Nonmotor and Dopamine Transporter Change in REM Sleep Behavior Disorder by Olfactory Impairment

OBJECTIVE: It is unclear whether the decline in dopamine transporters (DAT) differs among idiopathic rapid eye movement sleep behavior disorder (iRBD) patients with different levels of olfactory impairment. This study aimed to characterize DAT changes in relation to nonmotor features in iRBD patients by olfactory loss. METHODS: This prospective cohort study consisted of three age-matched groups: 30 polysomnography-confirmed iRBD patients, 30 drug-naïve Parkinson's disease patients, and 19 healthy controls without olfactory impairment. The iRBD group was divided into two groups based on olfactory testing results. Participants were evaluated for reported prodromal markers and then underwent 18F-FP-CIT positron emission tomography and 3T MRI. Tracer uptakes were analyzed in the caudate, anterior and posterior putamen, substantia nigra, and raphe nuclei. RESULTS: Olfactory impairment was defined in 38.5% of iRBD patients. Mild parkinsonian signs and cognitive functions were not different between the two iRBD subgroups; however, additional prodromal features, constipation, and urinary and sexual dysfunctions were found in iRBD patients with olfactory impairment but not in those without. Tracer uptake showed significant group differences in all brain regions, except the raphe nuclei. The iRBD patients with olfactory impairment had uptake reductions in the anterior and posterior putamen, caudate, and substantia nigra (p < 0.016 in all, adjusted for age), which ranged from 0.6 to 0.8 of age-normative values. In contrast, those without olfactory impairment had insignificant changes in all regions ranging above 0.8. CONCLUSION: There was a clear distinction in DAT loss and nonmotor profiles by olfactory status in iRBD.

Fos expression in the prefrontal cortex and mesencephalic dorsal raphe nucleus in lactating rats after social instigation

Females are often less aggressive than males, but they exhibit high levels of agonistic behavior against an intruder in the area of ​​the nest during lactation. This behavior is referred to as maternal aggression. In rats, maternal aggressive behavior occurs more often from postpartum day 3 (PPD 3) to PPD 12. Social instigation is an experimental protocol used to increase the levels of aggression that are typical of the species. In the present study we used social instigation to analyze the expression of a marker of neuronal activity, c-fos. Lactating rats on PPD 5, in the presence of their pups, were divided into four groups: (1) no social instigation and no aggressive behavior, (2) social instigation and no aggressive behavior, (3) no social instigation and aggressive behavior, and (4) social instigation and aggressive behavior. Sixty minutes after the aggression test we used immunohistochemistry to detect Fos in two brain regions, the ventral-orbital region of the prefrontal cortex (VO PFC) and dorsal raphe nucleus (DRN). Our results showed that rats with aggressive behavior that were provoked exhibited an increase in Fos expression in the VO PFC compared with the control group (i.e., no social instigation and no aggressive behavior). No change in Fos expression was found in the DRN. These results complement previous findings with microinjection of serotonin 5-hydroxytryptamine-1B receptor agonists into the same region, demonstrating that the VO PFC is an important region in the modulation of maternal aggressive behavior.

Raphe obscurus neurons participate in thermoregulation in rats / Neurônios do núcleo obscuro da rafe participam da termorregulação em ratos

In mammalian, several evidences suggest that central serotonin participates in thermoregulation. Nucleus raphe obscurus (NRO), a serotonergic nucleus, has been recognized to be the source of generation of various hemodynamic patterns in different behavioral conditions, but its involvement in thermoregulation is unclear. In the present study, extracellular action potentials of NRO neurons were recorded in anesthetized rats, which were submitted to cold and warm stimuli in the tail. The firing rate of the neurons was compared before and after each stimulation. It was found that 59% of the neurons submitted to a cold stimulus trial had a significant increase in their firing frequency, while 48% of the neurons submitted to warm stimulation trial were inhibited. The opposite responses in neuronal activity of NRO units to cooling or heating suggest that these cells are involved in producing the homoeothermic vascular adaptations secondary to changes in cutaneous temperature in the rat tail.

A termorregulação em mamíferos envolve a participação da serotonina. O núcleo obscuro da rafe (NRO), que é serotoninérgico, participa do controle autonômico, mas seu envolvimento na termorregulação é incerto. Neste estudo, registramos potenciais de ação extracelulares de neurônios do NRO em ratos anestesiados nos quais a cauda foi submetida a estímulos de calor ou frio. A frequência de disparo dos neurônios foi comparada antes e depois dos estímulos. O grupo controle não apresentou modificação da frequência de disparo, enquanto que 59% dos neurônios registrados em animais submetidos a estímulo de frio tiveram sua frequência aumentada. Por outro lado, 48% dos animais submetidos a estímulo de calor tiveram sua frequência de disparo diminuída. As respostas opostas da frequência de disparo em neurônios de animais submetidos à estimulação com frio e calor sugere que estes neurônios estejam envolvidos na geração de respostas hemodinâmicas, que são coerentes com a termorregulação nesta espécie.

Efeito do lítio sobre a hiperatividade locomotora induzida pela lesão eletrolítica da região do núcleo mediano da rafe em ratos / Effect of lithium treatment on the locomotor hyperactivity induced by the lesion of the region of the median raphe nucleus in rats

A lesão do núcleo mediano da rafe (NMR) produz sintomas que sugerem validade de face ao episódio maníaco. Esta pesquisa avaliou o efeito do lítio sobre a hiperatividade locomotora induzida por esta lesão. Vinte e um ratos Wistar machos foram submetidos à lesão eletrolítica da região do NMR (LR) e 17 foram submetidos à lesão fictícia (LF). Após recuperação, a atividade locomotora foi avaliada na caixa de atividade (Med Associates/ENV-515). Parte dos animais destes grupos recebeu tratamentos com lítio (47,5 mg/kg/2x dia i.p.) por 10 dias, enquanto o restante foi tratado com salina no mesmo esquema. A reavaliação ao final dos tratamentos demonstrou que o lítio reduziu significantemente a atividade locomotora em relação à avaliação inicial no grupo LR (ANOVA/Bonferroni p < 0,05), tornando-a equivalente aos baixos níveis dos grupos LF. Estes dados sustentam a hipótese de que as manifestações induzidas pela lesão do NMR podem constituir um modelo animal de mania.

The lesion of the Median Raphe Nucleus (MRN) produces symptoms that suggest face validity for manic episodes. This research evaluated the effect of lithium treatment on the locomotor hyperactivity induced by this lesion. Twenty-one Wistar male rats were submitted to the lesion of the region of the MRN (LR) and 17 were sham lesioned (LF). After recovery, the locomotor activity was evaluated in an activity chamber (Med Associates/ENV-515). A subgroup received lithium (47.5 mg/kg/twice a day i.p.) for 10 days, while the other animals received saline in the same schedule. The reevaluation at the end of the treatments showed that only lithium significantly reduced the activity of LR group compared to baseline levels (ANOVA/Bonferroni p < 0.05), making it equivalent to low levels of LF groups. These data support the hypothesis that the behavioral manifestations induced by the lesion of the MRN may constitute an animal model of mania.

Envolvimento de receptores 5-HT2C do hipocampo ventral em comportamentos de defesa de ratos no labirinto em cruz elevado / Involvement of ventral hippocampus 5-HT2C receptors on defensive behaviors of rats in the elevated plus-maze

A ativação farmacológica dos receptores 5-HT2C induz comportamentos de defesa em modelos animais. O estudo busca investigar se o bloqueio seletivo de receptores 5-HT2C no hipocampo ventral (HV) previne comportamentos defensivos induzidos por um agonista de receptor 5-HT2C administrado perifericamente em ratos expostos ao labirinto em cruz elevado (LCE). Quinze minutos após injeções intraperitoniais (IP, 1ml/kg) do agonista 5-HT2C WAY-161503, ratos foram microinjetados bilateralmente no HV com o antagonista seletivo de receptores 5-HT2C SB-242084 (0, 0,1, 0,5 ou 1.5μg). Dez minutos após, cada animal foi exposto ao LCE para o registro de categorias de ansiedade. Injeções sistêmicas do WAY-161503 reduziram seletivamente as explorações nos braços abertos e aumentaram padrões de avaliação de risco. Esse efeito foi atenuado de maneira dose-dependente pela microinjeção de SB-242084 no HV, confirmando a ação ansiogênica de agonistas 5-HT2C e sugerindo que esse perfil comportamental seja mediado, pelo menos em parte, por receptores 5-HT2C do HV.

Pharmacological 5-HT2C receptor activation induces defensive behaviors in several animal models of anxiety. The present study investigated whether the selective blockade of 5-HT2C receptors in the ventral hippocampus (VH) prevents defensive behaviors induced by a 5-HT2C agonist administered systemically in rats exposed to the elevated plus-maze (EPM). Fifteen minutes after intraperitonial (IP, 1ml/kg) injections of the selective 5-HT2C receptor agonist WAY-161503 (3 mg/kg), rats were bilaterally microinjected with the selective 5-HT2C antagonist SB-242084 (0, 0.1, 0.5 or 1.5μg) into the VH. Ten minutes after, each animal was exposed to the EPM for measuring classical and ethological anxiety measures. IP WAY-161503 injections selectively decreased open-arm exploration while increasing risk-assessment. This anxiogenic-like action was dose-dependently attenuated by intra-VH SB-242084 microinjections. These results not only further confirm the anxiogenic-like action of 5-HT2C agonists, but also suggest that this behavioral profile might be mediated at least in part by VH 5-HT2C receptors.

Effect of serotonin depletion on seizures learning-memory in pilocarpine-induced epileptic rats / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To investigate the relationship between serotonin (5-HT) and epilepsy and the mechanism of learning-memory in pilocarpine (PILO)-induced epileptic rats after 5,7-dihydroxytryptamine (5,7-DHT) microinjection in median raphe nucleus.</p><p><b>METHODS</b>Adult S D rats were randomly divided into 3 groups: PILO group, PILO+ 5,7-DHT group, vehicle control group; PILO group was divided into two groups by status epilepticus (SE): PILO + SE group and PILO - SE group. The rats' seizures and cortex electroencephalography (EEG) were observed by video EEG. The rats' spatial learning-memory was evaluated by Morris water maze. Finally, serotonergic neuron in raphe nuclei was observed by immunohistochemistry.</p><p><b>RESULTS</b>After treatment of 5,7-DHT (PILO + 5,7-DHT group), the success rate, the mortality and the frequency of chronic spontaneous seizures in pilocarpine-induced epilepsy model were all improved. Compared with the control group, the number of serotonergic neuron in raphe nuclei was decrease in PILO + SE group (P < 0.05). Moreover, it's extremely decrease in PILO + 5,7-DHT group (P < 0.01). Compared with control group, the mean escape latency was prolonged, the times of crossing target was decreased and the retention time in target zone was shortened in PILO + SE group (P < 0.05), but there was no significant difference between PILO + SE group and PILO + 5,7-DHT group.</p><p><b>CONCLUSION</b>Depletion of serotonin may facility the rats' epileptic seizures, but we could not interpret which may cause epileptic rats' cognitive deficit.</p>

5-HT1A autoreceptor modulation of locomotor activity induced by nitric oxide in the rat dorsal raphe nucleus

The dorsal raphe nucleus (DRN) is the origin of ascending serotonergic projections and is considered to be an important component of the brain circuit that mediates anxiety- and depression-related behaviors. A large fraction of DRN serotonin-positive neurons contain nitric oxide (NO). Disruption of NO-mediated neurotransmission in the DRN by NO synthase inhibitors produces anxiolytic- and antidepressant-like effects in rats and also induces nonspecific interference with locomotor activity. We investigated the involvement of the 5-HT1A autoreceptor in the locomotor effects induced by NO in the DRN of male Wistar rats (280-310 g, N = 9-10 per group). The NO donor 3-morpholinosylnomine hydrochloride (SIN-1, 150, and 300 nmol) and the NO scavenger S-3-carboxy-4-hydroxyphenylglycine (carboxy-PTIO, 0.1-3.0 nmol) were injected into the DRN of rats immediately before they were exposed to the open field for 10 min. To evaluate the involvement of the 5-HT1A receptor and the N-methyl-D-aspartate (NMDA) glutamate receptor in the locomotor effects of NO, animals were pretreated with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 8 nmol), the 5-HT1A receptor antagonist N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY-100635, 0.37 nmol), and the NMDA receptor antagonist DL-2-amino-7-phosphonoheptanoic acid (AP7, 1 nmol), followed by microinjection of SIN-1 into the DRN. SIN-1 increased the distance traveled (mean ± SEM) in the open-field test (4431 ± 306.1 cm; F7,63 = 2.44, P = 0.028) and this effect was blocked by previous 8-OH-DPAT (2885 ± 490.4 cm) or AP7 (3335 ± 283.5 cm) administration (P < 0.05, Duncan test). These results indicate that 5-HT1A receptor activation and/or facilitation of glutamate neurotransmission can modulate the locomotor effects induced by NO in the DRN.

The relationships among raphe magnus nucleus, locus coeruleus and dorsal motor nucleus of vagus in the descending regulation of gastric motility / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To explore the interrelationship among dorsal motor nucleus of the vagus (DMV), locus coeruleus (LC) and raphe magnus nucleus (NRM) in the mechanism of the descending regulation on gastric motility, which may constitute a parasympathetic local circuit, work as a neural center of gastric modulation in brainstem.</p><p><b>METHODS</b>Using nucleus location, electric stimulation and lesion, together with microinjection, and recording the inter-gastric pressure.</p><p><b>RESULTS</b>(1) LC stimulation could inhibit the gastric motility significantly (P < 0.01), DMV lesion weaken this effect, while blocking the a receptor on DMV could reverse the effect. (2) NRM stimulation reduced the amplitude of gastric constriction (P < 0.01), DMV lesion could abolish the effect, but blocking the 5-HT2A receptor on DMV depressed the gastric motility heavily (P < 0.01) like NRM stimulation. While LC lesion could abolish the effect of NRM stimulation, and microinjection of ritanserin into LC could likewise abolish it.</p><p><b>CONCLUSION</b>(1) LC inhibit the gastric motility via a receptor in DMV, and meanwhile may excite it through 5-HT2A receptor in DMV, these two ways work together to keeping the gastric motility amplitude normally. (2) NRM inhibit the gastric motility via 5-HT2A receptor in LC.</p>

Normal Sleep in Children and Adolescents

Sleep is not just a rest for brain activity during daytime, but also has a vital function for memory consolidation after learning as well as restoration of both body and brain. While restoration of the body mainly occurs during non-rapid eye movement (NREM) sleep, especially during slow wave sleep, restoration of brain and memory consolidation occurs mainly during REM sleep. Adenosine acts as a sleep-inducing agent, so called somnogen or hypnotoxin which accumulates while awake. Sleep deprivation results in the disruption of every aspect of physical, cognitive, and behavioral function, which can be reversed only by sleep. Many neurotransmitter-secreting nuclei in the brain stem, hypothalamus, and basal forebrain are key structures for wakefulness, NREM, and REM sleep. They have been localized in the basal forebrain (acetylcholine), ventrolateral preoptic area (VLPO, GABA and galanin), tuberomamillary nucleus (TMN, histamine), lateral and posterior hypothalamus (orexin/hypocretin), reticular formation (glutamate), substantia nigra/ventral tegmental area (SN/VTA, dopamine), pedunculopontine nucleus and lateral dorsal tegmentum (PPT-LDT, acetylcholine), locus ceruleus (norepinephrine), and the raphe nuclei (serotonin). All are activated during wakefulness except VLPO which secrets GABA and galanin, which suppress other nuclei for sleep induction. Acetylcholine-secreting PPT-LDT is a major locus for REM sleep, and is inhibited by the raphe nuclei and locus ceruleus which act as REM-off neurons inducing NREM sleep. The suprachiasmatic nucleus is a pacemaker for circadian rhythms, which can be modified by bright light and melatonin. It should be emphasized that the best performance of cognitive function including reactivity, abstract thinking, creativity, memory, executive function, and accurate and efficient work as well as physical well-being is achieved by sufficient and appropriate sleep.

Serotonin and circadian rhythms

All mammal behaviors and functions exhibit synchronization with environmental rhythms. This is accomplished through an internal mechanism that generates and modulates biological rhythms. The circadian timing system, responsible for this process, is formed by connected neural structures. Pathways receive and transmit environmental cues to the central oscillator, the hypothalamic suprachiasmatic nucleus, which mediates physiological and behavioral alterations. The suprachiasmatic nucleus has three major inputs: the retinohypothalamic tract (a direct projection from the retina), the geniculohypothalamic tract (an indirect photic projection originating in the intergeniculate leaflet), and a dense serotonergic plexus from the raphe nuclei. The serotonergic pathway, a source of non-photic cues to the suprachiasmatic nucleus, modulates its activity. The importance of raphe nuclei in circadian rhythms, especially in photic responses, has been demonstrated in many studies. Serotonin is the raphe neurotransmitter that triggers phase shifts, inhibits light-induced phase-shifts, and plays a role in controlling the sleep-wake cycle. All data to date have demonstrated the importance of the raphe, through serotonergic afferents, in adjusting circadian rhythms and must therefore be considered a component of the circadian timing system. The aim of this paper is to review the literature addressing the involvement of serotonin in the modulation of circadian rhythm

5-hydroxy-L-tryptophan Suppressed Food Intake in Rats Despite an Increase in the Arcuate NPY Expression

This study was conducted to define the underlying mechanism of hypophagia induced by increased central serotonergic action. Rats received 3 daily injections of 5-hydroxy-L-tryptophan (5-HTP), a serotonin precursor, at a dose of 100 mg/kg/10 ml saline at 1 h before lights off. A significant suppression in food intake was observed shortly after the 5-HTP injection and persisted during 3 daily 5-HTP injections. Neuropeptide Y (NPY) expression in the arcuate nucleus increased after 3 days of 5-HTP treatment, as high as in the pair-fed group. Immunoreactivity of phosphorylated extracellular signal-regulated protein kinase (pERK1/2) in the hypothalamic paraventricular nucleus (PVN) was increased markedly by 3 days of 5-HTP treatment, but not by 3 days of pair-fed. mRNA expression levels of serotonin reuptake transporter (5-HTT) was increased in the dorsal raphe nucleus of the 5-HTP treated rats, but not in the pair-fed group. Results suggest that increased pERK1/2 in the PVN of 5-HTP injected rats may be a part of serotonergic anorectic signaling, perhaps blunting the orectic action of NPY; i.e., 5-HTP injected rats showed hypophagia despite of increased NPY expression in the arcuate nucleus.

Effect of Electroacupuncture on Visceral Hyperalgesia, Serotonin and Fos Expression in an Animal Model of Irritable Bowel Syndrome

BACKGROUND/AIMS: While it is well established that acupuncture relieves somatic pain, its therapeutic effect on visceral pain such as irritable bowel syndrome (IBS) is unclear. We evaluated the effect of acupuncture in treating visceral hyperalgesia in an animal model. METHODS: Sprague-Dawley rats (n = 8 per group) with prior neonatal maternal separation stress were randomly allocated to receive 3-day treatment of either electroacupuncture (EA) or sham acupuncture at acupoint ST-36. Another group of rats without prior maternal separation was included as non-handled controls. Colorectal distension was performed on the day after acupuncture treatment. The 3 groups were compared for pain threshold as determined by abdominal withdrawal reflex and visceromotor response as measured by electromyogram. Colon, spinal cord, and brainstem were sampled for topographic distribution and quantitative assessment of serotonin and Fos expression by immunohistochemistry. RESULTS: Rats in EA group had significantly higher pain threshold compared to those in sham acpuncture group (25.0 +/- 5.7 mmHg vs 18.7 +/- 5.2 mmHg, p = 0.01) and it was comparable with that of non-handled treatment naive controls (29.4 +/- 9.3 mmHg, p = 0.28). They also had lower visceromotor response as measured by electromyogram compared to those received sham acupuncture at all colorectal distension pressures. EA significantly suppressed Fos expression in doral raphe nuclei of brainstem, superficial dorsal horn of spinal cord and colonic epithelium but suppressed 5-HT expression only in brainstem and spinal cord. CONCLUSIONS: Electro acupuncture attenuates visceral hyperlagesia through down-regulation of central serotonergic activities in the brain-gut axis.

[ effect of hydrochloric extraction of valerian on number and size of raphe magnus neurons in adult rats]

Effective materials from Valerian officinalis L. have too much usage in the pharmacological industry. It is used as a sedative, anticonvulsion, and antidepressant drug. Serotonin has a widespread role in vital function such as sleep, awareness and calmness. In this study we evaluated the effect of hydrochloric extract of valerian on number and size of raphe magnus neurons in adult rat. In this experimental study, which was conducted at Yasuj University of Medical Sciences in 2009, forty adult Wistar rats, each 170-250 gr, were divided randomly into four groups [one control group and three experimental groups]. The animals were injected daily for one month with doses of 300, 400 and 600 mg/kg of the extract. The control group just received distilled water. After transcardial perfusion, the whole brain was separated, then 10 micro m sections of the brain stem were prepared, and hematoxylin and eosin [H and E] staining were done. Number and size of raphe magna neurons were observed under light microscope. The gathered data were analyzed by the SPSS software using One-way ANOVA and LSD. The control group did not statistically show significant changes in number of raphe magna neurons. Comparison of the means of long and short diameter neurons showed significant increases in experimental groups with control group [P<0.05]. In experimental groups the neuron nucleuses were more euchromatic than the control group. Hydrochloric extract of valerian has no effect on raphe magnus neurons, but it is effective on neurons' size. It can be concluded that the extract increases both neurons activity and serotonin secretion

Vardenafil Increases Cell Proliferation in the Dentate Gyrus through Enhancement of Serotonin Expression in the Rat Dorsal Raphe

This study was conducted to evaluate the effects of vardenafil (Levitra), a phosphodiesterase-5 (PDE-5) inhibitor, on cell proliferation in the hippocampal dentate gyrus and on 5-hyroxytryptamine (5-HT, serotonin) synthesis and tryptophan hydroxylase (TPH) expression in the rat dorsal raphe nucleus. Male Sprague-Dawley rats were divided into 6 groups (n=5 in each group): a control group, a 0.5 mg/kg-1 day vardenafil-treated group, a 1 mg/kg-1 day vardenafil-treated group, a 2 mg/kg-1 day vardenafil-treated group, a 1 mg/kg-3 day vardenafil-treated group, and a 1 mg/kg-7 day vardenafil-treated group. 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry was then performed to evaluate cell proliferation in the dentate gyrus. In addition, 5-HT and TPH immunohistochemistry was conducted to evaluate serotonin expression in the dorsal raphe. The results revealed that treatment with vardenafil increased cell proliferation in the dentate gyrus and enhanced 5-HT synthesis and TPH expression in the dorsal raphe in a dose- and duration-dependent manner. The findings demonstrate that the increasing effect of vardenafil on cell proliferation is closely associated with the enhancing effect of vardenafil on serotonin expression under normal conditions.

Changes in the firing activity of serotonergic neurons in the dorsal raphe nucleus in a rat model of Parkinson's disease / 生理学报

In the present study, changes in the neuronal activity of serotonergic neurons in the dorsal raphe nucleus (DRN) and the effect of the selective 5-HT(1A) receptor antagonist WAY-100635 in a rat model of Parkinson's disease (PD) were investigated by using extracellular single unit recording. Rat model of PD was produced by microinjection of 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta on the right side of the brain. The results showed that the mean spontaneous firing rate of DRN serotonergic neurons in the control and 6-OHDA-lesioned rats were (1.76+/-0.11) spikes/s (n=24) and (2.43+/-0.17) spikes/s (n=21), respectively. The firing rate of serotonergic neurons in 6-OHDA-lesioned rats was significantly higher than that in the control rats (P<0.001). In the control rats, 92% (22/24) of the neurons fired regularly and 8% (2/24) fired in bursts. In rats with 6-OHDA lesions, 9% (2/21) of neurons fired regularly, 43% (9/21) exhibited irregular pattern and 48% (10/21) fired in bursts. The percentage of DRN serotonergic neurons firing in bursts was obviously higher in 6-OHDA-lesioned rats than that in the control rats (P<0.001). Local injection of WAY-100635 (3 microg in 200 nL) into the DRN significantly increased the firing rate of serotonergic neurons with no change in firing pattern in the control rats (n=19, P<0.002), but did not change the firing rate and firing pattern of serotonergic neurons in 6-OHDA-lesioned rats (n=17, P>0.05). These results suggest the dysfunction of 5-HT(1A) receptor in 6-OHDA-lesioned rats and the involvement of the DRN in the pathophysiological mechanism of PD.

The lesion of CSF contacting neurons in rat brain parenchyma inhibits the development of morphine dependence and withdrawal / 中国应用生理学杂志

<p><b>AIM</b>To investigate the effect of CSF contacting neurons (CSF-CNs) lesion in rat dorsal raphe nucleus (DRN) on the scores of morphine withdrawal symptoms precipitated by naloxone and the nNOS expression in dorsal horn of spinal cord, and study the relationship between the distal CSF-CNs in rat brain parenchyma and the development of morphine dependence and withdrawal.</p><p><b>METHODS</b>Chemical lesion of neurons the injection of cholera toxin subunit B with horseradish peroxidase (CB-HRP) into one of the rats lateral ventricles, TMBST reaction, nNOS immunohistochemistry and Western blot were used in this study.</p><p><b>RESULTS</b>The withdrawal symptoms by the naloxone precipitated attenuated obviously after the lesion of CSF-CNs in rat DRN, scores of all signs were significantly decreased about 38% compared to that of withdrawal group without lesion (P < 0.05). The withdrawal symptoms scores of vehicle withdrawal group and side lesion withdrawal group were not changed significantly (P > 0.05). Neurons in the location of CSF-CNs concentrated in the rat brain slices of lesion group were damaged obviously, there were only few CB-HRP positive neurons around the lesion location. But the location and the quantity of the CB-HRP positive neurons in the brain slices of the group without lesion was stable relatively, and their appearance was very clear. After the lesion, the nNOS expression and the quantity of the nNOS positive neurons in dorsal horn of spinal cord decreased significantly compared to that of withdrawal group without lesion (P < 0.05), but it also increased significantly compared to that of normal group and dependence group (P < 0.01).</p><p><b>CONCLUSION</b>The lesion of distal CSF contacting neurons attenuated the scores of morphine withdrawal symptoms precipitated by naloxone and the nNOS expression in dorsal horn of spinal cord. The distal CSF contacting neurons in rat brain parenchyma partly participated in the development of morphine dependence and naloxone precipitated withdrawal possibly by the modulation of NO (nitric oxide).</p>

Neuroanatomy of Sleep-Wake Regulation and its Application to Pharmacotherapy / 대한정신약물학회지

A current hypothesis of sleep-wake regulation proposes that the sleep process starts with the activation of sleep-promoting neurons located in the preoptic area of the anterior hypothalamus. This activation leads to the inhibition of wake-promoting neurons located in the posterior hypothalamus, basal forebrain, and mesopontine tegmentum, which, in turn removes inhibition from the sleep-promoting structures(i.e., disinhibition) to initiate the sleep process. Mutual inhibition between these wake- and sleep-promoting neurons results in switching properties that define discrete wakeful and sleep states with sharp transitions between them. Wake-promoting nuclei include the orexinergic lateral hypothalamic/perifornical area, the histaminergic tuberomammillary nucleus, the cholinergic pedunculopontine tegmental nucleus, the noradrenergic locus coeruleus, the 5-hydroxytryptaminergic raphe nuclei, and possibly the dopaminergic ventral tegmental area. The major sleep-promoting nucleus is the GABAergic ventrolateral preoptic nucleus of the hypothalamus. The regulation of sleep is classically viewed as the dual interaction of circadian(SCN-based) and homeostatic processes, and the propensity to be asleep or awake at any given time is a consequence of a sleep debt and its interaction with signals from the SCN circadian clock. To better understand the mechanisms of sleep and wakefulness, the focus of pharmacotherapy is on targeting specific therapies to the particular defect in sleep-wake regulation.

Immunohistochemical Study on the Distribution of Kv1.2 in Aged Rat Brain / 체질인류학회지

In the present study, we demonstrated age-related changes in Kv1.2 immunoreactivity in the rat brain for the first time. Twelve adult (4~6 month old) and 15 aged (20~29 month old) Sprague-Dawley rats were examined in this study. Immunohistochemistry was performed in accordance with the free-floating method, and densitometric measurement using a NIH image program (Scion Image) determined the staining density. In the cerebral cortex of aged rats, there was a significant increase in the number of Kv1.2-immunoreactive neurons in the cingulate cortex, infralimbic cortex and piriform cortex, compare to adult rats. In the hippocampal CA1-3 regions, moderate Kv1.2 immunoreactivity was found in the cell bodies and processes of some medium to large-sized neurons in aged rats. The intensity was increased in the cell bodies of Kv1.2-positive neurons in the amygdala of aged rats, whereas the number of immunoreactive neurons was not significantly increased. It was noteworthy that age-related changes in Kv1.2-immunoreactive neurons were prominent in the facial nuclei, raphe magnus nuclei, and pontine and medullary reticular formation. Although the present study has not addressed multiple mechanisms contributing to neuronal degeneration during aging, the first demonstration of age-related changes in Kv1.2 immnuoreactivity may offer a comprehensive understanding of the pathophysiology of aging and age-related neurodegenerative diseases such as Alzheimer's disease.

Effect of Exogenous Thyroxine on the Postnatal Development of Serotonin-containing Neuron in Fetal Alcohol Effects in the Rat Raphe Nuclei / 체질인류학회지

Serotonin (5-hydroxytryptamine, 5-HT) has been concerned in the pathophysiology of various neuropsychiatric disorders. It is known to modulate emotion, cognition, endocrine activity, motor function, and pain. In the present study, the effects of exogenous thyroxine (T4) on the postnatal development of serotonin-containing neuron in the rat raphe nuclei with fetal alcohol effects were investigated using immunohistochemistry. These experimental animals were divided into three groups : the alcohol-fed group received 35 calories liquid ethanol diet; the control pair-fed group was fed a liquid diet in dextrin replaced alcohol isocalorically; alcohol+T4 group received alcohol diet and exogenous thyroxine subcutaneously. After the pups were born, the pups of each were fostered by surragate mother. An average of four pups, one from each litter, were killed at days 0, 7, 14, 21, and 28 for each of the above three groups. As a result, in alcohol group, serotonin-immunoreactivity was weakly stained at all postnatal ages compared to control pair-fed and alcohol+T4 group. The intensity of serotonin immunoreactivity was more prominent in alcohlol+T4 group than in control pair-fed group at P0. Mature patterns of serotonin-containing neurons were observed in control pair-fed and alcohol+T4 group at P7. A similar developmental pattern of serotonin-containing neuron was observed on and after P7 in control pair-fed and alcohol+T4 group. These results suggest that the increase of serotonin synthesis during early postnatal life caused by maternal administration of exogenous thyroxine may ameliorate fetal alcohol effects, one of the ill effects as a result of the dysthyroid state following maternal alcohol abuse.

A dopaminergic projection from the dorsal raphe nucleus to the inner ear / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>To investigate the efferent pathway from the dorsal raphe nucleus to the inner ear.</p><p><b>METHODS</b>Eleven adult cats weighing 2.0 - 3.0 kg were used. The animals had no middle-ear disease and their auricle reflex was sensitive to sound. They were divided into experimental group (8 cats) and control group (3 cases). The fluorescent tracer cholera toxin subunit-B (CTB) was injected into cat cochlea and the CTB-labelled neurons of dorsal raphe nucleus (DRN) were identified using an immunofluorescence technique after a survival period of 7 days. For studying other fluorescence labelling, the sections containing CTB-labelled neurons were divided into four groups and incubated in antisera directed against tyrosine hydroxylase (TH), serotonin (5-HT), gamma-aminobutyric acid (GABA) and dopamine B-hydroxylase (DBH), respectively. Single-and double-labelled neurons were identified from the DRN.</p><p><b>RESULTS</b>(1) A subpopulation of dorsal raphe nucleus (DRN) neurons were intensely labelled with CTB and these CTB-labelled neurons were densely distributed in a dorsomedial part of the DRN; (2) Four immunolabelling, TH, 5-HT, GABA and DBH were presented throughout the DRN. Of the total population of CTB-labelled neurons, 100% were TH-labelled neurons (double labelling) and no double-stained neuron with 5-HT, GABA and DBH was observed in the DRN.</p><p><b>CONCLUSIONS</b>There was a projection from DRN to the inner ear and this pathway might be a dopaminergic projection.</p>