Peter Morgan | University College London (original) (raw)

Papers by Peter Morgan

Reprod Fert Develop, 1992

The American Journal of Psychiatry, Oct 10, 2014

The purpose of the present study was to determine the effect of morning-dosed modafinil on sleep ... more The purpose of the present study was to determine the effect of morning-dosed modafinil on sleep and daytime sleepiness in chronic cocaine users. Twenty cocaine-dependent participants were randomly assigned to receive modafinil, 400 mg (N=10), or placebo (N=10) every morning at 7:30 a.m. for 16 days in an inpatient, double-blind randomized trial. Participants underwent polysomnographic sleep recordings on days 1 to 3, 7 to 9, and 14 to 16 (first, second, and third weeks of abstinence). The Multiple Sleep Latency Test was performed at 11:30 a.m., 2:00 p.m., and 4:30 p.m. on days 2, 8, and 15. For comparison of sleep architecture variables, 12 healthy comparison participants underwent a single night of experimental polysomnography that followed 1 night of accommodation polysomnography. Progressive abstinence from cocaine was associated with worsening of all measured polysomnographic sleep outcomes. Compared with placebo, modafinil decreased nighttime sleep latency and increased slow-wave sleep time in cocaine-dependent participants. The effect of modafinil interacted with the abstinence week and was associated with longer total sleep time and shorter REM sleep latency in the third week of abstinence. Comparison of slow-wave sleep time, total sleep time, and sleep latency in cocaine-dependent and healthy participants revealed a normalizing effect of modafinil in cocaine-dependent participants. Modafinil was associated with increased daytime sleep latency, as measured by the Multiple Sleep Latency Test, and a nearly significant decrease in subjective daytime sleepiness. Morning-dosed modafinil promotes nocturnal sleep, normalizes sleep architecture, and decreases daytime sleepiness in abstinent cocaine users. These effects may be relevant in the treatment of cocaine dependence.

Mol Cell Endocrinol, 1994

Journal of Neuroendocrinology, Feb 1, 2007

Body mass and the level of adiposity of many adult mammals tends to remain constant over long int... more Body mass and the level of adiposity of many adult mammals tends to remain constant over long intervals, despite changes in the availability of food and levels of energy expenditure (1-4). This stability suggests that there is a regulatory system for body mass and adiposity that may include regulation around a target encoded in the brain. Accordingly, perturbations of body adiposity away from the target, trigger adaptive responses in energy intake and energy expenditure, which are compensatory and operate to restore the defended level of body fatness (5). It has been suggested that defects or limitations of the energy homeostasis system are important in the aetiology of obesity, a condition that is not easily reversed in humans, and diet-or age-induced obese rodents.

Neuroendocrinology, 1994

The function of the pars tuberalis as a mediator of the action of melatonin remains elusive. As a... more The function of the pars tuberalis as a mediator of the action of melatonin remains elusive. As a direct method of assessing the potential role of secretory proteins, ovine pars tuberalis cells have been cultured and radiolabelled with 35S-methionine, and the accumulation of specific radioactive products in the medium, measured after separation by SDS-PAGE and fluorography. The synthesis and secretion of a number of labelled proteins are increased by forskolin (1 microM) and inhibited dose dependently by melatonin (IC50, 300 pM), although consistently a 72-kD protein (p72), is the most intensely labelled of these. Thus, 72 acts as a useful marker of cellular activity for melatonin, whereas prolactin (p23) provides a melatonin non-responsive marker in ovine pars tuberalis cell cultures. The synthesis and secretion of p72 and other melatonin-sensitive proteins is regulated through the cyclic AMP/protein kinase A second-messenger pathway, as analogues of cyclic AMP mimic the action of forskolin, yet 1,9-dideoxyforskolin, a forskolin analogue that is not active on adenylate cyclase, has no effect. However, the phorbol ester, phorbol-12,13-myristate acetate, also regulates the synthesis and secretion of the same profile of proteins as forskolin indicating a potential role for protein kinase C, which occurs through an independent rather than a synergistic pathway. The differential effects of nocadazole (1 microM) and extracellular calcium depletion upon p72 and prolactin secretion indicates that p72 is secreted by a calcium and microtubule independent pathway, in contrast to prolactin. These observations in conjunction with the absence of dense-core storage vesicles in melatonin-responsive cells of the ovine PT are consistent with constitutive secretion of p72 from the latter and regulated secretion of prolactin from melatonin non-responsive cells. Using immunoprecipitation de novo synthesis and secretion of either LH or LH-like proteins from ovine pars tuberalis cells could not be detected under the conditions used. The absence of 125I-(Des-Gly10[D-Ala6]-LHRH-ethylamide) binding over most, but not all, of the ovine pars tuberalis supports the contention that the majority of the cells of the ovine pars tuberalis are not gonadotrophs. These results provide further support for the unique function for the pars tuberalis.

Brain Research, Feb 8, 2008

The American Journal of Psychiatry, May 1, 2008

ajp.psychiatryonline.org References 1. Aleman A, Sommer IE, Kahn RS: Efficacy of slow repetitive ... more ajp.psychiatryonline.org References 1. Aleman A, Sommer IE, Kahn RS: Efficacy of slow repetitive transcranial magnetic stimulation in the treatment of resistant auditory hallucinations in schizophrenia: a meta-analysis. J Clin Psychiatry 2007; 68:416-421 2. Poulet E, Brunelin J, Kallel L, Bediou B, Dalery J, D'amato T, Saoud M: Is rTMS efficient as a maintenance treatment for auditory verbal hallucinations? a case report.

J Comp Physiol B, 1983

The use of conventional microelectrodes has revealed that the basal membrane potential (Emb) and ... more The use of conventional microelectrodes has revealed that the basal membrane potential (Emb) and the transepithelial potential (Tm) in Locusta Malpighian tubules are -39.4 mV and + 4.4 mV respectively. No change in Em b was noted after stimulation by diuretic hormone (DH) or cAMP (5 raM), suggesting electroneutral coupling of ions entering the cell.

J Mol Biol, 1998

Pneumolysin, a member of the thiol-activated cytolysin family of toxins, is a virulence factor fr... more Pneumolysin, a member of the thiol-activated cytolysin family of toxins, is a virulence factor from the Gram-positive bacterium Streptococcus pneumoniae. The toxin forms large oligomeric pores in cholesterol-containing membranes of eukaryotic cells. A plethora of biochemical and mutagenesis data have been published on pneumolysin, since its initial characterization in the 1930s. Here we present an homology model of the monomeric and oligomeric forms of pneumolysin based on the recently determined crystal structure of perfringolysin O and electron microscopy data. A feature of the model is a striking electronegative surface on parts of pneumolysin that may reflect its cytosolic location in the bacterial cell. The models provide a molecular basis for understanding the effects of published mutagenesis and biochemical modifications on the toxic activity of pneumolysin. In addition, spectroscopic data are presented that shed new light on pneumolysin activity and have guided us to hypothesise a detailed model of membrane insertion. These data show that the environment of some tryptophan residues changes on insertion and/or pore formation. In particular, spectroscopic analysis of a tryptophan mutant, W433F, suggests it is the residue mainly responsible for the observed effects. Furthermore, there is no change in the secondary structure content when the toxin inserts into membranes. Finally, the basis of the very low activity shown by a pneumolysin molecule from another strain of S. pneumoniae may be due to the movements of a key domain-domain interface. The molecular basis of pneumolysin-induced complement activation may be related to the structural similarity of one of the domains of pneumolysin to Fc, rather than the presumed homology of the toxin to C-reactive protein as previously suggested.

Biochemical Society Transactions, Jun 1, 1996

American Journal of Physiology Regulatory Integrative and Comparative Physiology, 2000

Siberian hamsters decreased body weight by 30% during 18 wk in short day (SD) vs. long day (LD) c... more Siberian hamsters decreased body weight by 30% during 18 wk in short day (SD) vs. long day (LD) controls. Subsequent imposed food deprivation (FD; 24 h) caused a further 10% decrease. In the hypothalamic arcuate nucleus (ARC), SDs reduced proopiomelanocortin (POMC) gene expression and agouti-related protein (AGRP) mRNA was elevated, changes that summate to reduced catabolic drive through the melanocortin receptors. There was no effect of photoperiod on neuropeptide Y (NPY), melanin concentrating hormone, orexin, or corticotropin-releasing factor mRNAs. Superimposed FD increased AGRP gene expression and caused a localized elevation of NPY mRNA in the ARC. Both adipose tissue leptin and ARC leptin receptor (OB-Rb) mRNAs were downregulated in SDs, whereas FD increased OB-Rb gene expression. Thus OB-Rb mRNA is differentially regulated by acute and chronic changes in plasma leptin in this species. In a separate experiment in LDs, AGRP gene expression was increased by 24 or 48 h FD, whereas POMC mRNA was downregulated in the caudal ARC. AGRP and NPY mRNAs were extensively coexpressed in the ARC, and their differential regulation by photoperiod and FD is suggestive of transcript-specific regulation at the level of individual neurons.

Endocrinology, Jul 1, 2013

The Siberian hamster survives winter by decreasing food intake and catabolizing abdominal fat res... more The Siberian hamster survives winter by decreasing food intake and catabolizing abdominal fat reserves, resulting in a sustained, profound loss of body weight. VGF gene expression is photoperiodically regulated in the hypothalamus with significantly higher expression in lean Siberian hamsters. The aim of this study was to investigate the role of VGF in regulating these seasonal cycles by determining the effects of a VGF-derived peptide (TLQP-21) on food intake and body weight. Acute intracerebroventricular administration of TLQP-21 decreased food intake, and chronic treatment caused a sustained reduction in food intake and body weight and decreased abdominal fat depots. Behavioral analysis revealed that TLQP-21 reduced meal size but not the frequency of feeding bouts, suggesting a primary action on satiety. Hamsters treated with TLQP-21 lost a similar amount of weight as a pair-fed group in which food intake was matched to that of the TLQP-21-treated group. Central or peripheral treatment with TLQP-21 did not produce a significant effect on resting metabolic rate. We conclude that the primary action of TLQP-21 is to decrease food intake rather than increase energy expenditure. TLQP-21 treatment caused a decrease in UCP-1 mRNA in brown adipose tissue, but hypothalamic expression of orexigenic and anorexigenic neuropeptide genes remained unchanged after TLQP-21 treatment, although compensatory increases in NPY and AgRP mRNA were observed in the pair-fed hamsters. The effects of TLQP-21 administration are similar to those in hamsters in short days, suggesting that increased VGF activity may contribute to the hypophagia that underlies the seasonal catabolic state. (Endocrinology 148: 4044 -4055, 2007) P RO-VGF PROTEIN IS the primary 68-kDa product of the vgf gene (1). VGF mRNA is synthesized widely and found to be abundantly expressed in neurons in the hippocampus, cerebral cortex, amygdala, midbrain and thalamus (2-6). The VGF protein is selectively processed into peptides in a tissue-specific manner in neuroendocrine and neuronal cells and released through a regulated secretory pathway (7-9). The highest concentrations of VGF immunoreactivity have been found in the medial hypothalamus, particularly in the arcuate nucleus (Arc), the paraventricular nucleus, the supraoptic nucleus, and in the suprachiasmatic nucleus (3, 4). VGF-containing neurons in these nuclei project both to the median eminence and to the posterior pituitary (10); thus, hypothalamic VGF or VGF-derived peptides may have central actions as well as peripheral functions after reaching target tissues via the circulation.

Neuroscience, Feb 1, 2003

The expression of precursor-protein convertase (PC)1, PC2 and paired basic amino acid cleaving en... more The expression of precursor-protein convertase (PC)1, PC2 and paired basic amino acid cleaving enzyme four mRNA was studied by in situ hybridisation in regions of the hypothalamus involved in energy regulation in relation to obese (ob) gene mutation and energy deficit. PC1 gene was differentially expressed in hypothalamic nuclei of mice from different genetic backgrounds or energetic status, whereas no differences in expression were observed for either the PC2 or paired basic amino acid cleaving enzyme four genes. In obese ob/ob mice, PC1 mRNA levels were increased in the paraventricular nucleus, decreased in the lateral hypothalamus and unchanged in the ventromedial nucleus and arcuate nucleus relative to lean controls. In response to intraperitoneal injection of murine leptin, PC1 mRNA levels in obese ob/ob mice decreased in the arcuate nucleus, increased in the lateral hypothalamus and were unchanged in both the paraventricular nucleus and ventromedial nucleus. In mice deprived of food for 24 h, PC1 mRNA levels were reduced in the ventromedial nucleus, increased in the lateral hypothalamus and unchanged in the paraventricular nucleus and arcuate nucleus relative to ad libitum-fed controls. Overall, whilst the data show effects related to leptin and energetic status, they do not support a strong and consistent link between PC1 gene expression and energy balance. This suggests that if PC1 is important to the control of energy balance then protein expression and activity, rather than gene expression may be the more critical parameters of regulation. The relationship between PC1 and candidate energy balance-related genes in the lateral hypothalamus was investigated by dual in situ hybridisation. PC1 mRNA was localised in preproorexin mRNA expressing neurons in the lateral hypothalamus, which suggests a functional relationship.

J Neuroendocrinol, 2003

In Soay rams in which the pituitary gland has been surgically separated from the hypothalamus, bl... more In Soay rams in which the pituitary gland has been surgically separated from the hypothalamus, blood prolactin concentrations vary in response to changes in photoperiod and the administration of melatonin, as in intact animals, providing evidence that melatonin acts within the pituitary gland to control prolactin secretion. In this study the presence of potentially functional melatonin receptors in the pars tuberalis and zona tuberalis (PT/ZT) of hypothalamo-pituitary disconnected (HPD) Soay rams is confirmed using both in vitro autoradiography with the ligand 2-(125I)-iodomelatonin and in situ hybridization for the melatonin receptor. There was no effect of the HPD operation on the pattern and quantity of 2-(125I)iodomelatonin binding in the brain demonstrating that this binding is independent of hypothalamic regulation. The possibility that melatonin may control prolactin secretion directly via specific receptors on lactotrophs was investigated using dual in situ hybridization with a (35S) labelled probe for the ovine melatonin receptor (Mel 1a(b)) and a Digoxigenin labelled probe for ovine prolactin. Melatonin receptor gene expression was observed in the PT/ZT in both intact and HPD rams, however, there was no colocalization with prolactin gene expression; only in the ZT was there a close association between cells expressing the melatonin receptor and lactotrophs. The results provide strong support for the view that melatonin acts via the PT/ZT to mediate the effects of photoperiod on the seasonal cycle in prolactin secretion.

Glia, Jan 3, 2015

Thyroid hormone (TH) is essential for adult brain function and its actions include several key ro... more Thyroid hormone (TH) is essential for adult brain function and its actions include several key roles in the hypothalamus. Although TH controls gene expression via specific TH receptors of the nuclear receptor class, surprisingly few genes have been demonstrated to be directly regulated by TH in the hypothalamus, or the adult brain as a whole. This study explored the rapid induction by TH of retinaldehyde dehydrogenase 1 (Raldh1), encoding a retinoic acid (RA)-synthesizing enzyme, as a gene specifically expressed in hypothalamic tanycytes, cells that mediate a number of actions of TH in the hypothalamus. The resulting increase in RA may then regulate gene expression via the RA receptors, also of the nuclear receptor class. In vivo exposure of the rat to TH led to a significant and rapid increase in hypothalamic Raldh1 within 4 hours. That this may lead to an in vivo increase in RA is suggested by the later induction by TH of the RA-responsive gene Cyp26b1. To explore the actions of R...

Frontiers of Hormone Research, 1997

Insect Biochemistry, 1985

AIrstraet--The role of cAMP in diuretic hormone (DH) action on Locusta mtgratorta Malpighlan tubu... more AIrstraet--The role of cAMP in diuretic hormone (DH) action on Locusta mtgratorta Malpighlan tubules has been investigated The rate of fluid secretion by semi-isolated tubules is elevated by the phosphodiesterase lnhlbltors theophylhne (10 3 M) and 3-isobutyl-l-methylxanthme (IBMX, I0 3 M), although the latter is more effective Removal of these inhibltors returns the rate of fired secretion to basal levels IBMX (I0 4 M) is shown to elevate the mtracellular cAMP levels of tubules, but no significant elevation was observed in response to theophylhne (10 4M) Shmulatlon of isolated tubules with DH (methanol extracted storage lobes) increases the intracellular cAMP levels of tubules by 7 to 8-fold, after 3 min stimulation at 30°C, the response to DH stlmulahon is lower after 10mm Using plasma membrane preparations of Locusta migratorta Malpighmn tubules, DH stimulates adenylate cyclase catalysed synthesis of cAMP from ATP, with optimum stimulation using 0.5-2 mg tubule membrane proteln/ml. Dose-response data show that a saturated response occurs at doses of DH of greater than 0.2 storage lobe equivalents/75/d of incubation medium The proteolytic enzymes trypsin (0 01 mg/ml) and chymotrypsin (0 01 mg/ml) both destroy diuretic activity, tested using the semi-isolated tubule preparation Trypsin 0.01 mg/ml also reduces the actlvlty of the "DH" activating adenylate cyclase Chromatography of methanol extracts of storage lobes on a TSK 2000 SW high performance size-exclusion chromatography column eluted m 0 1% TFA, separate the DH, activating adenylate cyclase, in fractions 7 and 8 Comparison of these active fracUons with those tested using semi-isolated Malplghlan tubule preparations suggests two distinct receptor sites on Locusta tubules.