, forming the so-called 'direct pathway'. A second population is positive for enkephalin mRNA (ENK+), and these cells influence the substantia nigra indirectly, via the globus pallidus and subthalamic nucleus. Psychostimulant drugs, such as amphetamine and cocaine, are reported to induce immediate early genes (IEGs) in only one subpopulation of dorsal striatal projection neurons, DYN+ cells. However, this apparent selectivity appears to be a function of environmental context. We found that when given in the animal's home cage, amphetamine and cocaine increased expression of the IEG, c-fos, almost exclusively in DYN+ cells. However, when given in a novel environment, amphetamine and cocaine increased c-fos mRNA in both DYN+ and ENK+ cells. Furthermore, amphetamine and cocaine increased c-fos mRNA expression in the subthalamic nucleus when administered in the novel environment, but not when given at home. We conclude that the neural circuitry engaged by psychostimulant drugs, and their ability to induce specific patterns of gene expression, are determined by the environmental context in which they are experienced. This may be related to the ability of environmental novelty to facilitate psychostimulant drug-induced neuroplasticity.

Amphetamine↗

PubMed2001

Corticosteroid receptors: a dynamic interplay between protein folding and homeostatic control. Possible implications in psychiatric disorders.

Glucocorticoids are key elements in the maintenance of an organism's homeostasis, a dynamic balance that is constantly challenged by internal and external stressors. Chronic exposure to elevated glucocorticoids may induce profound effects on an individual's physical and mental well-being. Therefore, a complex neuroendocrine system, the limbic-hypothalamo-pituitary-adrenocortical (LHPA) axis, exists to regulate glucocorticoid homeostasis. Dysregulation of the LHPA axis has been linked to numerous psychiatric disorders, including eating disorders, anxiety, depression, posttraumatic stress disorder, memory impairment, neurodegenerative disorders, and even Alzheimer disease. At a molecular level, the actions of glucocorticoids are mediated by two different cytoplasmic receptors, the mineralocorticoid receptor and the glucocorticoid receptor. These corticosteroid receptors are heteromeric complexes found in dynamic association with a still growing number of chaperone proteins and other factors mediating their actions. Because this dynamic association is extremely sensitive to changes in cellular environment, energy, and metabolic state, we hypothesize that these corticosteroid receptors act as "sensor" signal transducers critical for homeostasis. In this review, we focus on the interplay among protein folding, transport, and function of the corticosteroid receptors at the cellular level, which provides a foundation for understanding the pathogenesis of glucocorticoid resistance or hypersensitivity, causing imbalances in the LHPA axis, and possibly triggering psychiatric disorders.

Animals↗

PubMed2000

The "chip" as a specific genetic tool.

DNA microarrays are powerful tools for the analysis of the organization and regulation of the brain, in both illness and health. Such messenger RNA expression methods are outgrowths of a marriage between the several genome sequencing projects and a wide variety of physical, chemical, optical, and electronic systems. The advantages of microarray analyses include the ability to study the regulation of several genes or even the entire genome in a single experiment. However, there are substantive issues associated with the use of these tools that need to be considered before drawing conclusions about the genomic regulation of the brain. These issues include the loss of most anatomic (i.e., cellular and circuit) specificity, only fair sensitivity, lack of absolute quantitative data, poor comparability between studies, and high variability in sample values, to mention the most obvious. In this review we point to some of the solutions proposed for these problems and novel techniques and approaches for newer methods. Among these are methods for making arrays more sensitive, including nonarray messenger RNA expression systems. The future of this field and its links to deeper protein and cell biology are both emphasized.

Clinical Laboratory Techniques↗

PubMed2000

Neurobiological correlates of individual differences in novelty-seeking behavior in the rat: differential expression of stress-related molecules.

It is well established that individual rats exhibit marked differences in behavioral responses to a novel environment. Rats that exhibit high rates of locomotor activity and sustained exploration in such an environment also exhibit high concentrations of stress-induced plasma corticosterone, linking this behavior to the stress system. Furthermore, these high-responding (HR) rats, in contrast to their low-responding (LR) counterparts, have a greater propensity to self-administer drugs. Thus, HR rats have been described as "novelty" seeking in that they are more active and explore novel stimuli more vigorously, despite the fact that this elicits in them high stress responses. In this study, we have further characterized the behavior of HR and LR rats in tests of anxiety and characterized their stress responses to either experimenter- or self-imposed stressors. We then investigated the physiological basis of these individual differences, focusing on stress-related molecules, including the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), corticotropin-releasing hormone (CRH) and pro-opiomelanocortin (POMC) in the context of the limbic-hypothalamo-pituitary adrenal axis. We have found that HR rats did not differ from LR in their basal expression of POMC in the pituitary. However, HR rats exhibited higher levels of CRH mRNA in the hypothalamic paraventricular nucleus but lower basal levels in the central nucleus of the amygdala. The basal expression of hippocampal MR is not different between HR and LR rats. Interestingly, the basal expression of hippocampal GR mRNA is significantly lower in HR than in LR rats. This low level of hippocampal GR expression in HR rats appears to be responsible, at least in part, for their decreased anxiety in exploring novelty. Indeed, the anxiety level of LR rats becomes similar to HR rats after the administration into the hippocampus of a GR antagonist, RU38486. These data indicate that basal differences in gene expression of key stress-related molecules may play an important role in determining individual differences in responsiveness to stress and novelty. They point to a new role of hippocampal GR, strongly implicating this receptor in determining individual differences in anxiety and novelty-seeking behavior.

Amygdala↗

PubMed2000

Selectivity of mu-opioid receptor determined by interfacial residues near third extracellular loop.

We hypothesized that the selectivity profile of the rat mu-opioid receptor for opioid receptor-selective ligands is determined by the nature of the amino acid residues at highly divergent sites in the ligand-binding pocket. To determine which characteristics of these residues contribute to opioid receptor ligand selectivity, we made various mutant receptors that replaced the Lys(303) and Trp(318) residues near the extracellular interface of transmembrane domains VI and VII, respectively. Ligand binding determinations using transiently transfected monkey kidney epithelial (COS-1) cells show that Lys(303) mutations cause little change in the receptor binding profile, whereas the Trp(318) mutant receptors have considerably lower affinity for micro-opioid receptor-selective ligands and greatly increased affinity for delta-opioid receptor-selective ligands. The nature of these mutations show that this effect is not due to sterics or charge alone. [35S]guanosine-5'-O-(3-thio)-triphosphate ([35S]GTPgammaS) activity assays show that these residues may influence functional, as well as binding selection. We conclude that a primary role for Trp(318) is to form a basis for ligand selectivity.

Amino Acid Substitution↗

PubMed2000

Switching agonist/antagonist properties of opiate alkaloids at the delta opioid receptor using mutations based on the structure of the orphanin FQ receptor.

In an earlier study, we have demonstrated that by mutating five amino acid residues to those conserved in the opioid receptors, the OFQ receptor could be converted to a functional receptor that bound many opioid alkaloids with nanomolar affinities. Surprisingly, when the reciprocal mutations, Lys-214 --> Ala (TM5), Ile-277 --> Val/His-278 --> Gln/Ile-279 --> Val (TM6), and Ile-304 --> Thr (TM7), are introduced in the delta receptor, neither the individual mutations nor their various combinations significantly reduce the binding affinities of opioid alkaloids tested. However, these mutations cause profound alterations in the functional characteristics of the mutant receptors as measured in guanosine 5'-3-O-(thio)triphosphate binding assays. Some agonists become antagonists at some constructs as they lose their ability to activate them. Some alkaloid antagonists are transformed into agonists at other constructs, but their agonistic effects can still be blocked by the peptide antagonist TIPP. Even the delta inverse agonist 7-benzylidenenaltrexone becomes an agonist at the mutant containing both the Ile-277 --> Val/His-278 --> Gln/Ile-279 --> Val and Ile-304 --> Thr mutations. Thus, although the mutated residues are thought to be part of the binding pocket, they are critically involved in the control of the delta receptor activation process. These findings shed light on some of the structural bases of ligand efficacy. They are also compatible with the hypothesis that a ligand may achieve high affinity binding in several different ways, each having different effects on receptor activation.

Animals↗

PubMed2000

Direct evidence of nitric oxide presence within mitochondria.

Nitric oxide (NO) has been implicated in the modulation of mitochondrial respiration, membrane potential, and subsequently in apoptosis. Although the presence of a mitochondrial NO synthase (mtNOS) has been described, there is no direct evidence in vivo of the presence of NO within mitochondria. It was the aim of this study to demonstrate the in vivo production of NO within mitochondria. Using the novel fluorometric NO detection system, 4,5-diaminofluorescein diacetate (DAF-2/DA), we observed the presence of NO production in PC12 and COS-1 cells by conventional and confocal fluorescence microscopy. Part of the overall NO signal was colocalized within a subpopulation of mitochondria, labeled with the potential-dependent probe MitoTracker red. These findings demonstrate for the first time that the subcellular distribution of NO production is consistent with the presence of a mitochondrial NOS. Our results provide a new tool to directly study the modulatory role of NO in mitochondrial respiration and membrane potential, in vivo.

Animals↗

PubMed2000

Temporal and anatomical distribution of nitric oxide synthase mRNA expression and nitric oxide production during central nervous system inflammation.

Nitric oxide (NO) has important roles in inflammatory processes. It was the aim of this study to ascertain whether changes in nitric oxide synthase (NOS) mRNA expression lead to similar temporal and anatomical changes in NO production in an experimental model of CNS inflammation. NOS-II (inducible NOS) mRNA expression was analyzed 2, 4, 6 and 24 h after intracerebroventricular (i.c.v.) injection of interleukin-1beta (IL-1beta) or vehicle. Increased expression of NOS-II mRNA was observed surrounding the microinjection site and meninges. The changes were significantly higher than controls at 4 and 6 h, returning to baseline at 24 h. Using the novel fluorometric NO detection system, 4,5-Diaminofluorescein diacetate (DAF-2/DA), for the direct detection of NO production, we observed a significant increase in NO production after 4 and 6 h. NO production was observed in areas surrounding the injection site, meninges surrounding the brain and perivascular cells and neuron-like cells throughout the cortex. However, increases in NO production in these areas remained significantly higher than controls at 24 h. These findings demonstrate for the first time that, in fresh frozen tissue, that the anatomical distribution of NOS-II mRNA is consistent with the distribution of NO production. We conclude that increases in NOS-II mRNA following i.c.v. administration of IL-1beta lead to increases in NO production. While the mRNA is degraded by 24 h post treatment, the enzyme remains active. We propose that the DAF-2/DA method can be used as a potential marker in the diagnosis of CNS inflammation.

Animals↗

PubMed2000

Science and the future of psychiatry.

If humanity is lucky, the evolution of our knowledge of the living world will result in the elaboration of more perfect scientific eyes to probe the nature of the human brain and to understand the complexities of the human mind. This seems to be the best path to truly helping individuals who are battling psychiatric illnesses and to actually preventing many brain-related disorders. For such accomplishments to take place, the trajectory of our science has to change, to move from its unrelenting reductionism to a serious attempt at integrating knowledge that spans from the structure of the gene to the expression of complex cognition. The tension between the biomedical and the psychotherapeutic approaches in psychiatry needs to be eliminated and transformed into a fully integrated approach that is mindful of the biological, emotional, cognitive, and social complexity of each individual.

Biological Psychiatry↗

PubMed2000

Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting.

To further understand the functions of the orexin/hypocretin system, we examined the expression and regulation of the orexin/hypocretin receptor (OX1R and OX2R) mRNA in the brain by using quantitative in situ hybridization. Expression of OX1R and OX2R mRNA exhibited distinct distribution patterns. Within the hypothalamus, expression for the OX1R mRNA was largely restricted in the ventromedial (VMH) and dorsomedial hypothalamic nuclei, while high levels of OX2R mRNA were contained in the paraventricular nucleus, VMH, and arcuate nucleus as well as in mammilary nuclei. In the amygdala, OX1R mRNA was expressed throughout the amygdaloid complex with robust labeling in the medial nucleus, while OX2R mRNA was only present in the posterior cortical nucleus of amygdala. High levels of OX2R mRNA were also observed in the ventral tegmental area. Moreover, both OX1R and OX2R mRNA were observed in the hippocampus, some thalamic nuclei, and subthalamic nuclei. Furthermore, we analyzed the effect of fasting on levels of OX1R and OX2R mRNA in the hypothalamic and amygdaloid subregions. After 20 h of fasting, levels of OX1R mRNA were significantly increased in the VMH and the medial division of amygdala. An initial decrease (14 h) and a subsequent increase (20 h) in OX1R mRNA levels after fasting were observed in the dorsomedial hypothalamic nucleus and lateral division of amygdala. Levels of OX2R mRNA were augmented in the arcuate nucleus, but remained unchanged in the dorsomedial hypothalamic nucleus, paraventricular hypothalamic nucleus, and amygdala following fasting. The time-dependent and region-specific regulatory patterns of OX1R and OX2R suggest that they may participate in distinct neural circuits under the condition of food deprivation.

Amygdala↗

PubMed2000

Hormonal evidence for altered responsiveness to social stress in major depression.

In patients with major depression, abnormalities in baseline cortisol secretion and resistance to negative feedback are well established. However, it is unclear if patients with major depression have alterations in the hypothalamic-pituitary-adrenal (HPA) response to stressors. While other challenges to the HPA axis have used endocrine stimuli such as insulin-induced hypoglycemia, we now report of the response to a social stressor in patients with major depression and matched control subjects. We used the Trier Social Stress Test (TSST), a public speaking task followed by mental arithmetic challenge in front of a panel of judges. The results suggest that depressed patients manifest normal cortisol response to a social stressor, despite increased pre-stressor plasma cortisol. However, the beta-endorphin response to the TSST was significantly smaller in the depressed patients compared to matched controls. These data are similar to data found with exogenous corticotropin-releasing-hormone challenge studies and suggest that elevated baseline cortisol can modulate the pituitary corticotroph response to a stressor, but that changes in adrenal sensitivity to ACTH result in a robust cortisol response to this stressor.

Adult↗