George Fink

University of Melbourne | MSD · Florey Institute of Neuroscience and Mental Health

We have studied the possible role of the hypothalamic-pituitary system in the control of the release of plasminogen activator (PA) into peripheral blood of male rats. Plasminogen activator was measured by euglobulin lysis time. Desamino-D-arginine 8 vasopressin (dDAVP) and adrenaline injected i.v. induced an increase in plasma PA as did electrical...

Stress in mammals triggers a neuroendocrine response mediated by the hypothalamic–pituitary–adrenal (HPA) axis and the autonomic nervous system (ANS). Increased activity of these two systems induces behavioral, cardiovascular, endocrine, and metabolic cascades that enable the individual to fight or flee and cope with stress. Our understanding of st...

Hans Selye in a note to Nature in 1936 initiated the field of stress research by showing that rats exposed to nocuous stimuli responded by way of a ‘general adaptation syndrome’ (GAS). One of the main features of the GAS was the ‘formation of acute erosions in the digestive tract, particularly in the stomach, small intestine and appendix’. This pro...

Stress in mammals triggers a neuroendocrine response mediated by the hypothalamic–pituitary–adrenal (HPA) axis and the autonomic nervous system (ANS). Increased activity of these two systems induces behavioral, cardiovascular, endo-crine, and metabolic cascades that enable the individual to fight or flee and cope with stress. Our understanding of s...

Stress: Neuroendocrinology and Neurobiology: Handbook of Stress Series, Volume 2, focuses on neuroendocrinology, the discipline that deals with the way that the brain controls hormonal secretion, and in turn, the way that hormones control the brain. There have been significant advances in our understanding of neuroendocrine molecular and epigenetic...

Hans Selye in a note to Nature in 1936 initiated the field of stress research by showing that rats exposed to nocuous stimuli responded by way of a 'general adaptation syndrome' (GAS). One of the main features of the GAS was the 'formation of acute erosions in the digestive tract, particularly in the stomach, small intestine and appendix'. This pro...

Stress has a different meaning for different people under different conditions. The first and most generic definition of stress was that proposed by Hans Selye: “Stress is the nonspecific response of the body to any demand.” Selye's generic definition is applicable to the stress response in all three phylogenetic domains of organisms ranging from b...

The present volume on concepts, cognition, emotion, and behavior, is the first in this new Handbook series. The purpose of this first chapter is to provide an outline of stress, stress definitions, the response to stress and neuroendocrine mechanisms involved, and stress consequences such as anxiety and posttraumatic stress disorder. Study of the n...

Hans Selye in a note to Nature in 1936 initiated the field of stress research by showing that rats exposed to nocuous stimuli responded by way of a "general adaptation syndrome" (GAS). One of the main features of the GAS was the "formation of acute erosions in the digestive tract, particularly in the stomach, small intestine and appendix". This pro...

The discovery in 1936 that rats respond to various damaging stimuli with a general response that involves alarm, resistance and exhaustion launched the discipline of stress research.

Stress: Concepts, Cognition, Emotion, and Behavior: Handbook in Stress Series, Volume 1, examines stress and its management in the workplace and is targeted at scientific and clinical researchers in biomedicine, psychology, and some aspects of the social sciences. The audience is appropriate faculty and graduate and undergraduate students intereste...

Geoffrey Harris, while still a medical student at Cambridge, was the first (1937) to provide experimental proof for the then tentative view that the anterior pituitary gland was controlled by the central nervous system. The elegant studies carried out by Harris in the 1940s and early 1950s, alone and in collaboration with John Green and Dora Jacobs...

This chapter focuses on the principles of neural control of the anterior lobe of the pituitary gland. Derived embryologically from a neural downgrowth, the neural lobe is composed of axons that project from nerve cells in the hypothalamus and terminate on capillaries of the inferior hypophysial artery. Neurohemal junctions are the fundamental funct...

This chapter focuses on the principles of negative feedback control using the hypothalamic pituitary adrenal (HPA) system as an example. Feedback control systems are fundamental for the normal physiological functioning of the body. Glucocorticoid feedback inhibition of ACTH release protects the organism against the deleterious effects of hypercorti...

Neuroendocrinology, the discipline concerned with how the nervous system controls hormonal secretion and how hormones control the brain, is pivotal to physiology and medicine. Neuroendocrinology has disclosed and underpins fundamental physiological, molecular biological and genetic principles such as the regulation of gene transcription and transla...

Treatment resistance remains a major obstacle in schizophrenia, with antipsychotic drugs (APDs) being ineffective in about one third of cases. Poor response to standard therapy leaves the APD clozapine as the only effective treatment for many patients. The reason for the superior efficacy of clozapine is unknown, but as we have proposed previously...

Pituitary luteinizing hormone (LH) and hypothalamic gonadotropin-releasing hormone (GnRH) contents were measured in male voles trapped in the field over a period of 5 years. Pituitary LH contents were positively correlated with testicular and seminal vesicle weights but hypothalamic GnRH contents showed no correlation with pituitary LH contents or...

Stress in mammals triggers a neuroendocrine response mediated by the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. Increased activity of these two systems induces behavioural, cardiovascular, endocrine and metabolic cascades that enable the individual to fight or flee and cope with the stress. Our understanding of stress and...

Stress has a different meaning for different people under different conditions. The first and most generic definition of stress was that proposed by Hans Selye: "Stress is the nonspecific response of the body to any demand." Other definitions have evolved to cater for different situations-for example, cognitive. This article explores the basis for...

The hypothalamic-pituitary-adrenocortical (HPA) system, together with the sympathetic-medullary system, plays a pivotal role in the neuroendocrine response to stress. Homeostasis within the hypothalamic HPA is maintained by a precise negative feedback system by which the adrenal glucocorticoids (the afferent feedback signal), cortisol or corticoste...

Neuroendocrinology is the study of how the nervous system controls hormonal secretion and how, in turn, hormones affect the nervous system. The brain-pituitary neuroendocrine system processes information from and enables endocrine responses to external factors, such as stress, day length, and changes in ambient temperature. Attention here is focuse...

A secretagogue is an agent that promotes the secretion of hormones, neurohormones, chemical neurotransmitters, enzymes, or other molecules synthesized and secreted by cells. The selectivity or specificity of a secretagogue is determined by the structure of the secretagogue and that of its receptors on or within the cell. Secretagogues may be endoge...

Like the first edition, the second edition of the Encyclopedia of Stress covers nearly every conceivable aspect and ramification of stress including a wide range of related topics such as neuroimmune interactions, cytokines, enzymatic disorders, effects on the cardiovascular system, immunity and inflammation, and physical illnesses. Over the last d...

chromatography, and cytosolic PLA 2 activity was measured in blood serum using a fluorometric HPTLC-based assay. Measurements were performed before and after a 6 month interval of placebo-controlled supplementation with n-3 fatty acids. Results: At baseline significant associations were found between (n-9) and (n-6)-PUFA levels and psychopathology...

The atypical antipsychotic drug clozapine is effective in treatment-refractory schizophrenia. The intracellular signaling pathways that mediate clozapine action remain unknown. A potential candidate is the mitogen-activated protein kinase extracellular signal-regulated kinase (MAPK-ERK) cascade that links G-protein-coupled receptor and ErbB growth...

The endocrine system is one of three control systems of the body, along with the nervous and the immune/inflammatory systems. Endocrinology is concerned with hormones, chemical compounds synthesized and secreted by glands and transported by the blood stream to their target organs. The endocrine system is under the control of the nervous system and...

Progesterone can either facilitate or inhibit the oestradiol (E(2))-induced gonadotrophin surge. We have previously developed immature female rat models to characterise and investigate the mechanisms of progesterone inhibition or facilitation. The aim of the present study was to determine the role of pituitary responsiveness to gonadotrophin-releas...

Sex steroids have potent effects on mood, mental state and cognition. Our previous findings and those of others suggest that these effects may be due at least in part to estradiol actions on central serotonergic mechanisms. Specifically, estradiol-17beta in its acute positive feedback mode for gonadotropin release in the female rat induces expressi...

Clozapine invokes the EGF system to activate ERK: a novel target in treatment resistant schizophrenia? - Volume 18 Issue 6 - A Pereira, G Fink, S Sundram

Exogenous and endogenous cannabinoids have been shown to have neuroprotective effects in vitro and in vivo. Although many of the pharmacological effects of cannabinoids have been identified, the mechanism of neuroprotection still represents a controversy. Here we demonstrate for the first time protective effects of the synthetic cannabinoid dexanab...

The therapeutic potential of cannabinoids has been described previously for several inflammatory diseases, but the molecular mechanisms underlying the anti-inflammatory properties of cannabinoids are not well understood. In this study, we investigated the mechanism of action of a novel synthetic cannabinoid, [(+)(6aS,10aS)-6,6-Dimethyl-3-(1,1-dimet...

The endopeptidase EC 3.4.24.15 (EP24.15) is a zinc metalloendopeptidase that is widely distributed in a variety of tissues, including the testes, pituitary and the central nervous system. Among its numerous roles in metabolizing and processing biologically-active peptides, the enzyme degrades gonadotropin-releasing hormone (GnRH) by cleaving the ce...

Consultant in child and adolescent psychiatry St George's, University College, and Florence Nightingale Hospitals, London (b Melbourne, Australia, 1938; q Melbourne 1960; MPhil, FRACP, FRCPsych), died from malignant glioma on June 7 2003. 2003. Figure 1 Torn between medicine and literature, Harold Caplan read both with distinction, graduating MB...

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Oestrogen and testosterone, the main sex steroid hormones, have long been known to affect behaviour. They also affect mood, mental state and cognition. Recent experimental findings suggest that these effects of sex hormones may be mediated by serotonin, an important neurotransmitter, dysfunction of which has been implicated in mood disorders and sc...

The human pituitary gland weighs no more than 1 g, but nonetheless controls all the major endocrine systems and is indispensable for life. Located at the base of the brain, and closely surrounded by protective dense bone and fibrous membranes, the gland is comprised of the neurohypophysis or neural lobe and the adenohypophysis. Embryologically deri...

Estradiol-17beta (E(2)), in its positive feedback mode for gonadotropin release in the female rat, induces expression of the genes for the 5-hydroxytryptamine(2A) receptor (5-HT(2A)R) and the serotonin transporter (SERT) in the dorsal raphe nucleus (DRN) with a concomitant increase in the densities of 5-HT(2A)R and the SERT in rat forebrain. The fo...

Sex steroids exert potent effects on mood and mental state in the human. Our previous experimental findings in female rats suggest that these effects may be mediated, in part, by the action of estrogen on the 5-hydroxytryptamine2A receptor (5-HT(2A)R) and serotonin transporter (SERT) in brain. Here we review our recent findings on the effect of acu...

Serotonin (5-HT) plays a role in mediating the oestradiol-induced surge of luteinising hormone (LH), but so far the 5-HT receptor subtype involved has not been identified. Our previous in-situ hybridization and pharmacological studies suggest that the action of 5-HT involves the 5-HT2A receptor. The aim of the present study was to investigate this...

Estrogen increases serotonin transporter (SERT) mRNA and binding sites in female rat brain. In order to determine whether changes in SERT are gender- and steroid-specific we have now carried out studies on adult male Wistar rats which were either intact or castrated (under halothane anesthesia) and injected with arachis oil, estradiol benzoate (EB)...

Activation of cAMP synthesis by intracellular Ca2+ is thought to be the main mode of cAMP generation in the brain. Accordingly, the Ca2+-activated adenylyl cyclases I and VIII are expressed prominently in forebrain neurons. The present study shows that the novel adenylyl cyclase type IX is inhibited by Ca2+ and that this effect is blocked selective...

Serotonin (5-HT) plays a role in mediating the oestradiol-induced surge of luteinising hormone (LH), but so far the 5-HT receptor subtype involved has not been identified. Our previous in-situ hybridization and pharmacological studies suggest that the action of 5-HT involves the 5-HT2A receptor. The aim of the present study was to investigate this...

Feedback control systems are fundamental for physiological mechanisms. Disruption of feedback control almost inevitably leads to a pathological state. The consequence of a failure in negative feedback is exemplified by the adrenogenital syndrome. Failure in positive feedback is exemplified by disruption of the estrogen positive feedback on the hypo...

1. Sex steroid hormones exert profound effects on mood and mental state. Thus, in women, oestrogen is thought to protect against depression and delay the onset of schizophrenia and Alzheimer's disease. 2. Our studies in the female rat show that oestradiol, in its positive feedback mode for gonadotrophin release, increases the expression of genes fo...

Our previous findings in female rats suggest that the potent effects of sex steroids on mood and mental state may be mediated, in part, by the effect of estrogen on the 5-hydroxytryptamine2A receptor (5-HT2AR) in brain. The aim of the present study was to determine the effect of acute (approximately 32h) sex steroid manipulation on central 5-HT2AR...

G-protein-coupled receptors of the rhodopsin family transduce many important neural and endocrine signals. These receptors activate heterotrimeric G proteins and in many cases also cause activation of phospholipase D, an enzyme that can be controlled by the small G proteins ARF and RhoA. Here we show that the activation of phospholipase D that is i...

Xuesaitong is an injectable preparation of the ginseng species Panax Notoginseng used in Chinese traditional medicine to treat thrombosis. We examined the mechanism of action of Xuesaitong (a kind gift of E Roberts, University of East London) in the human endothelial cell line, EAhy926. Confluent cells were incubated for 24 h in serum-free medium c...

The endopeptidase EC 3.4.24.15 (EP24.15) is a zinc metalloendopeptidase that is widely distributed in a variety of tissues, including the testes, pituitary and the central nervous system. Among its numerous roles in metabolizing and processing biologically-active peptides, the enzyme degrades gonadotropin-releasing hormone (GnRH) by cleaving the ce...

We have shown previously that in ovariectomised rats, oestradiol-17beta, in its positive-feedback mode for luteinizing hormone (LH) release, induces a significant increase in the density of 5-hydroxytryptamine2A (5-HT2A) receptors in the forebrain. Here we investigated whether there are any changes in 5-HT2A receptor density in relation to the spon...

The aim of the present study was to determine the effect of estradiol-17 beta (E2), in its positive feedback mode for gonadotropin release, on the serotonin transporter (SERT) in female rat brain. Levels of SERT mRNA were determined by in situ hybridization and SERT-binding sites were measured by quantitative [3H]paroxetine receptor autoradiography...

1. Estrogen exerts profound effects on mood, mental state and memory by acting on both “classical” monoamine and neuropeptide transmitter mechanisms in brain. Here we review an example of each type of action. 2. With respect to the effect of estrogen on central monoamine neurotransmission, low levels of estrogen in women are associated with the pre...

BACKGROUND; The serotonin transporter of the brain provides the primary target for the action of selective antidepressant drugs. We set out to identify polymorphisms of the serotonin transporter gene and to find out whether there was a relation between any such polymorphisms and the occurrence of affective disorder. A comparison of a polymorphic re...

We have recently reported an association between a polymorphism of a variable number tandem repeat (VNTR) region of the serotonin transporter gene and susceptibility to major depressive disorder. We identified three alleles containing respectively 9 (STin2.9), 10 (STin2.10) and 12 (STin2.12) copies of a repetitive element. We report here the sequen...

Estrogen exerts a profound effect on mood and mental function in man. Based on our finding that estradiol selectively stimulates the expression of 5-hydroxytryptamine2A (5-HT2A) receptor mRNA in the dorsal raphe nucleus of the female rat, we investigated the effects of estradiol on the density of 5-HT2A receptors in brain. The distribution and dens...

Pituitary adenylate cyclase activating polypeptide (PACAP) was first isolated from ovine hypothalamus as two molecular forms, the basic 38 residue amidated peptide PACAP-38 and the N-terminal 27 amino acid sequence PACAP-27. A dense plexus of PACAP immunoreactive fibres is present in the internal and external layers of the median eminence and in ot...

We showed previously that the surge of luteinizing hormone-releasing hormone (LHRH) induced by estradiol-17 beta (E2) in the female rat can be blocked by an alpha 1 adrenergic antagonist. The aim of the present study was to determine whether this was due to a direct action of E2 on noradrenergic projections to LHRH neurons or whether it also involv...

Pituitary adenylate cyclase activating polypeptide (PACAP) was first isolated from ovine hypothalamus as two molecular forms, the basic 38 residue amidated peptide PACAP-38 and the N-terminal 27 amino acid sequence PACAP-27. A dense plexus of PACAP immunoreactive fibres is present in the internal and external layers of the median eminence and in ot...

8-OH-DPAT, a selective 5-HT1A agonist, produced a hypothermic response in mice at a dosage of 0.5 mg/kg. Administration of corticosterone-21-acetate (0.5, 5 and 50 mg/kg, daily for 3 and 10 days) produced a dose-dependent attenuation of this hypothermic response in mice. When all controls and corticosterone treated mice were retested, 14 days after...

To characterize the mechanisms of the pituitary-adrenal (P-A) response to tissue injury, rats were injected intramuscularly (IM) with turpentine. This resulted in marked elevations in the plasma concentrations of ACTH and corticosterone within the first hour after injection, which were attenuated by either total deafferentation of the medial basal...

The role of serotonin (5-HT) in generating the spontaneous preovulatory surge of luteinizing hormone (LH) has been investigated by studying the effect of ketanserin (a mixed 5-HT2/alpha 1 adrenoreceptor antagonist); the selective 5-HT2 receptor antagonist, ritanserin; and the selective alpha 1 adrenoreceptor antagonist, prazosin, on the plasma conc...

The study of steroid action on the brain and the pituitary gland offers a powerful method of establishing key principles about the molecular mechanisms that underlie central neurotransmission. This chapter focuses on the acute and longer-term stimulatory effects of gonadal steroids: (1) the stimulation by estradiol-l7β (E2) of luteinizing hormone r...

We have previously demonstrated that the concentrations of immunoreactive atrial natriuretic peptide (IR-ANP) are significantly higher in hypophysial portal compared with peripheral blood of the rat, and that ANP suppresses the pituitary release of ACTH and beta-endorphin in vitro and in vivo. Using HPLC, we have now shown that the predominant spec...

We have cloned and sequenced a cDNA (RPR4) encoding a new member of the secretin/calcitonin/parathyroid hormone (PTH) receptor family. RPR4 was identified by PCR of rat pituitary cDNA, and a full-length clone was isolated from a rat olfactory bulb cDNA library. When RPR4 was functionally expressed in COS 7 cells, cyclic adenosine monophosphate (cAM...

Day-time plasma β-endorphin /β-lipothropic hormone (β-ENDO/β-LPH), ACTH and cortisol have been determined in 26 patients with major depression and 25 controls. β-ENDO/β-LPH and cortisol were significantly elevated in patients, while ACTH was not. Cortisol levels were significantly negatively correlated with age in controls as were β-ENDO/β-LPH and...

We have cloned and sequenced a novel cDNA (RPR7) encoding a receptor for pituitary adenylate cyclase activating polypeptide (PACAP). RPR7 was identified by PCR of rat pituitary cDNA, and full-length clones were isolated from a rat olfactory bulb cDNA library. When expressed in COS cells, RPR7 was functionally coupled to increases in intracellular c...

The aim of this study was to determine the effects of sex, corticosterone and oestradiol-17 beta on the hypothermia and motor behavioural syndrome induced by the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in the rat. The hypothermia, but not the behavioural syndrome induced by 8-OH-DPAT was significantly greater in f...

Excessive glucocorticoid levels increase the metabolic vulnerability of hippocampal neurons to a wide variety of insults. Since glucocorticoid hypersecretion occurs in Alzheimer's-type dementia it has been proposed that a primary reduction in hippocampal glucocorticoid receptor expression leads to failure of feedback, hypercortisolemia and hence fu...

Steroid-metabolizing enzymes modulate the effects of androgens on brain differentiation and function, but no similar enzymatic system has been demonstrated for adrenocorticosteroids which exert feedback control on the hypothalamus. 11β-Hydroxysteroid dehydrogenase (11β-OHSD) rapidly metabolizes physiological glucocorticoids (corticosterone, cortiso...

The aim of the present study was to determine the effect of estradiol-17beta, in its positive feedback mode for the release of prolactin and luteinizing hormone (LH), on gene expression of 5-hydroxytryptamine (5-HT) and dopamine receptors. Gene expression was determined by measurement of the levels of receptor mRNA by in situ hybridization in brain...

The bed nucleus of the stria terminalis (BNST) in rodents contains arginine vasopressin (AVP) neurons which project to the lateral septum (LS) and habenula (LH) and are thought to be important for social recognition or memory. In previous studies we demonstrated that AVP immunoreactivity in the LS and LH is absent in the hypogonadal (hpg) mouse and...

The actions of gonadal steroids on neuronal activity in the hypothalamus are well documented, but the effects on glial cells are less clear. Here we have investigated glial cell activity in normal and hypogonadal (hpg) mice, in which gonadal development is arrested postnatally. Astrocytes immunoreactive for filial fibrillary acidic protein (GFAP) w...

The aim of this study was to determine the effect of sex and sex steroids on the distribution of glial fibrillary acidic protein (GFAP) -containing astrocytes in the hippocampal CA1 region of normal, testicular feminized (Tfm/Y) and hypogonadal (hpg) mice. The number of GFAP-immunoreactive (GFAP-IR) cells, assessed by immunohistochemistry, was sign...

The aims of this study were to determine whether the administration of cortisol has a significant effect on mood in patients with depression and whether the effects of cortisol on changes in plasma hormone concentrations are like those of synthetic corticosteroids. Twelve patients had major depression and one each had dysthymic disorder and a depre...