George Fink | University of Melbourne (original) (raw)

Papers by George Fink

The Journal of Neuroscience, Dec 1, 1998

Activation of cAMP synthesis by intracellular Ca 2ϩ is thought to be the main mode of cAMP genera... more Activation of cAMP synthesis by intracellular Ca 2ϩ is thought to be the main mode of cAMP generation in the brain. Accordingly, the Ca 2ϩ-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 Ca 2ϩ and that this effect is blocked selectively by inhibitors of calcineurin such as FK506 and cyclosporin A. Moreover, adenylyl cyclase IX is inhibited by the same range of intracellular free Ca 2ϩ concentrations that stimulate adenylyl cyclase I. Adenylyl cyclase IX is expressed prominently in the forebrain. Substantial arrays of neurons positive for AC9 mRNA were found in the olfactory lobe, in limbic and neocortical areas, in the striatum, and in the cerebellar system. These data show that the initiation of the cAMP signal by adenylyl cyclase may be controlled by Ca 2ϩ / calcineurin and thus provide evidence for a novel mode of tuning the cAMP signal by protein phosphorylation/dephosphorylation cascades.

BMJ, Mar 29, 1986

Patients and met The number of glucocorticoid receptor sites in lymphocytes was estimated and pla... more Patients and met The number of glucocorticoid receptor sites in lymphocytes was estimated and plasma cortisol concentrations measured in 17 depressed patients, 12 patients with chronic schizophrenia, and 31 healthy control subjects. The number of receptor sites was significantly lower in the depressed patients than in either the controls or the patients with chronic schizophrenia, but there were no differences between the groups in the dissociation constants of the glucocorticoid receptors or the plasma cortisol concentrations. When two control subjects were studied intensively over 28 hours a slight diurnal variation in the number of glucocorticoid receptors was detected. The lower numbers of glucocorticoid receptors in the lymphocytes of depressed patients may explain why such patients, who often have hypercortisolaemia, do not show the clinical features of excess production of cortisol.

Electroencephalography and Clinical Neurophysiology, 1987

Book Reviews Review of Gross Anatomy. By B. PANSKY. 5th edition. (Pp. xiv + 585; many figures; £30.

Journal of Endocrinology, 1977

SUMMARY Plasma concentrations of oestradiol-17β were measured by a non-chromatographic radioimmun... more SUMMARY Plasma concentrations of oestradiol-17β were measured by a non-chromatographic radioimmunoassay during the oestrous cycle, after the s.c. injection of 2·5 or 10 pg oestradiol benzoate (OB), or the s.c. implantation of Silastic capsules containing crystalline oestradiol-17β. The profile of endogenous plasma oestradiol-17β concentrations was similar to that reported by other workers, and lay between the concentrations produced by the low and high doses of OB. The rectangular pulses of increased plasma oestradiol concentrations, produced during the period of implantation of the Silastic capsules, were used to determine the time taken for oestradiol-17β to exert its facilitatory effect on the gonadotrophin response to LH-releasing factor (RF). In animals ovariectomized at dioestrus, oestradiol, at concentrations similar to those reached during the peak of the spontaneous surge, first reduced the LH response. However, after 7 h, responsiveness increased significantly to reach a p...

Journal of Endocrinology, Apr 13, 2015

Geoffrey Harris, while still a medical student at Cambridge, was the first researcher (1937) to p... more Geoffrey Harris, while still a medical student at Cambridge, was the first researcher (1937) to provide experimental proof for the then tentative view that the anterior pituitary gland was controlled by the CNS. The elegant studies carried out by Harris in the 1940s and early 1950s, alone and in collaboration with John Green and Dora Jacobsohn, established that this control was mediated by a neurohumoral mechanism that involved the transport by hypophysial portal vessel blood of chemical substances from the hypothalamus to the anterior pituitary gland. The neurohumoral control of anterior pituitary secretion was proved by the isolation and characterisation of the 'chemical substances' (mainly neuropeptides) and the finding that these substances were released into hypophysial portal blood in a manner consistent with their physiological functions. The new discipline of neuroendocrinology-the way that the brain controls endocrine glands and vice versa-revolutionised the treatment of endocrine disorders such as growth and pubertal abnormalities, infertility and hormone-dependent tumours, and it underpins our understanding of the sexual differentiation of the brain and key aspects of behaviour and mental disorder. Neuroendocrine principles are illustrated in this Thematic Review by way of Harris' major interest: hypothalamic-pituitary-gonadal control. Attention is focussed on the measurement of GnRH in hypophysial portal blood and the role played by the self-priming effect of GnRH in promoting the onset of puberty and enabling the oestrogen-induced surge or pulses of GnRH to trigger the ovulatory gonadotrophin surge in humans and other spontaneously ovulating mammals. Key Words " neurohormones " hypophysial portal vessel blood " gonadotrophin-releasing hormone (GnRH) " self-priming effect of GnRH " oestrogen-induced ovulatory GnRH surge " oestrogen-induced increase in pituitary responsiveness to GnRH

Obstetrical & Gynecological Survey, May 1, 1980

The Journal of Physiology, Jun 1, 1977

1. Previous studies on the effect of preoptic and median eminence stimulation on the immunoreacti... more 1. Previous studies on the effect of preoptic and median eminence stimulation on the immunoreactive LRF content of pituitary stalk blood from pro-oestrous rats have been extended. Stimulation of the suprachiasmatic nuclei and anterior hypothalamic area produced increments in LRF which were 66 and 18 %, respectively, of that produced by preoptic stimulation, and 38 and 9 %, respectively, of that produced by stimulation of the median eminence. Stimulation of the amygdala and hippocampus had no effect. 2. The LRF response was not affected significantly when preoptic stimulation was accompanied by stimulation of the hippocampus. 3. In animals subjected to section of the dorsal afferents of the diencephalon, the LRF response to preoptic stimulation was similar to that in intact rats. However, the facilitatory effect of oestrogen on the LRF response to preoptic stimulation was significantly reduced in the roof sectioned compared with intact animals. The post-operative resumption of oestrous cycles was delayed but not abolished by dorsal deafferentation.

Endocrinology, Nov 1, 1980

We have studied the effects of various anesthetics on the spontaneous release of gonadotropin-rel... more We have studied the effects of various anesthetics on the spontaneous release of gonadotropin-releasing hormone (GnRH) into hypophysial portal vessel blood and used the techniques of prolonged electrical stimulation of the hypothalamus and iv infusion of GnRH to determine more precisely the relationships between GnRH and LH release and between stored hormone and the amount released. A surge of GnRH (measured by RIA) occurred at the expected time of the spontaneous surge of plasma LH in rats anesthetized on proestrus with Althesin (alphaxalone and alphadolone acetate) but not in rats anesthetized with α-chloralose, ketamine hydrochloride, or urethane. The average amount of GnRH released into portal blood during the surge (128 pg) was relatively small compared to the amount stored in the hypothalamus (6–8 ng). Electrical stimulation of the medial preoptic area in rats anesthetized with urethane produced a surge of LH that was similar to the spontaneous LH surge. This induced surge of LH was preceded by a re...

Schizophrenia Research, Apr 1, 2010

Journal of Endocrinology, Sep 1, 1976

Blood was collected from the cut pituitary stalk of male and female rats before and during the ap... more Blood was collected from the cut pituitary stalk of male and female rats before and during the application of an electrical stimulus to the medial preoptic area. The plasma was assayed for immunoreactive LH releasing factor (RF) by a double antibody radioimmunoassay using a specific antiserum raised in rabbits against the free acid derivative of the decapeptide LH-RF conjugated to bovine serum albumin. The decapeptide (used as a standard) and pituitary stalk plasma cross-reacted in a similar manner with the antiserum. Stimulation of the preoptic area increased significantly the amount of LH-RF in pituitary stalk plasma in both male and female rats. The increase in LH-RF was linearly related to the strength of the stimulating current, and the amount of LH-RF liberated diminished on cessation of the stimulus. The concentration of LH-RF in pituitary stalk plasma from female rats was significantly greater than that in jugular venous plasma. The magnitudes of the mean increments of LH-RF in pituitary stalk plasma (stimulation minus pre-stimulation values) at various times of the oestrous cycle in female rats suggests that between 18.00 h of dioestrus and 13.00 h of pro-oestrus there is an increase in sensitivity of the LH-RF secretory mechanism to electrical stimulation. However, the increments decreased in magnitude between 13.00 and 18.00 h of pro-oestrus, indicating that the marked increase in responsiveness of the hypothalamo-hypophysial system to electrical stimulation which occurs during this period is due mainly to a change in sensitivity of the pituitary gonadotrophs to LH-RF. The LH-RF in pituitary stalk plasma collected before application of the stimulus was higher at some of the times examined during pro-oestrus than at other times of the oestrous cycle. A higher level of the secretion of the factor may be important for the full development of the priming effect of LH-RF and, consequently, the marked increase in responsiveness of the pituitary gland which occurs during the afternoon of pro-oestrus.

Journal of Molecular Neuroscience, Mar 10, 2009

The atypical antipsychotic drug clozapine is effective in treatment-refractory schizophrenia. The... more 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 factor signaling systems, thereby regulating synaptic plasticity and connectivity, processes impaired in schizophrenia. Here, we examined how clozapine differentially modulated phosphorylation of the MAPK isoforms, ERK1/ERK2 in primary murine prefrontal cortical neurons compared to the typical antipsychotic drug haloperidol. While clozapine and haloperidol acutely decreased cortical pERK1 activation, only clozapine but not haloperidol stimulated pERK1 and pERK2 with continued drug exposure. This delayed ERK increase however, did not occur via the canonical dopamine D(2)-Gi/o-PKA or serotonin 5HT(2A)-Gq-phospholipase-C-linked signaling pathways. Rather, epidermal growth factor (EGF) receptor signaling mediated clozapine-induced ERK activation, given dose-dependent reduction of pERK1 and pERK2 stimulation with the EGF receptor inhibitor, AG1478. Immunocytochemical studies indicated that clozapine treatment increased EGF receptor (Tyr1068) phosphorylation. In vivo mouse treatment studies supported the in vitro findings with initial blockade, subsequent activation, and normalization of the cortical ERK response over 24 h. Furthermore, in vivo clozapine-induced ERK activation was significantly reduced by AG1478. This is the first report that clozapine action on prefrontal cortical neurons involves the EGF signaling system. Since EGF receptor signaling has not been previously linked to antipsychotic drug action, our findings may implicate the EGF system as a molecular substrate in treatment-resistant schizophrenia.

The International Journal of Neuropsychopharmacology, Sep 27, 2011

Treatment resistance remains a major obstacle in schizophrenia, with antipsychotic drugs (APDs) b... more 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 it may involve modulation of neuroplasticity and connectivity through induction of interconnected mitogenic signalling pathways. These include the mitogen-activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) cascade and epidermal growth factor (EGF)/ErbB systems. Clozapine, distinct from other APDs, induced initial inhibition and subsequent activation of the ERK response in prefrontal cortical (PFC) neurons in vitro and in vivo, an action mediated by the EGF receptor (ErbB1). Here we examine additionally the striatum of C57Bl/6 mice to determine if clozapine, olanzapine, and haloperidol differentially regulate the ERK1/2 pathway in a region or time-specific manner conditional on the EGF receptor. Following acute treatment, only clozapine caused delayed striatal ERK phosphorylation through EGF receptor phosphorylation (tyrosine 1068 site) and MEK that paralleled cortical ERK phosphorylation. Olanzapine induced initial pERK1-specific blockade and an elevation 24-h later in PFC but had no effect in the striatum. By contrast, haloperidol significantly stimulated pERK1 in striatum for up to 8 h, but exerted limited effect in PFC. Clozapine but not olanzapine or haloperidol recruited the EGF receptor to signal to ERK. These in-vivo data reinforce our previous findings that clozapine's action may be uniquely linked to the EGF signalling system, potentially contributing to its distinctive clinical profile.

Acta Neuropsychiatrica, Dec 1, 2006

Background: Research identifying vulnerability and resilience factors that may affect an individu... more Background: Research identifying vulnerability and resilience factors that may affect an individual's likelihood of developing post-traumatic stress disorder (PTSD) is hampered by the dearth of information on those who are resilient and, although exposed to the trauma, remain unaffected by it. Methods: Such a study eventuated in Canberra where the Centre for Mental Health Research is conducting a longitudinal study of over 7000 participants from three age groups. Reinterviewed participants were asked about their level of exposure and reaction to this trauma and their fi re-related PTSD symptoms. Information on a range of sociodemographic, health and personality measures was collected both before and after the trauma. Results: Almost 80% of Wave 2 respondents were exposed to the fi re, while around 2000 reported having experienced fi re-related PTSD symptoms in the week prior to their interview. Structural equation modeling of pre-trauma risk and resilience factors associated with PTSD symptoms was undertaken. When level of exposure and immediate reaction to the fi re were taken into account, pre-trauma resilience measures had the greatest impact on PTSD symptoms. Those with higher levels of resilience were signifi cantly less likely to report PTSD symptoms. Conclusion: These fi ndings indicate that reducing risk of PTSD by increasing individuals' levels of resilience in the face of specifi c traumas has the potential to be an effective strategy to limit the negative psychological impact of trauma exposure.