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.
Brain ; Cognition ; Cohort Studies ; Constipation ; Dopamine Plasma Membrane Transport Proteins ; Dopamine ; Humans ; Magnetic Resonance Imaging ; Parkinson Disease ; Positron-Emission Tomography ; Prospective Studies ; Putamen ; Raphe Nuclei ; REM Sleep Behavior Disorder ; Sleep, REM ; Smell ; Substantia Nigra

OBJECTIVETo 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.

METHODSAdult 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.

RESULTSAfter 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.

CONCLUSIONDepletion of serotonin may facility the rats' epileptic seizures, but we could not interpret which may cause epileptic rats' cognitive deficit.

5,7-Dihydroxytryptamine ; toxicity ; Animals ; Epilepsy ; chemically induced ; metabolism ; psychology ; Male ; Maze Learning ; Memory ; Pilocarpine ; adverse effects ; Raphe Nuclei ; Rats ; Rats, Sprague-Dawley ; Serotonin ; metabolism

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.
Adenosine ; Adolescent ; Brain ; Brain Stem ; Child ; Circadian Rhythm ; Creativity ; Executive Function ; Eye Movements ; Galanin ; gamma-Aminobutyric Acid ; Humans ; Hypothalamus ; Hypothalamus, Posterior ; Learning ; Light ; Locus Coeruleus ; Melatonin ; Memory ; Neurons ; Preoptic Area ; Prosencephalon ; Raphe Nuclei ; Reticular Formation ; Sleep Deprivation ; Sleep, REM ; Suprachiasmatic Nucleus ; Thinking ; Wakefulness

OBJECTIVETo 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.

METHODSUsing nucleus location, electric stimulation and lesion, together with microinjection, and recording the inter-gastric pressure.

RESULTS(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.

CONCLUSION(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.

Animals ; Brain Stem ; physiology ; Female ; Gastrointestinal Motility ; physiology ; Locus Coeruleus ; physiology ; Male ; Motor Neurons ; physiology ; Raphe Nuclei ; physiology ; Rats ; Rats, Sprague-Dawley ; Vagus Nerve ; physiology

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.
Acupuncture ; Acupuncture Points ; Animals ; Axis, Cervical Vertebra ; Benzodiazepines ; Brain Stem ; Colon ; Down-Regulation ; Electroacupuncture ; Epithelium ; Horns ; Hyperalgesia ; Immunohistochemistry ; Irritable Bowel Syndrome ; Models, Animal ; Nociceptive Pain ; Pain Threshold ; Raphe Nuclei ; Rats ; Rats, Sprague-Dawley ; Reflex ; Salicylamides ; Serotonin ; Spinal Cord ; Visceral Pain

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.
5-Hydroxytryptophan ; Animals ; Arcuate Nucleus ; Eating ; Hypothalamus ; Light ; Neuropeptide Y ; Paraventricular Hypothalamic Nucleus ; Protein Kinases ; Raphe Nuclei ; Rats ; RNA, Messenger ; Serotonin

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.
Animals ; Cell Proliferation/*drug effects ; *Dentate Gyrus/cytology/drug effects/metabolism ; Imidazoles/*pharmacology ; Male ; Phosphodiesterase Inhibitors/*pharmacology ; Piperazines/*pharmacology ; *Raphe Nuclei/cytology/drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; Serotonin/*biosynthesis ; Sulfones/pharmacology ; Triazines/pharmacology ; Tryptophan Hydroxylase/metabolism

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.
Adult ; Aging ; Alzheimer Disease ; Amygdala ; Animals ; Brain Stem ; Brain* ; Cerebral Cortex ; Gyrus Cinguli ; Hippocampus ; Humans ; Immunohistochemistry ; Neurodegenerative Diseases ; Neurons ; Raphe Nuclei ; Rats* ; Rats, Sprague-Dawley ; Reticular Formation

AIMTo 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.

METHODSChemical 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.

RESULTSThe 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).

CONCLUSIONThe 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).

Animals ; Brain ; drug effects ; pathology ; Male ; Morphine Dependence ; metabolism ; Neurons ; drug effects ; pathology ; Nitric Oxide Synthase Type I ; metabolism ; Raphe Nuclei ; cytology ; pathology ; Rats ; Rats, Sprague-Dawley ; Substance Withdrawal Syndrome ; metabolism

Animals ; Blood Pressure ; drug effects ; Electric Stimulation ; Female ; Habenula ; physiology ; Lidocaine ; pharmacology ; Male ; Raphe Nuclei ; physiology ; Rats ; Rats, Wistar ; Respiration ; drug effects ; Serotonin ; physiology