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2.
Science ; 384(6691): 35, 2024 Apr 05.
Article in English | MEDLINE | ID: mdl-38574133

ABSTRACT

Father of neuroendocrinology.

3.
PLoS One ; 18(11): e0289027, 2023.
Article in English | MEDLINE | ID: mdl-38019814

ABSTRACT

It is widely acknowledged that emotions and cognition are closely related, and that negative emotions are detrimental on school achievement, especially on mathematical performance. On the other hand, positive emotions have a positive impact on motivation and cognitive abilities underlying the learning processes. Nevertheless, studies about the effects of experienced emotions on problem solving, a specific type of mathematical activity, are sparse. The present research focuses on experienced epistemic and achievement emotions after the resolution of two types of numerical word problems: the application problems, that requires the use of a specific and expected algorithm to be solved and are regularly proposed at school; and the non-application problems, which cannot be solved directly but using different solving strategies. This type of numerical word problems appears less frequently in French school curricula. In experiment 1, 105 adults (M = 24.4 years), of which the majority was university students, were involved in an online experiment with APs and NAPs problems and were asked to rate their experienced emotions after the resolution of the problems. In experiment 2, 65 children aged 9-year-old were asked to individually solve APs and NAPs problems with age-appropriate difficulty and then rate their associated emotions. The adults' sample reported higher epistemic and achievement positive emotions towards APs compared to NAPs. In both adults and children NAPs were more associated to surprise than APs. In children anxiety was more experienced after resolution of NAPs than APs. Results suggest the importance of varying the types of problems proposed in school curricula so that children become accustomed to using different solving strategies. This approach could be useful in decreasing negative emotions toward mathematics such as anxiety, which begins to settle as early as elementary school.


Subject(s)
Cognition , Emotions , Humans , Child , Adult , Problem Solving , Anxiety/psychology , Motivation
4.
J Med Chem ; 59(3): 854-66, 2016 Feb 11.
Article in English | MEDLINE | ID: mdl-26789203

ABSTRACT

CRF mediates numerous stress-related endocrine, autonomic, metabolic, and behavioral responses. We present the synthesis and chemical and biological properties of astressin B analogues {cyclo(30-33)[D-Phe(12),Nle(21,38),C(α)MeLeu(27,40),Glu(30),Lys(33)]-acetyl-h/r-CRF(9-41)}. Out of 37 novel peptides, 17 (2, 4, 6-8, 10, 11, 16, 17, 27, 29, 30, 32-36) and 16 (3, 5, 9, 12-15, 18, 19, 22-26, 28, 31) had k(i) to CRF receptors in the high picomolar and low nanomole ranges, respectively. Peptides 1, 2, and 11 inhibited h/rCRF and urocortin 1-induced cAMP release from AtT20 and A7r5 cells. When Astressin C 2 was administered to adrenalectomized rats at 1.0 mg subcutaneously, it inhibited ACTH release for >7 d. Additional rat data based on the inhibitory effect of (2) on h/rCRF-induced stimulation of colonic secretory motor activity and urocortin 2-induced delayed gastric emptying also indicate a safe and long-lasting antagonistic effect. The overall properties of selected analogues may fulfill the criteria expected from clinical candidates.


Subject(s)
Corticotropin-Releasing Hormone/pharmacology , Peptide Fragments/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Corticotropin-Releasing Hormone/administration & dosage , Corticotropin-Releasing Hormone/chemistry , Cyclic AMP/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Molecular Structure , Peptide Fragments/administration & dosage , Peptide Fragments/chemistry , Rats , Structure-Activity Relationship , Urocortins/antagonists & inhibitors
5.
Front Neuroendocrinol ; 35(2): 161-70, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24269930

ABSTRACT

Elusive for more than half a century, corticotropin-releasing factor (CRF) was finally isolated and characterized in 1981 from ovine hypothalami and shortly thereafter, from rat brains. Thirty years later, much has been learned about the function and localization of CRF and related family members (Urocortins 1, 2 and 3) and their 2 receptors, CRF receptor type 1 (CRFR1) and CRF receptor type 2 (CRFR2). Here, we report the stepwise development of peptide CRF agonists and antagonists, which led to the CRFR1 agonist Stressin1; the long-acting antagonists Astressin2-B which is specific for CRFR2; and Astressin B, which binds to both CRFR1 and CRFR2.This analog has potential for the treatment of CRF-dependent diseases in the periphery, such as irritable bowel syndrome.


Subject(s)
Corticotropin-Releasing Hormone/analogs & derivatives , Corticotropin-Releasing Hormone/antagonists & inhibitors , Peptide Fragments/pharmacology , Peptides, Cyclic/pharmacology , Animals , Corticotropin-Releasing Hormone/pharmacology , Humans , Receptors, Corticotropin-Releasing Hormone/agonists , Stress, Physiological
6.
Front Neuroendocrinol ; 35(2): 221-33, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24211830

ABSTRACT

Alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) axis through brain-based mechanisms in which endogenous corticotropin-releasing factor (CRF) plays a major role. This review first discusses the evidence for this role, as well as the possible importance of intermediates such as vasopressin, nitric oxide and catecholamines. We then illustrate the long-term influence exerted by alcohol on the HPA axis, such as the ability of a first exposure to this drug during adolescence, to permanently blunt neuroendocrine responses to subsequent exposure of the drug. In view of the role played by CRF in addiction, it is likely that a better understanding of the mechanisms through which this drug stimulates the HPA axis may lead to the development of new therapies used in the treatment of alcohol abuse, including clinically relevant CRF antagonists.


Subject(s)
Alcohols/pharmacology , Corticotropin-Releasing Hormone/metabolism , Hypothalamo-Hypophyseal System/metabolism , Pituitary Hormone-Releasing Hormones/metabolism , Pituitary-Adrenal System/metabolism , Alcoholism/drug therapy , Animals , Humans , Hypothalamo-Hypophyseal System/drug effects , Neurons/drug effects , Neurons/physiology
7.
J Neurosci ; 32(22): 7563-71, 2012 May 30.
Article in English | MEDLINE | ID: mdl-22649234

ABSTRACT

Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid release via the hypothalamic-pituitary-adrenal axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol drinking. Our results showed that rats exposed to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio responding, and persistent alcohol consumption despite punishment, assessed by adding quinine to the alcohol solution, compared with control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharin-sweetened water. Acute alcohol withdrawal was accompanied by downregulated GR mRNA in various stress/reward-related brain regions [i.e., prefrontal cortex, nucleus accumbens (NAc), and bed nucleus of the stria terminalis (BNST)], whereas protracted alcohol abstinence was accompanied by upregulated GR mRNA in the NAc core, ventral BNST, and central nucleus of the amygdala. No significant alterations in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked escalated alcohol drinking and compulsive responding during protracted abstinence. Thus, the GR system appears to be involved in the development of alcohol dependence and may represent a potential pharmacological target for the treatment of alcoholism.


Subject(s)
Alcohol Drinking/metabolism , Brain/metabolism , Receptors, Glucocorticoid/metabolism , Substance Withdrawal Syndrome/metabolism , Up-Regulation , Alcohol Drinking/drug therapy , Alcohol Drinking/pathology , Analysis of Variance , Animals , Behavior, Addictive/drug therapy , Behavior, Addictive/metabolism , Central Nervous System Depressants/administration & dosage , Compulsive Behavior/physiopathology , Conditioning, Operant/drug effects , Ethanol/administration & dosage , Hormone Antagonists/therapeutic use , Male , Mifepristone/therapeutic use , RNA, Messenger/metabolism , Rats , Rats, Wistar , Receptors, Glucocorticoid/genetics , Receptors, Mineralocorticoid/genetics , Receptors, Mineralocorticoid/metabolism , Reinforcement Schedule , Self Administration , Substance Withdrawal Syndrome/drug therapy , Up-Regulation/drug effects
9.
PLoS One ; 6(2): e16377, 2011 Feb 16.
Article in English | MEDLINE | ID: mdl-21359208

ABSTRACT

Corticotropin-releasing factor (CRF) signaling pathways are involved in the stress response, and there is growing evidence supporting hair growth inhibition of murine hair follicle in vivo upon stress exposure. We investigated whether the blockade of CRF receptors influences the development of hair loss in CRF over-expressing (OE)-mice that display phenotypes of Cushing's syndrome and chronic stress, including alopecia. The non-selective CRF receptors antagonist, astressin-B (5 µg/mouse) injected peripherally once a day for 5 days in 4-9 months old CRF-OE alopecic mice induced pigmentation and hair re-growth that was largely retained for over 4 months. In young CRF-OE mice, astressin-B prevented the development of alopecia that occurred in saline-treated mice. Histological examination indicated that alopecic CRF-OE mice had hair follicle atrophy and that astressin-B revived the hair follicle from the telogen to anagen phase. However, astressin-B did not show any effect on the elevated plasma corticosterone levels and the increased weights of adrenal glands and visceral fat in CRF-OE mice. The selective CRF2 receptor antagonist, astressin2-B had moderate effect on pigmentation, but not on hair re-growth. The commercial drug for alopecia, minoxidil only showed partial effect on hair re-growth. These data support the existence of a key molecular switching mechanism triggered by blocking peripheral CRF receptors with an antagonist to reset hair growth in a mouse model of alopecia associated with chronic stress.


Subject(s)
Alopecia/drug therapy , Alopecia/prevention & control , Corticotropin-Releasing Hormone/genetics , Peptide Fragments/pharmacology , Peptide Fragments/therapeutic use , Alopecia/genetics , Animals , Corticotropin-Releasing Hormone/administration & dosage , Corticotropin-Releasing Hormone/pharmacology , Corticotropin-Releasing Hormone/therapeutic use , Drug Evaluation, Preclinical , Female , Hair/drug effects , Hair/growth & development , Hormone Antagonists/administration & dosage , Hormone Antagonists/pharmacology , Hormone Antagonists/therapeutic use , Injections, Intraperitoneal , Injections, Subcutaneous , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Peptide Fragments/administration & dosage , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Up-Regulation
10.
Brain Behav Immun ; 25 Suppl 1: S50-60, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21300146

ABSTRACT

Alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) axis. Part of this influence is likely exerted directly at the level of the corticotropin-releasing factor (CRF) gene, but intermediates may also play a role. Here we review the effect of alcohol on this axis, provide new data on the effects of binge drinking during adolescence, and argue for a role of catecholaminergic circuits. Indeed, acute injection of this drug activates brain stem adrenergic and noradrenergic circuits, and their lesion, or blockade of α1 adrenergic receptors significantly blunts alcohol-induced ACTH release. As alcohol can influence the HPA axis even once discontinued, and alcohol consumption in young people is associated with increased adult drug abuse (a phenomenon possibly mediated by the HPA axis), we determined whether alcohol consumption during adolescence modified this axis. The number of CRF-immunoreactive (ir) cells/section was significantly decreased in the central nucleus of the amygdala of adolescent self-administering binge-drinking animals, compared to controls. When another group of adolescent binge-drinking rats was administered alcohol in adulthood, the number of colocalized c-fos-ir and PNMT-ir cells/brain stem section in the C3 area was significantly decreased, compared to controls. As the HPA axis response to alcohol is blunted in adult rats exposed to alcohol vapors during adolescence, a phenomenon which was not observed in our model of self-administration, it is possible that the blood alcohol levels achieved in various models play a role in the long-term consequences of exposure to alcohol early in life. Collectively, these results suggest an important role of brain catecholamines in modulating the short- and long-term consequences of alcohol administration.


Subject(s)
Alcohols/pharmacology , Ethanol/pharmacology , Hypothalamo-Hypophyseal System/drug effects , Neurons/drug effects , Pituitary-Adrenal System/drug effects , Animals , Rats
11.
Neuropeptides ; 45(2): 131-7, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21256589

ABSTRACT

The synthesis and release of testosterone (T) depends both on circulating luteinizing hormone (LH) and on an array of testicular factors whose role remains incompletely understood. Corticotropin-releasing factor (CRF) had been reported in the rat testes, where it was thought to inhibit T secretion. However, the discovery that the CRF-related peptides urocortins (Ucns), of which there are currently three subtypes (Ucn 1, 2 and 3), cross-react with many reagents previously used to detect CRF, has cast doubt on this concept. Here we show that while CRF was readily measurable in rat hypothalami (which served as controls), signals for this peptide were barely detectable in total RNA extracted from the testes. On the other hand, microarray, RT-PCR and real-time quantitative RT-PCR (qRT-PCR) analyses all indicated strong signals for Ucn 1 in the male gonads, with weaker levels of Ucn 2 and 3 mRNA gene expression. Results obtained for Ucn 1 gene expression were corroborated by immunohistochemical detection, which appeared restricted to Leydig cells. Finally, to investigate possible changes in testicular Ucn 1 levels induced by homeostatic challenges, we measured them in rats exposed to alcohol. We observed that indeed, the intragastric injection of this drug significantly increased testicular Ucn 1, but not Ucn 2, Ucn 3, CRF, CRFR1 or CRFR2 mRNA levels. Collectively, these results provide novel information regarding the presence of CRF-like peptides in the adult male rat testis.


Subject(s)
Protein Isoforms/metabolism , Testis/metabolism , Urocortins/metabolism , Animals , Corticotropin-Releasing Hormone/genetics , Corticotropin-Releasing Hormone/metabolism , Leydig Cells/metabolism , Male , Microarray Analysis , Protein Isoforms/genetics , Rats , Rats, Sprague-Dawley , Receptors, Corticotropin-Releasing Hormone/genetics , Receptors, Corticotropin-Releasing Hormone/metabolism , Testis/cytology , Urocortins/genetics
12.
Neuropeptides ; 45(1): 55-61, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21112087

ABSTRACT

The factors that influence Leydig cell activity currently include peptides such as neuropeptide Y (NPY). In this work we investigated the ability of this compound, injected directly into the testes of adult male rats, to alter testosterone (T) release into the general circulation. At a 5µg/kg dose administered 1h prior to challenge with human chorionic gonadotropin (hCG, 1.0 U/kg, iv), NPY significantly (P<0.01) blunted the T response to this gonadotropin. The inhibitory effect of NPY was observed in animals pretreated with an antagonist to gonadotropin-releasing hormone or not, indicating that the decrease in plasma T found was most likely independent of pituitary luteinizing hormone. However, testicular levels of steroidogenic acute regulatory (STAR) protein or translocator protein (TSPO) in the Leydig cells did not exhibit consistent changes, which suggested that other mechanisms mediated the blunted T response to hCG. We therefore used autoradiography and immunohistochemistry methodologies to identify NPY receptors in the testes, and found them primarily located on blood vessels. Competition studies further identified these receptors as being Y(1), a subtype previously reported to modulate the vasoconstrictor effect of NPY. The absence of significant changes in STAR and TSPO levels, as well as the absence of Y(1) receptors on Leydig cells, suggest that NPY-induced decreases in T release is unlikely to represent a direct effect of NPY on these cells. Rather, the very high expression levels of Y(1) found in testicular vessels supports the concept that NPY may alter gonadal activity, at least in part, through local vascular impairment of gonadotropin delivery to, and/or blunted T secretion from, Leydig cells.


Subject(s)
Neuropeptide Y/pharmacology , Testis/drug effects , Testis/metabolism , Testosterone/metabolism , Adult , Animals , Chorionic Gonadotropin/pharmacology , Dose-Response Relationship, Drug , Gonadotropin-Releasing Hormone/antagonists & inhibitors , Humans , Leydig Cells/cytology , Leydig Cells/drug effects , Leydig Cells/metabolism , Male , Phosphoproteins/metabolism , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, GABA/metabolism , Receptors, Neuropeptide Y/metabolism , Testis/cytology
13.
Ann N Y Acad Sci ; 1144: 176-88, 2008 Nov.
Article in English | MEDLINE | ID: mdl-19076376

ABSTRACT

Adult rats and mice born to dams exposed to alcohol (fetal alcohol-exposed [FAE]) exhibit enhanced activity of their hypothalamic-pituitary-adrenal (HPA) axis when exposed to stressors. However, the mechanisms responsible for this phenomenon remain incompletely understood. Here two possibilities are reviewed: one that pertains to nitric oxide (NO), an unstable gas that stimulates the HPA axis; and one that focuses on catecholamines, which also stimulate this axis. Significant alterations were not observed in levels of NO synthase, the enzyme responsible for NO formation, in the paraventricula nucleus (PVN) of FAE rats. However, the stimulatory influence of this gas on the hypothalamic-pituitary-adrenal (HPA) axis was enhanced in these animals, thereby providing a mechanism likely to participate in the neuroendocrine hyperactivity that is the hallmark of this model. It was also recently shown that, while the ability of catecholamines to release adrenocorticotropic hormone (ACTH) was comparable in control rats and rats exposed to alcohol during embryonic development, there was a significant upregulation of the C1 brain-stem region when these latter animals were exposed to mild footshocks. Since this region sends prominent projections to the PVN, its increased activity may participate in the HPA axis hyperactivity observed in FAE offspring. Finally, microarray technology was used to search for potential differences in genes present in the brains of control and FAE mice. When these brains were collected on day 17.5 of embryonic development, several genes were upregulated, while others were downregulated, which may provide potential new candidates that mediate the influence of prenatal alcohol on the HPA axis of adult offspring.


Subject(s)
Ethanol/pharmacology , Hypothalamo-Hypophyseal System/drug effects , Neuropeptides/blood , Pituitary-Adrenal System/drug effects , Prenatal Exposure Delayed Effects/blood , Adrenocorticotropic Hormone/blood , Animals , Corticotropin-Releasing Hormone/blood , Female , Fetal Alcohol Spectrum Disorders/metabolism , Humans , Hypothalamo-Hypophyseal System/physiology , Mice , Neurotransmitter Agents/metabolism , Pituitary-Adrenal System/physiology , Pregnancy , Rats , Vasopressins/blood
14.
Eur J Neurosci ; 28(8): 1641-53, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18979677

ABSTRACT

Clinical studies link disruption of the neuroendocrine stress system with alcoholism, but remaining unknown is whether functional differences in the hypothalamic-pituitary-adrenal (HPA) axis precede alcohol abuse and dependence or result from chronic exposure to this drug. Using an operant self-administration animal model of alcohol dependence and serial blood sampling, we show that longterm exposure to alcohol causes significant impairment of HPA function in adult male Wistar rats. Acute alcohol (voluntary self-administration or experimenter-administered) stimulated the release of corticosterone and its upstream regulator, adrenocorticotropic hormone, but chronic exposure sufficient to produce dependence led to a dampened neuroendocrine state. HPA responses to alcohol were most robust in 'low-responding' non-dependent animals (averaging < 0.2 mg/kg/session), intermediate in nondependent animals (averaging approximately 0.4 mg/kg/session), and most blunted in dependent animals (averaging approximately 1.0 mg/kg/session) following several weeks of daily 30-min self-administration sessions, suggesting that neuroendocrine tolerance can be initiated prior to dependence and relates to the amount of alcohol consumed. Decreased expression of corticotropin-releasing factor (CRF) mRNA expression in the paraventricular nucleus of the hypothalamus and reduced sensitivity of the pituitary to CRF may contribute to, but do not completely explain, neuroendocrine tolerance. The present results, combined with previous studies, suggest that multiple adaptations to stress regulatory systems may be brought about by excessive drinking, including a compromised hormonal response and a sensitized brain stress response that together contribute to dependence.


Subject(s)
Alcohol-Induced Disorders, Nervous System/physiopathology , Endocrine System Diseases/chemically induced , Endocrine System Diseases/physiopathology , Ethanol/toxicity , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/physiopathology , Adrenocorticotropic Hormone/blood , Adrenocorticotropic Hormone/metabolism , Alcoholism/complications , Alcoholism/physiopathology , Animals , Central Nervous System Depressants/toxicity , Corticosterone/blood , Corticosterone/metabolism , Corticotropin-Releasing Hormone/genetics , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Schedule , Hypothalamo-Hypophyseal System/metabolism , Male , Neurosecretory Systems/drug effects , Neurosecretory Systems/physiopathology , Paraventricular Hypothalamic Nucleus/drug effects , Paraventricular Hypothalamic Nucleus/metabolism , Paraventricular Hypothalamic Nucleus/physiopathology , Pituitary-Adrenal System/drug effects , Pituitary-Adrenal System/physiopathology , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Rats , Rats, Wistar
15.
Endocrinology ; 149(12): 6425-32, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18719027

ABSTRACT

Corticotropin-releasing factor (CRF) has previously been reported in rat testes in which it inhibits Leydig cells activity. However, recent studies in our laboratory have suggested that some of the effects originally attributed to CRF were instead due to the related peptide Urocortin 1 (Ucn 1) and that this latter hormone, not CRF, was detectable in Leydig cells. We show here that Ucn 1 [a mixed CRF receptor (CRFR) type 1 and CRFR2 agonist] and the CRFR1-selective peptide Stressin 1, but not Ucn 2 or Ucn 3 (both considered selective CRFR2 ligands), significantly blunt the testosterone response to human chorionic gonadotropin. The effect of Ucn 1 is observed regardless of whether this peptide is injected iv or directly into the testes, and it is reversed by the mixed CRFR1/R2 antagonist Astressin B. Blockade of GnRH receptors with the antagonist Azalin B does not interfere with the influence of Ucn 1, thereby demonstrating that pituitary luteinizing hormone does not appear to be involved in this model. Collectively these results suggest that Ucn 1, not CRF, is present in the rat testes and interferes with Leydig cell activity. However, whereas we previously reported that alcohol up-regulated gonadal Ucn 1 gene expression, CRF receptor antagonists were unable to reverse the inhibitory effect exerted by alcohol on human chorionic gonadotropin-induced testosterone release. The functional role played by testicular Ucn 1 in stress models characterized by blunted androgen levels therefore needs to be further investigated.


Subject(s)
Leydig Cells/drug effects , Testis/drug effects , Urocortins/pharmacology , Animals , Corticotropin-Releasing Hormone/pharmacology , Leydig Cells/metabolism , Male , Peptide Fragments/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Corticotropin-Releasing Hormone/agonists , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Receptors, Corticotropin-Releasing Hormone/metabolism , Testis/cytology , Testis/metabolism , Testosterone/pharmacology , Time Factors
16.
PLoS Biol ; 6(2): e17, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18254658

ABSTRACT

Amyloids are highly organized protein aggregates that are associated with both neurodegenerative diseases such as Alzheimer disease and benign functions like skin pigmentation. Amyloids self-polymerize in a nucleation-dependent manner by recruiting their soluble protein/peptide counterpart and are stable against harsh physical, chemical, and biochemical conditions. These extraordinary properties make amyloids attractive for applications in nanotechnology. Here, we suggest the use of amyloids in the formulation of long-acting drugs. It is our rationale that amyloids have the properties required of a long-acting drug because they are stable depots that guarantee a controlled release of the active peptide drug from the amyloid termini. This concept is tested with a family of short- and long-acting analogs of gonadotropin-releasing hormone (GnRH), and it is shown that amyloids thereof can act as a source for the sustained release of biologically active peptides.


Subject(s)
Amyloid , Drug Carriers , Biological Availability , Delayed-Action Preparations , Humans
17.
Dev Neurobiol ; 68(5): 575-89, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18264994

ABSTRACT

Hippocampal function and plasticity differ with gender, but the regulatory mechanisms underlying sex differences remain elusive and may be established early in life. The present study sought to elucidate sex differences in hippocampal plasticity under normal developmental conditions and in response to repetitive, predictable versus varied, unpredictable prenatal stress (PS). Adult male and diestrous female offspring of pregnant rats exposed to no stress (control), repetitive stress (PS-restraint), or a randomized sequence of varied stressors (PS-random) during the last week of pregnancy were examined for hippocampal proliferation, neurogenesis, cell death, and local microenvironment using endogenous markers. Regional volume was also estimated by stereology. Control animals had comparable proliferation and regional volume regardless of sex, but females had lower neurogenesis compared to males. Increased cell death and differential hippocampal precursor kinetics both appear to contribute to reduced neurogenesis in females. Reduced local interleukin-1beta (IL-1beta) immunoreactivity (IR) in females argues for a mechanistic role for the anti-apoptotic cytokine in driving sex differences in cell death. Prenatal stress significantly impacted the hippocampus, with both stress paradigms causing robust decreases in actively proliferating cells in males and females. Several other hippocampal measures were feminized in males such as precursor kinetics, IL-1beta-IR density, and cell death, reducing or abolishing some sex differences. The findings expand our understanding of the mechanisms underlying sex differences and highlight the critical role early stress can play on the balance between proliferation, neurogenesis, cell death, and hippocampal microenvironment in adulthood.


Subject(s)
Hippocampus/physiology , Nervous System/growth & development , Stress, Psychological/physiopathology , Animals , Cell Count , Cell Death/physiology , Data Interpretation, Statistical , Dentate Gyrus/pathology , Dentate Gyrus/physiopathology , Environment , Female , Feminization/physiopathology , Hippocampus/cytology , Immunohistochemistry , Interleukin-1beta/metabolism , Male , Pregnancy , Prenatal Exposure Delayed Effects , Rats , Rats, Sprague-Dawley , Sex Characteristics
18.
Behav Pharmacol ; 19(1): 1-12, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18195589

ABSTRACT

A 'binge' is defined by National Institute on Alcohol Abuse and Alcoholism as an excessive pattern of alcohol drinking that produces blood-alcohol levels (BALs) greater than 0.08 g% within a 2-h period and may or may not be associated with dependence. The purpose of this investigation was to explore the effects of several neuropharmacological agents in an animal model in which outbred rats voluntarily and orally self-administer pharmacologically meaningful alcohol doses that produce BALs >or=0.08 g% in daily limited access two-bottle choice and operant drinking sessions. Rats were trained to self-administer either 10% (w/v) alcohol solution sweetened with 'supersac' (3% glucose+0.125% saccharin) or supersac alone versus water in a two-bottle choice or operant situation during 30-min daily sessions. Rats were then injected systemically with multiple doses of duloxetine, naltrexone, and the corticotropin-releasing factor antagonist, MPZP, in Latin-square designs. Alcohol binge drinkers reliably consumed amounts of alcohol sufficient to produce BALs >or=0.08 g%. Duloxetine dose-dependently suppressed two-bottle choice alcohol binge drinking and operant alcohol responding as well as operant supersac responding, but did not affect two-bottle choice supersac drinking. Naltrexone-suppressed alcohol binge drinking at very low doses and suppressed supersac drinking at moderate-to-high doses. MPZP did not affect alcohol or supersac consumption. Different profiles for drugs that suppress binge-like alcohol drinking compared with dependence-induced drinking provide a heuristic foundation for future medications development.


Subject(s)
Alcohol Deterrents/pharmacology , Ethanol/poisoning , Naltrexone/pharmacology , Pyrimidines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Thiophenes/pharmacology , Animals , Behavior, Addictive/prevention & control , Behavior, Addictive/psychology , Conditioning, Operant/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Duloxetine Hydrochloride , Ethanol/blood , Male , Rats , Rats, Wistar , Saccharin/pharmacology , Self Administration , Sweetening Agents/pharmacology
19.
J Med Chem ; 50(7): 1668-74, 2007 Apr 05.
Article in English | MEDLINE | ID: mdl-17335188

ABSTRACT

The potencies and selectivity of peptide CRF antagonists is increased through structural constraints, suggesting that the resulting ligands assume distinct conformations when interacting with CRF1 and CRF2 receptors. To develop selective CRF receptor agonists, we have scanned the sequence -Gln-Ala-His-Ser-Asn-Arg- (residues 30-35 of [DPhe12,Nle21,38]Ac-hCRF4-41) with an i-(i+3) bridge consisting of the Glui-Xaa-Xbb-Lysi+3 scaffold, where residues i=30, 31, and 32. When i=31, stressin1-A, a potent CRF1 receptor-selective agonist was generated. In vitro, stressin1-A was equipotent to h/rCRF to release ACTH. Astressin1-A showed a low nanomolar affinity for CRF1 receptor (Ki=1.7 nM) and greater than 100-fold selectivity versus CRF2 receptor (Ki=222 nM). Stressin1-A released slightly less ACTH than oCRF in adult adrenal-intact male rats, with increased duration of action. Stressin1-A, injected intraperitoneally in rats, induced fecal pellet output (a CRF1 receptor-mediated response) and did not influence gastric emptying and blood pressure (CRF2 receptor-mediated responses).


Subject(s)
Corticotropin-Releasing Hormone/analogs & derivatives , Peptides, Cyclic/chemical synthesis , Receptors, Corticotropin-Releasing Hormone/agonists , Adrenocorticotropic Hormone/blood , Animals , Blood Pressure/drug effects , Cells, Cultured , Colon/drug effects , Colon/physiology , Corticotropin-Releasing Hormone/chemical synthesis , Corticotropin-Releasing Hormone/chemistry , Corticotropin-Releasing Hormone/pharmacology , Defecation/drug effects , Gastric Emptying/drug effects , Gastrointestinal Transit/drug effects , Humans , Male , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Pituitary Gland, Anterior/cytology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
20.
Alcohol Clin Exp Res ; 30(9): 1479-91, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16930210

ABSTRACT

BACKGROUND: Alcohol has been shown to interfere with testosterone (T) release from Leydig cells. However, the mechanisms responsible for this phenomenon, which may include decreased activity of the luteinizing hormone-releasing hormone (LHRH)-LH axis, as well as a direct influence of the drug on the testes, are not fully understood. In this work, we investigated the influence of alcohol, administered intragastrically (i.g.) or delivered via vapors, on Leydig cell activity and T release. Leydig cell function was studied by measuring changes in the levels of the steroidogenic proteins steroidogenic acute regulatory (StAR), the peripheral-type benzodiazepine receptor (PBR), and the cytochrome P450 side-chain cleavage enzyme (P450scc). Testosterone release was studied under basal conditions or in response to human chorionic gonadotropin (hCG). Finally, to identify potential factors mediating the influence of alcohol, we measured the testicular variant of the neuronal nitric oxide (NO) synthase (NOS), TnNOS, in semipurified Leydig cells. METHODS: Adult male Sprague-Dawley rats were either injected with alcohol i.g. once or exposed to alcohol vapors (4 h/d) for 1 or 5 days. Controls received the vehicle (i.g. model) or were kept in boxes through which no vapors were circulated. Following these treatments, one series of experiments was devoted to investigate Leydig cell responsiveness by measuring plasma T levels before or after the intravenous injection of hCG (1 U/kg). In another series of experiments, we used semipurified Leydig cell preparations to measure StAR, PBR, P450scc, and TnNOS by Western blot analysis. RESULTS: In the i.g. model, the T response to hCG was blunted for 12 hours following alcohol injection, but showed a rebound at 48 hours. Levels of StAR protein and of PBR, but not of P450scc, were significantly decreased within 10 minutes of drug administration. While StAR then remained depressed for 24 hours, PBR values were variable over this time course. By 48 hours, StAR, PBR, and P450scc levels had increased above control values. Both StAR and PBR levels showed correlations with plasma T levels. In the alcohol vapor models, both regimens of the drug also significantly depressed StAR and PBR protein concentrations, blunted the T response to hCG, and did not alter P450scc. Finally, we observed that alcohol delivered i.g. or via vapors up-regulated TnNOS levels in Leydig cells, but that blockade of NO formation failed to restore a normal T response to hCG. CONCLUSIONS: Collectively, these results suggest that (a) the ability of Leydig cells to release T does not show a simple correlation with changes in StAR, PBR, and P450scc levels; (b) the time course of the alcohol-induced changes were protein-specific; and (c) despite the ability of alcohol to stimulate TnNOS expression, NO does not appear to mediate the inhibitory influence of this drug on testicular steroidogenesis in the models that we studied.


Subject(s)
Central Nervous System Depressants/pharmacology , Ethanol/pharmacology , Leydig Cells/drug effects , Nitric Oxide/physiology , Administration, Inhalation , Animals , Blotting, Northern , Blotting, Western , Cell Separation , Central Nervous System Depressants/administration & dosage , Central Nervous System Depressants/blood , Cholesterol Side-Chain Cleavage Enzyme/metabolism , Chorionic Gonadotropin/pharmacology , Enzyme Inhibitors/pharmacology , Ethanol/administration & dosage , Ethanol/blood , Indicators and Reagents , Injections, Intravenous , Male , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase Type I/metabolism , Phosphoproteins/metabolism , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/drug effects , Receptors, GABA-A/metabolism , Testosterone/metabolism , Time Factors
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