Pierre Clément - Academia.edu (original) (raw)

Papers by Pierre Clément

chloroamphetamine (PCA) is an amphetamine derivative that liberates catecholamines and serotonin ... more chloroamphetamine (PCA) is an amphetamine derivative that liberates catecholamines and serotonin within the CNS and noradrenaline at the periphery. PCA induces ejaculation in both conscious (Humphries et al., 1980; Rènyi, 1985) and anaesthetised rats by acting at spinal and/or peripheral levels (Yonezawa et al., 2000). The goal of the study is to investigate the mechanism of action of PCA by carrying out, in anaesthetised rats, differential selective lesions at distinct levels of the peripheral autonomic pathways involved in the command of the various physiological events leading to ejaculation. Introduction and Objective::PCA is an amphetamine derivative that induces ejaculation in conscious and anaesthetised rats. Serotonin (5-HT) and norepinephrine (NE) are suggested to play respectively primary and secondary roles in mediating PCA effects likely occurring at the spinal and peripheral levels. The aim of the present study is to investigate the mechanism of action of PCA by carryin...

Annual review of sex research

Ejaculation is the final stage of coitus in the mammalian male and results in the expulsion of sp... more Ejaculation is the final stage of coitus in the mammalian male and results in the expulsion of sperm out of the urethral meatus. Two successive phases, emission and expulsion, can be distinguished during ejaculatory response. Normal anterograde ejaculation requires close coordination of sympathetic, parasympathetic, and somatic components commanding the different peripheral anatomical structures (accessory sexual glands, ducti, and striated muscles) involved in ejaculation. The efferent pathways innervating these anatomical structures drive motor outputs originating from spinal thoracolumbar and lumbosacral nuclei. These spinal ejaculatory centers, the synchronized activation of which is likely carried out by a group of spinal cells, are under the control of both peripheral sensory afferents coming from genital areas and supraspinal information arising from specific brain regions.

European Urology Supplements, 2006

European Urology Supplements, 2009

Cancer and Sexual Health, 2011

... Notably, the VTA contains A10 DAergic cell group belonging to the mesolimbic system and has p... more ... Notably, the VTA contains A10 DAergic cell group belonging to the mesolimbic system and has previously been shown activated in human during cocaine or heroin rush [74, 75]. These observations make the VTA a key element of the neuronal substrate for orgasm. ...

Neuroscience, 2005

CNS activity is generally coupled to the vigilance state, being primarily active during wakefulne... more CNS activity is generally coupled to the vigilance state, being primarily active during wakefulness and primarily inactive during deep sleep. During periods of high neuronal activity, a significant volume of oxygen is used to maintain neuronal membrane potentials, which subsequently produces cytotoxic reactive oxygen species (ROS). Glutathione, a major endogenous antioxidant, is an important factor protecting against ROS-mediated neuronal degeneration. Glutathione has also been proposed to be a sleep-promoting substance, yet the relationship between sleep and cerebral oxidation remains unclear. Here we report that i.c.v. infusion of the organic peroxide t-butyl-hydroperoxide at a concentration below that triggering neurodegeneration (0.1 micromol/100 microl/10 h) promotes sleep in rats. Also, microinjection (2 nmol, 2 microl) or microdialysis (100 microM, 20 min) of t-butyl-hydroperoxide into the preoptic/anterior hypothalamus (POAH) induces the release of the sleep-inducing neuromodulators, nitric oxide and adenosine, without causing neurodegeneration. Nitric oxide and adenosine release was inhibited by co-dialysis of the N-methyl-D-aspartate receptor antagonist, d(-)-2-amino-5-phosphonopentanoic acid (D-AP5; 1 mM), suggesting that glutamate-induced neuronal excitation mediates the peroxide-induced release of nitric oxide and adenosine. Indeed, Ca2+ release from mitochondria and delayed-onset Ca2+ influx via N-methyl-D-aspartate receptors was visualized during peroxide exposure using Ca2+ indicator proteins (YC-2.1 and mitochondrial-targeted Pericam) expressed in organotypic cultures of the POAH. In the in vitro models, t-butyl-hydroperoxide (50 microM) causes dendritic swelling followed by the intracellular Ca2+ mobilization, and D-AP5 (100 microM) or glutathione (500 microM) inhibited t-butyl-hydroperoxide-induced intracellular Ca2+ mobilization and protected POAH neurons from oxidative stress. These data suggest that low-level subcortical oxidation under the control of an antioxidant system may trigger sleep via the Ca(2+)-dependent release of sleep-inducing neuromodulators in the POAH, and thus we propose that a moderate increase of ROS during wakefulness in the neuronal circuits regulating sleep may be an initial trigger in sleep induction.

Neuroscience, 2007

The pivotal role of the medial preoptic area (MPOA) of the hypothalamus in the dopaminergic cereb... more The pivotal role of the medial preoptic area (MPOA) of the hypothalamus in the dopaminergic cerebral control of ejaculation has been investigated for years; nevertheless the function of different dopamine receptors subclasses and their exact interrelations merit additional research. One hundred nanograms of a preferential D(3) agonist 7-OH-DPAT (7-hydroxy-N,N-di-n-propylaminotetralin hydrobromide) was microinjected unilaterally into the MPOA of male rats anesthetized with urethane. An ejaculation-related response (bulbospongiosus muscles rhythmic contractions and/or seminal vesicle pressure increases and/or expulsion of a semen plug) was observed in 8 of 10 rats devoid of sexual stimuli, while a similar response was observed in only one rat administered with 10 ng of 7-OH-DPAT. The effect of 7-OH-DPAT 100 ng was mostly abolished by simultaneous MPOA microinjection of 300 ng of a preferential D(3) antagonist N-[(n-butyl-2-pyrrolidinyl) methyl]-1-methoxy-4-cyanonaphthalene-2-carboxamide tartrate (nafadotride). Our results support the hypothesis that supraspinal command of ejaculation is mediated by D(2)-like receptors, probably by D(3) receptors, in the MPOA, and draw attention to the idea of these receptors serving as a promising target for pharmacological treatment of human ejaculatory disorders.

Neuroscience, 2007

In addition to serotonin, dopamine within the CNS is known to play a primary role in the control ... more In addition to serotonin, dopamine within the CNS is known to play a primary role in the control of ejaculation. However, whether D(2) and/or D(3) dopamine receptor subtypes mediate this effect is still unclear. In order to clarify this issue, a pharmacological competitive study using the preferential D(3) agonist 7-hydroxy-2-(di-N-propylamino)tetralin (7-OH-DPAT) alone or in combination with competitive nonpreferential or preferential D(2) and D(3) antagonists delivered intracerebroventricularly (i.c.v.) was undertaken in anesthetized rats. Urethane-anesthetized male rats were implanted into the cerebral ventricle with a cannula for i.c.v. injections, and recording electrodes were placed within the bulbospongiosus (BS) muscle to monitor BS muscle contractions, which were used as a marker for the expulsion phase of ejaculation. Following i.c.v. injection, 7-OH-DPAT induced ejaculation and rhythmic BS muscle contractions. Co-injected i.c.v. with 7-OH-DPAT, the nonselective D(2)/D(3) antagonist (raclopride), and the preferential D(3) antagonist (S(-)-N[n-butyl-2-pyrrolidinyl)methyl]-1-methoxy-4-cyanonaphtalene-2-carboxamide; nafadotride) but not the preferential D(2) antagonist ((+/-)-3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole; L 741,626) inhibited the occurrence of ejaculation and BS muscle contractions. These results suggest that i.c.v. delivery of 7-OH-DPAT does represent a pertinent model to investigate the physio-pharmacology of ejaculation. It is inferred that targeting brain D(3) receptors may provide a therapeutic approach for treating ejaculatory disorders in humans.

Contributions from Science Education Research, 2014

ABSTRACT This book features 35 of the best papers from the 9th European Science Education Researc... more ABSTRACT This book features 35 of the best papers from the 9th European Science Education Research Association Conference, ESERA 2011, held in Lyon, France, September 5th-9th 2011. The ESERA international conference featured some 1,200 participants from Africa, Asia, Australia, and Europe as well as North and South America offering insight into the field at the end of the first decade of the 21st century. This book presents studies that represent the current orientations of research in science education and includes studies in different educational traditions from around the world. It is organized into six parts around the three poles of science education (content, students, teachers) and their interrelations: after a general presentation of the volume (first part), the second part concerns SSI (Socio- Scientific Issues) dealing with new types of content, the third the teachers, the fourth the students, the fifth the relationships between teaching and learning, and the sixth the teaching resources and the curricula.

European Urology Supplements, 2005

European Urology Supplements, 2005

European Urology Supplements, 2005

Procedia in Vaccinology, 2009

Q fever is a worldwide zoonosis that may cause reproductive disorders such as abortion, endometri... more Q fever is a worldwide zoonosis that may cause reproductive disorders such as abortion, endometritis or infertility in livestock. The implementation of a vaccination with a phase I vaccine is the nowadays the most relevant way to control the spread of the infection within herds. Annual boosters are recommended for ruminants by the manufacturer whereas in humans, to prevent side effects, no booster must be done before 5 years and the lack of humoral and cellular immunity has to be confirmed before any additional vaccination. The aim of this study was to investigate, in dairy cattle, the interest of such annual booster by assessing the level of different immune markers among 142 animals (from infected and uninfected herds) vaccinated either 2 year (i.e. 2 times) or 1 year before with an efficient commercial phase I Q fever vaccine. One year after vaccination, more than 80 % of the vaccinated cows had still immune markers, whereas 68 % of the heifers from uninfected herd did not. These data suggested that an annual booster would not be necessary for all vaccinated animals within a herd. In order to detect the immune animals and then to optimize the number of animals needing a boost, the skin test method, performed at least 3 days before the vaccination could be used.

European Urology Supplements, 2008

Seminal vesicle (SV) contractility is important in ejaculation triphosphate (ATP) is known as a c... more Seminal vesicle (SV) contractility is important in ejaculation triphosphate (ATP) is known as a contracting agent. Alpha adrenergic receptor blocker, channel openers, and rho kinase receptor inihibitors are known as relaxing agents. However, serotonin is known is known to be both contracting and relaxing agent. Up till now, there are Material & Methods: HSV tissue was obtained from 15 patients (mean age 65 years old) who had undergone pelvic surgery due to malignancy. Using the organ bath techniques 2 increasing concentration (10 nM -10µM) of ATP and 5-HT was tested. Norepinephrine (NE) was used as standard.

Sleep Medicine Reviews, 2005

Extensive evidences now suggest that an association between inducible nitric oxide synthase and o... more Extensive evidences now suggest that an association between inducible nitric oxide synthase and oxidative stress takes place during aging. Since the part played by inducible nitric oxide synthase in the sleep impairments associated with aging still remains unexplored, we compared its involvement in old rats (20 -24 months) versus adult ones (3-5 months) using polygraphic, biochemical, voltammetric and immunohistochemical techniques. The experiments were conducted either in basal condition or after a systemic injection of selected inducible nitric oxide synthase inhibitors. We found that 2-amino-5,6-dihydro-6-methyl-4H-1,3thiazine (10 mg/kg, i.p.) or aminoguanidine (400 mg/kg, i.p.) was capable to suppress rapid-eye-movement sleep and induce a delayed enhancement in slow-wave sleep in old rats. These effects did not occur in adult animals. Within the frontal cortex, the laterodorsal tegmentum and dorsal raphe nuclei, the basal inducible nitric oxide synthase activity was 85-200% higher in old rats than in adult ones. In contrast, the neuronal nitric oxide synthase activity did not vary in both groups. 2-Amino-5,6-dihydro-6-methyl-4H-1,3-thiazine administration significantly reduced inducible nitric oxide synthase activity (70 -80% according to the brain areas) independently of age, but significantly decreased the cortical nitric oxide release in old rats. Finally, in frontal cortex and dorsal raphe immunohistochemical analysis showed inducible nitric oxide synthase-positive cells again only in old animals. These data support the idea that nitric oxide produced by inducible nitric oxide synthase plays a role in the triggering and maintenance of rapid-eye-movement sleep during aging. © 2005 Published by Elsevier Ltd on behalf of IBRO. oxide; NOS, nitric oxide synthase; PBS, phosphate-buffer saline; PBST, phosphate-buffer saline with 0.3% Triton X-100; REM sleep, rapideye-movement sleep; SAM, senescence accelerated prone inbred strains of mice; SWS, slow wave sleep; W, waking state. Neuroscience 135 (2005) 347-355 0306-4522/05$30.00ϩ0.00

Psychopharmacology, 2013

Flibanserin, a 5-HT1A agonist and 5-HT2A antagonist, is developed for the treatment of hypoactive... more Flibanserin, a 5-HT1A agonist and 5-HT2A antagonist, is developed for the treatment of hypoactive sexual desire disorder in women, and its efficacy has been evidenced in several clinical studies. Flibanserin prosexual effects have been also evidenced in preclinical animal models. However, the mechanism of action of flibanserin remains not fully understood. The aim of the present study was to examine brain neuronal activation in female rats treated with flibanserin, using single immunocytochemical labeling of Fos protein, a marker of neuronal activation, and co-localization of Fos and catecholaminergic marker. Six groups of female rats received either acute or chronic administrations of vehicle, flibanserin 15 mg/kg or flibanserin 45 mg/kg. The brains were collected and processed for immunocytochemical labeling. Acute flibanserin increased levels of Fos immunoreactivity in the nucleus accumbens, arcuate hypothalamic nucleus, locus coeruleus, lateral paragigantocellular nucleus, and nucleus of the solitary tract. Chronic 22-day treatment with flibanserin increased Fos expression in the medial preoptic area and arcuate nucleus of the hypothalamus, ventral tegmental area, locus coeruleus, and lateral paragigantocellular nucleus. Both acute and chronic flibanserin increased the density of activated catecholaminergic neurons in the ventral tegmental area but not in the locus coeruleus. Altogether, our results showed that flibanserin, at the dose known to enhance female sexual motivation, preferentially activated the brain regions belonging to the mesolimbic dopaminergic pathway and hypothalamic structures involved in the integration of sexual cues related to sexual motivation.

chloroamphetamine (PCA) is an amphetamine derivative that liberates catecholamines and serotonin ... more chloroamphetamine (PCA) is an amphetamine derivative that liberates catecholamines and serotonin within the CNS and noradrenaline at the periphery. PCA induces ejaculation in both conscious (Humphries et al., 1980; Rènyi, 1985) and anaesthetised rats by acting at spinal and/or peripheral levels (Yonezawa et al., 2000). The goal of the study is to investigate the mechanism of action of PCA by carrying out, in anaesthetised rats, differential selective lesions at distinct levels of the peripheral autonomic pathways involved in the command of the various physiological events leading to ejaculation. Introduction and Objective::PCA is an amphetamine derivative that induces ejaculation in conscious and anaesthetised rats. Serotonin (5-HT) and norepinephrine (NE) are suggested to play respectively primary and secondary roles in mediating PCA effects likely occurring at the spinal and peripheral levels. The aim of the present study is to investigate the mechanism of action of PCA by carryin...

Annual review of sex research

Ejaculation is the final stage of coitus in the mammalian male and results in the expulsion of sp... more Ejaculation is the final stage of coitus in the mammalian male and results in the expulsion of sperm out of the urethral meatus. Two successive phases, emission and expulsion, can be distinguished during ejaculatory response. Normal anterograde ejaculation requires close coordination of sympathetic, parasympathetic, and somatic components commanding the different peripheral anatomical structures (accessory sexual glands, ducti, and striated muscles) involved in ejaculation. The efferent pathways innervating these anatomical structures drive motor outputs originating from spinal thoracolumbar and lumbosacral nuclei. These spinal ejaculatory centers, the synchronized activation of which is likely carried out by a group of spinal cells, are under the control of both peripheral sensory afferents coming from genital areas and supraspinal information arising from specific brain regions.

European Urology Supplements, 2006

European Urology Supplements, 2009

Cancer and Sexual Health, 2011

... Notably, the VTA contains A10 DAergic cell group belonging to the mesolimbic system and has p... more ... Notably, the VTA contains A10 DAergic cell group belonging to the mesolimbic system and has previously been shown activated in human during cocaine or heroin rush [74, 75]. These observations make the VTA a key element of the neuronal substrate for orgasm. ...

Neuroscience, 2005

CNS activity is generally coupled to the vigilance state, being primarily active during wakefulne... more CNS activity is generally coupled to the vigilance state, being primarily active during wakefulness and primarily inactive during deep sleep. During periods of high neuronal activity, a significant volume of oxygen is used to maintain neuronal membrane potentials, which subsequently produces cytotoxic reactive oxygen species (ROS). Glutathione, a major endogenous antioxidant, is an important factor protecting against ROS-mediated neuronal degeneration. Glutathione has also been proposed to be a sleep-promoting substance, yet the relationship between sleep and cerebral oxidation remains unclear. Here we report that i.c.v. infusion of the organic peroxide t-butyl-hydroperoxide at a concentration below that triggering neurodegeneration (0.1 micromol/100 microl/10 h) promotes sleep in rats. Also, microinjection (2 nmol, 2 microl) or microdialysis (100 microM, 20 min) of t-butyl-hydroperoxide into the preoptic/anterior hypothalamus (POAH) induces the release of the sleep-inducing neuromodulators, nitric oxide and adenosine, without causing neurodegeneration. Nitric oxide and adenosine release was inhibited by co-dialysis of the N-methyl-D-aspartate receptor antagonist, d(-)-2-amino-5-phosphonopentanoic acid (D-AP5; 1 mM), suggesting that glutamate-induced neuronal excitation mediates the peroxide-induced release of nitric oxide and adenosine. Indeed, Ca2+ release from mitochondria and delayed-onset Ca2+ influx via N-methyl-D-aspartate receptors was visualized during peroxide exposure using Ca2+ indicator proteins (YC-2.1 and mitochondrial-targeted Pericam) expressed in organotypic cultures of the POAH. In the in vitro models, t-butyl-hydroperoxide (50 microM) causes dendritic swelling followed by the intracellular Ca2+ mobilization, and D-AP5 (100 microM) or glutathione (500 microM) inhibited t-butyl-hydroperoxide-induced intracellular Ca2+ mobilization and protected POAH neurons from oxidative stress. These data suggest that low-level subcortical oxidation under the control of an antioxidant system may trigger sleep via the Ca(2+)-dependent release of sleep-inducing neuromodulators in the POAH, and thus we propose that a moderate increase of ROS during wakefulness in the neuronal circuits regulating sleep may be an initial trigger in sleep induction.

Neuroscience, 2007

The pivotal role of the medial preoptic area (MPOA) of the hypothalamus in the dopaminergic cereb... more The pivotal role of the medial preoptic area (MPOA) of the hypothalamus in the dopaminergic cerebral control of ejaculation has been investigated for years; nevertheless the function of different dopamine receptors subclasses and their exact interrelations merit additional research. One hundred nanograms of a preferential D(3) agonist 7-OH-DPAT (7-hydroxy-N,N-di-n-propylaminotetralin hydrobromide) was microinjected unilaterally into the MPOA of male rats anesthetized with urethane. An ejaculation-related response (bulbospongiosus muscles rhythmic contractions and/or seminal vesicle pressure increases and/or expulsion of a semen plug) was observed in 8 of 10 rats devoid of sexual stimuli, while a similar response was observed in only one rat administered with 10 ng of 7-OH-DPAT. The effect of 7-OH-DPAT 100 ng was mostly abolished by simultaneous MPOA microinjection of 300 ng of a preferential D(3) antagonist N-[(n-butyl-2-pyrrolidinyl) methyl]-1-methoxy-4-cyanonaphthalene-2-carboxamide tartrate (nafadotride). Our results support the hypothesis that supraspinal command of ejaculation is mediated by D(2)-like receptors, probably by D(3) receptors, in the MPOA, and draw attention to the idea of these receptors serving as a promising target for pharmacological treatment of human ejaculatory disorders.

Neuroscience, 2007

In addition to serotonin, dopamine within the CNS is known to play a primary role in the control ... more In addition to serotonin, dopamine within the CNS is known to play a primary role in the control of ejaculation. However, whether D(2) and/or D(3) dopamine receptor subtypes mediate this effect is still unclear. In order to clarify this issue, a pharmacological competitive study using the preferential D(3) agonist 7-hydroxy-2-(di-N-propylamino)tetralin (7-OH-DPAT) alone or in combination with competitive nonpreferential or preferential D(2) and D(3) antagonists delivered intracerebroventricularly (i.c.v.) was undertaken in anesthetized rats. Urethane-anesthetized male rats were implanted into the cerebral ventricle with a cannula for i.c.v. injections, and recording electrodes were placed within the bulbospongiosus (BS) muscle to monitor BS muscle contractions, which were used as a marker for the expulsion phase of ejaculation. Following i.c.v. injection, 7-OH-DPAT induced ejaculation and rhythmic BS muscle contractions. Co-injected i.c.v. with 7-OH-DPAT, the nonselective D(2)/D(3) antagonist (raclopride), and the preferential D(3) antagonist (S(-)-N[n-butyl-2-pyrrolidinyl)methyl]-1-methoxy-4-cyanonaphtalene-2-carboxamide; nafadotride) but not the preferential D(2) antagonist ((+/-)-3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole; L 741,626) inhibited the occurrence of ejaculation and BS muscle contractions. These results suggest that i.c.v. delivery of 7-OH-DPAT does represent a pertinent model to investigate the physio-pharmacology of ejaculation. It is inferred that targeting brain D(3) receptors may provide a therapeutic approach for treating ejaculatory disorders in humans.

Contributions from Science Education Research, 2014

ABSTRACT This book features 35 of the best papers from the 9th European Science Education Researc... more ABSTRACT This book features 35 of the best papers from the 9th European Science Education Research Association Conference, ESERA 2011, held in Lyon, France, September 5th-9th 2011. The ESERA international conference featured some 1,200 participants from Africa, Asia, Australia, and Europe as well as North and South America offering insight into the field at the end of the first decade of the 21st century. This book presents studies that represent the current orientations of research in science education and includes studies in different educational traditions from around the world. It is organized into six parts around the three poles of science education (content, students, teachers) and their interrelations: after a general presentation of the volume (first part), the second part concerns SSI (Socio- Scientific Issues) dealing with new types of content, the third the teachers, the fourth the students, the fifth the relationships between teaching and learning, and the sixth the teaching resources and the curricula.

European Urology Supplements, 2005

European Urology Supplements, 2005

European Urology Supplements, 2005

Procedia in Vaccinology, 2009

Q fever is a worldwide zoonosis that may cause reproductive disorders such as abortion, endometri... more Q fever is a worldwide zoonosis that may cause reproductive disorders such as abortion, endometritis or infertility in livestock. The implementation of a vaccination with a phase I vaccine is the nowadays the most relevant way to control the spread of the infection within herds. Annual boosters are recommended for ruminants by the manufacturer whereas in humans, to prevent side effects, no booster must be done before 5 years and the lack of humoral and cellular immunity has to be confirmed before any additional vaccination. The aim of this study was to investigate, in dairy cattle, the interest of such annual booster by assessing the level of different immune markers among 142 animals (from infected and uninfected herds) vaccinated either 2 year (i.e. 2 times) or 1 year before with an efficient commercial phase I Q fever vaccine. One year after vaccination, more than 80 % of the vaccinated cows had still immune markers, whereas 68 % of the heifers from uninfected herd did not. These data suggested that an annual booster would not be necessary for all vaccinated animals within a herd. In order to detect the immune animals and then to optimize the number of animals needing a boost, the skin test method, performed at least 3 days before the vaccination could be used.

European Urology Supplements, 2008

Seminal vesicle (SV) contractility is important in ejaculation triphosphate (ATP) is known as a c... more Seminal vesicle (SV) contractility is important in ejaculation triphosphate (ATP) is known as a contracting agent. Alpha adrenergic receptor blocker, channel openers, and rho kinase receptor inihibitors are known as relaxing agents. However, serotonin is known is known to be both contracting and relaxing agent. Up till now, there are Material & Methods: HSV tissue was obtained from 15 patients (mean age 65 years old) who had undergone pelvic surgery due to malignancy. Using the organ bath techniques 2 increasing concentration (10 nM -10µM) of ATP and 5-HT was tested. Norepinephrine (NE) was used as standard.

Sleep Medicine Reviews, 2005

Extensive evidences now suggest that an association between inducible nitric oxide synthase and o... more Extensive evidences now suggest that an association between inducible nitric oxide synthase and oxidative stress takes place during aging. Since the part played by inducible nitric oxide synthase in the sleep impairments associated with aging still remains unexplored, we compared its involvement in old rats (20 -24 months) versus adult ones (3-5 months) using polygraphic, biochemical, voltammetric and immunohistochemical techniques. The experiments were conducted either in basal condition or after a systemic injection of selected inducible nitric oxide synthase inhibitors. We found that 2-amino-5,6-dihydro-6-methyl-4H-1,3thiazine (10 mg/kg, i.p.) or aminoguanidine (400 mg/kg, i.p.) was capable to suppress rapid-eye-movement sleep and induce a delayed enhancement in slow-wave sleep in old rats. These effects did not occur in adult animals. Within the frontal cortex, the laterodorsal tegmentum and dorsal raphe nuclei, the basal inducible nitric oxide synthase activity was 85-200% higher in old rats than in adult ones. In contrast, the neuronal nitric oxide synthase activity did not vary in both groups. 2-Amino-5,6-dihydro-6-methyl-4H-1,3-thiazine administration significantly reduced inducible nitric oxide synthase activity (70 -80% according to the brain areas) independently of age, but significantly decreased the cortical nitric oxide release in old rats. Finally, in frontal cortex and dorsal raphe immunohistochemical analysis showed inducible nitric oxide synthase-positive cells again only in old animals. These data support the idea that nitric oxide produced by inducible nitric oxide synthase plays a role in the triggering and maintenance of rapid-eye-movement sleep during aging. © 2005 Published by Elsevier Ltd on behalf of IBRO. oxide; NOS, nitric oxide synthase; PBS, phosphate-buffer saline; PBST, phosphate-buffer saline with 0.3% Triton X-100; REM sleep, rapideye-movement sleep; SAM, senescence accelerated prone inbred strains of mice; SWS, slow wave sleep; W, waking state. Neuroscience 135 (2005) 347-355 0306-4522/05$30.00ϩ0.00

Psychopharmacology, 2013

Flibanserin, a 5-HT1A agonist and 5-HT2A antagonist, is developed for the treatment of hypoactive... more Flibanserin, a 5-HT1A agonist and 5-HT2A antagonist, is developed for the treatment of hypoactive sexual desire disorder in women, and its efficacy has been evidenced in several clinical studies. Flibanserin prosexual effects have been also evidenced in preclinical animal models. However, the mechanism of action of flibanserin remains not fully understood. The aim of the present study was to examine brain neuronal activation in female rats treated with flibanserin, using single immunocytochemical labeling of Fos protein, a marker of neuronal activation, and co-localization of Fos and catecholaminergic marker. Six groups of female rats received either acute or chronic administrations of vehicle, flibanserin 15 mg/kg or flibanserin 45 mg/kg. The brains were collected and processed for immunocytochemical labeling. Acute flibanserin increased levels of Fos immunoreactivity in the nucleus accumbens, arcuate hypothalamic nucleus, locus coeruleus, lateral paragigantocellular nucleus, and nucleus of the solitary tract. Chronic 22-day treatment with flibanserin increased Fos expression in the medial preoptic area and arcuate nucleus of the hypothalamus, ventral tegmental area, locus coeruleus, and lateral paragigantocellular nucleus. Both acute and chronic flibanserin increased the density of activated catecholaminergic neurons in the ventral tegmental area but not in the locus coeruleus. Altogether, our results showed that flibanserin, at the dose known to enhance female sexual motivation, preferentially activated the brain regions belonging to the mesolimbic dopaminergic pathway and hypothalamic structures involved in the integration of sexual cues related to sexual motivation.