Aging regulates 5-HT1B receptors and serotonin reuptake sites in the SCN

Middle age is associated with changes in circadian rhythms (e.g., alterations in the timing of the circadian wheel running rhythm) which resemble changes induced by selective destruction of the serotonergic input to the suprachiasmatic nucleus (SCN), the principal mammalian circadian pacemaker. We hypothesized that serotonergic neurotransmission in the SCN is decreased in middle-aged hamsters, as compared to young adults. This hypothesis was tested indirectly by investigating the effect of aging on two markers of serotonin neurotransmission, 5-HT_1B receptors and serotonin reuptake sites, which are regulated by serotonin. Previous studies have shown that experimentally induced decreases in serotonergic neurotransmission increase 5-HT_1B receptors but decrease serotonin reuptake sites. Quantitative autoradiography was conducted using [¹²⁵I]iodocyanopindolol ([¹²⁵I]ICYP) and [³H]paroxetine, selective radioligands for the 5-HT_1B receptors and the serotonin reuptake sites, respectively. Consistent with the hypothesis, specific ([¹²⁵I]ICYP binding was significantly elevated in the SCN of middle-aged hamsters, as compared to young hamsters. The results also showed that serotonin reuptake sites in the SCN were significantly increased in both middle-aged and old hamsters, as compared to young controls. This result could not have been caused by decreased serotonin release. Alternatively, increased serotonin reuptake, which would reduce serotonin levels in the synaptic cleft, may cause or contribute to the increase in 5-HT_1B receptor binding in the SCN in middle aged animals. These results show that the SCN exhibits changes in serotonergic function during middle age, which has been characterized by changes in the expression of circadian rhythms. Because these changes occur during middle age, they probably reflect the aging process, rather than senescence or disease.     

Mechanisms of unilateral STN-DBS in patients with Parkinson’s disease

Bilateral symptoms and signs of Parkinson’s disease (PD) are often improved by unilateral subthalamic nucleus deep brain stimulation (STN-DBS). However, the mechanism for such bilateral effects is unknown. This study was intended to examine effects of unilateral STN-DBS using positron emission computed tomography (PET) and to elucidate mechanisms for bilateral improvement achieved by unilateral stimulation. We conducted ¹⁸F-fluorodeoxyglucose (¹⁸FDG) and ¹⁸F-fluorodopa (¹⁸F-DOPA ) PET scans in PD patients whose bilateral limb symptoms and axial symptoms were improved by unilateral DBS. Two scans were performed in each PET study: when DBS was on and off. We compared those images using statistic parametric mapping (SPM) 99. The significant clinical improvement obtained by unilateral DBS was shown as improvements in bilateral motor limb, axial, and gait subscores of the Unified PD Rating Scale (UPDRS). Moreover, ¹⁸FDG PET revealed significant metabolic increases in the ipsilateral ventrolateral thalamic areas and metabolic decrease at the contralateral globus pallidus interna (GPi). In contrast, ¹⁸F-DOPA PET showed no significant differences between DBS on and off. Ipsilateral thalamic activation might induce ipsilateral motor cortical activation, which explains the improvement of contralateral limb symptoms. Furthermore, deactivation of the contralateral GPi might disinhibit the thalamus and contralateral motor cortex, which explains reduction of ipsilateral limb symptoms. These results suggest the mechanisms for bilateral improvement achieved by unilateral DBS.     

p-Hydroxyamphetamine causes prepulse inhibition disruption in mice: contribution of serotonin neurotransmission

p-Hydroxyamphetamine (p-OHA) has been shown to have a number of pharmacological actions, including causing abnormal behaviors such as increased locomotor activity and head-twitch response in rodents. We have recently reported that intracerebroventricular (i.c.v.) administration of p-OHA dose-dependently induces prepulse inhibition (PPI) disruption in mice, which is attenuated by pretreatment with haloperidol, clozapine or several dopaminergic agents. Haloperidol and clozapine have affinities for serotonergic (especially 5-HT_2A) receptors. To investigate the involvement of the central serotonergic systems in p-OHA-induced PPI disruption, herein we tested several serotonergic agents to determine their effects on p-OHA-induced PPI disruption. p-OHA-induced PPI disruption was attenuated by pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, a neurotoxin which targets serotonin-containing neurons) and p-chlorophenylalanine (PCPA, a serotonin synthesis inhibitor). p-OHA-induced PPI disruption was also attenuated by pretreatment with ketanserin (a 5-HT_2A/2C receptor antagonist) and MDL100,907 (a selective 5-HT_2A receptor antagonist). These data suggest that p-OHA-induced PPI disruption may involve increased serotonin release into the synaptic cleft, which then interacts with the post-synaptic 5-HT_2A receptor.     

Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36

[¹¹C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT_2A) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [¹¹C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT_2A receptors with [¹¹C]Cimbi-36 PET. The two-tissue compartment model using arterial input measurements provided the most optimal quantification of cerebral [¹¹C]Cimbi-36 binding. Reference tissue modeling was feasible as it induced a negative but predictable bias in [¹¹C]Cimbi-36 PET outcome measures. In five subjects, pretreatment with the 5-HT_2A receptor antagonist ketanserin before a second PET scan significantly decreased [¹¹C]Cimbi-36 binding in all cortical regions with no effects in cerebellum. These results confirm that [¹¹C]Cimbi-36 binding is selective for 5-HT_2A receptors in the cerebral cortex and that cerebellum is an appropriate reference tissue for quantification of 5-HT_2A receptors in the human brain. Thus, we here describe [¹¹C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT_2A receptors in the human brain.     

Regional distribution and behavioral correlates of 5-HT2A receptors in Alzheimer's disease with [F]deuteroaltanserin and PET

Postmortem studies show reductions in brain serotonin 2A (5-HT_2A) receptors in Alzheimer's disease (AD). Converging evidence also suggests that serotonergic dysregulation may contribute to behavioral symptoms that frequently occur in AD. This study aimed to define regional reductions in 5-HT_2A binding in AD patients and to examine their behavioral correlates. Nine patients with probable AD and eight elderly controls were studied using a constant infusion paradigm for equilibrium modeling of [¹⁸F]deuteroaltanserin with positron emission tomography (PET). Region of interest analyses were performed on PET images coregistered to MRI scans. The outcome measures BP_P (ratio of specific brain uptake to total plasma parent concentration) and BP_ND (ratio of specific to nondisplaceable uptake) were obtained for pertinent cortical and subcortical regions. AD patients showed a statistically significant decrease in the anterior cingulate in both BP_P and BP_ND, but in no other region. Within the AD patient sample, no significant correlations were observed between regional 5-HT_2A binding and behavioral measures, including depressive and psychotic symptoms. These results confirm a reduction in cortical 5-HT_2A receptors in AD, specifically in the anterior cingulate. However, in a limited AD patient sample, they fail to demonstrate a relationship between regional 5-HT_2A binding and major behavioral symptoms.     

The impact of subthalamic deep brain stimulation on polysomnographic sleep pattern in patients with Parkinson's disease – Preliminary report

Aim of the study

We present the preliminary results of the study focused on the impact of subthalamic deep brain stimulation (DBS-STN) on sleep and other non-motor symptoms (NMS).

Elevated levels of serotonin 5-HT2A receptors in the orbitofrontal cortex of antisocial individuals

Antisocial behavior (ASB) is characterized by frequent violations of the rights and properties of others, as well as aggressive conduct. While ample evidence points to a critical role of serotonin in the emotional modulation of social responses, the implication of this neurotransmitter in ASB is unclear. Here, we performed the first-ever postmortem analysis of serotonergic markers in the orbitofrontal cortex (OFC) of male subjects with ASB (n = 9). We focused on this brain region, given its well-recognized role in social response and ASB pathophysiology. Given that all individuals also had a substance use disorder (SUD) diagnosis, two age-matched control groups were used: SUD only and unaffected controls. Tissues were processed for immunoblotting analyses on eight key serotonergic targets: tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of brain serotonin synthesis; serotonin transporter (SERT), the primary carrier for serotonin uptake; monoamine oxidase A (MAOA), the primary enzyme for serotonin catabolism; and five serotonin receptors previously shown to influence social behavior: 5-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2C, and 5-HT₄. Our analyses documented a significant increase in 5-HT_2A receptor levels in the ASB + SUD group compared to SUD-only controls. Furthermore, TPH2 levels were significantly reduced in the SUD group (including SUD only and ASB + SUD) compared to unaffected controls. No difference was detected in the expression of any other serotonergic target. These results are in keeping with previous evidence showing high 5-HT_2A receptor binding in the OFC of pathologically aggressive individuals and point to this molecule as a potential target for ASB treatment.

     

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT7 Receptor Imaging with PET

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Acupuncture ameliorates not only atopic dermatitis-like skin inflammation but also acute and chronic serotonergic itch possibly through blockade of 5-HT2 and 5-HT7 receptors in mice

Acupuncture has been known to be effective for atopic dermatitis, especially ameliorating itch; however, its mechanisms are still unclear. The aim of this study was to test the anti-itch effects of acupuncture and to investigate its possible mechanisms. Acupuncture was performed at Gok-Ji (LI11) acupoints just before the injection of pruritogens in the mouse cheek model of acute itch and of MC903-induced atopic dermatitis displaying serotonergic chronic itch. Acupuncture significantly reduced acute itch triggered by compound 48/80, chloroquine, or especially serotonin. It also markedly reduced scratching behaviors evoked by the serotonin 5-HT₂ receptor agonist α-methylserotonin and selective 5-HT₇ receptor agonist LP 44. In addition, acupuncture treatment at LI11 had the preventive and therapeutic effects on persistent itch as well as the robust skin inflammation with epidermal thickening in mice with MC903-induced atopic dermatitis. It also considerably reduced the increased expression of 5-HT_2A, 5-HT_2B and 5-HT₇ receptors in atopic dermatitis-like skin lesions in mice treated with MC903. Taken together, these findings highlight that acupuncture significantly ameliorates not only skin inflammation, but also acute and chronic serotonergic itch, possibly through blockade of serotonin 5-HT₂ and 5-HT₇ receptors.     

Bilateral STN-DBS fails to improve non-motor fluctuations in a PD patient

We report the case of a 60-year-old woman with Parkinson's disease and severe motor fluctuations. During OFF periods she presented both motor and non-motor symptoms, which ameliorated rapidly after each levodopa dose. After undergoing bilateral STN DBS, motor complications improved markedly while non-motor symptoms remained unchanged. Levodopa response is regarded as a good predictive factor for the prognosis of motor symptoms in PD patients undergoing surgery. However, our case suggests that its relation with the prognosis of non-motor symptoms might be different and remains to be addressed.     

Anterior cingulate serotonin 1B receptor binding is associated with emotional response inhibition

Serotonin has a well-established role in emotional processing and is a key neurotransmitter in impulsive aggression, presumably by facilitating response inhibition and regulating subcortical reactivity to aversive stimuli. In this study 44 men, of whom 19 were violent offenders and 25 were non-offender controls, completed an emotional Go/NoGo task requiring inhibition of prepotent motor responses to emotional facial expressions. We also measured cerebral serotonin 1B receptor (5-HT_1BR) binding with [¹¹C]AZ10419369 positron emission tomography within regions of the frontal cortex. We hypothesized that 5-HT_1BR would be positively associated with false alarms (failures to inhibit nogo responses) in the context of aversive (angry and fearful) facial expressions. Across groups, we found that frontal cortex 5-HT_1BR binding was positively correlated with false alarms when angry faces were go stimuli and neutral faces were nogo stimuli (p = 0.05, corrected alpha = 0.0125), but not with false alarms for non-emotional stimuli (failures to inhibit geometric figures). A posthoc analysis revealed the strongest association in anterior cingulate cortex (p = 0.006). In summary, 5-HT_1BRs in the anterior cingulate are involved in withholding a prepotent response in the context of angry faces. Our findings suggest that serotonin modulates response inhibition in the context of certain emotional stimuli.     

Acute levodopa administration reduces cortisol release in patients with Parkinson’s disease

Summary. Levodopa (LD) application improves motor symptoms in patients with Parkinson’s disease (PD) patients. Little is known on further effects of LD, which induced lower plasma levels of cortisol and lower serotonergic activity in certain brain areas of fish. Objectives of this trial were to analyse levels of cortisol, LD and 3-O-methyldopa (3-OMD) after administration of LD/benserazide in long term treated PD patients. 12 PD patients, taken off their regular treatment for at least 12 hours, received soluble 200 mg LD/50 mg benserazide under stress free conditions. Motor symptoms improved, LD and 3-OMD levels increased, whereas cortisol concentrations started to decrease significantly 30 minutes after LD intake. This reduced cortisol release may result from an overflow of exogenous LD in the brainstem. This hypothetically causes an reduced 5-HT content in neurons projecting to the hypothalamic structures, which are involved in the partial 5-HT dependent central regulation of peripheral cortisol release.     

Serotonin 1B receptor imaging in pathological gambling

Abstract

Objectives. Although serotonergic mechanisms have been implicated in pathological gambling (PG), no ligand-based imaging studies have assessed serotonin receptors in individuals with PG. Given its role in substance addictions and its abundance in brain regions implicated in PG, we evaluated serotonin 1B receptors (5-HT_1BRs) in PG. Methods. Ten medication-free subjects with PG (mean ± SD age = 36.3 ± 9.4 years, nine men) and ten control comparison (CC) subjects (mean ± SD age = 35.8 ± 9.9 years, nine men) underwent [¹¹C]P943 positron emission scanning on a high resolution research tomograph. Results. 5-HT_1BR BP_ND values were similar in PG and CC subjects (P > 0.1). Among PG subjects, scores on the South Oaks Gambling Screen (SOGS) correlated positively with 5-HT_1BR BP_ND values in the ventral striatum (r = 0.66; P = 0.04), putamen (r = 0.67; P = 0.03) and anterior cingulate cortex (r = 0.73; P = 0.02). Conclusions. These findings provide the first evidence that PG severity in humans is linked to increased levels of 5-HT_1BRs in regions previously implicated in functional neuroimaging studies of PG. These findings indicate a potential role for serotonergic function in the ventral striatum and anterior cingulate cortex contributing to problem gambling severity and warrant further studies to investigate whether numbers of available 5-HT_1BRs might represent a vulnerability factor for PG or develop in relationship to problem gambling.     

The impact of bilateral subthalamic stimulation on non-motor symptoms of Parkinson's disease

Objective

To evaluate the impact of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on the prevalence of non-motor symptoms reported by Parkinson's disease (PD) patients one year following surgery and to examine whether there was an association between number of non-motor symptoms reported and quality of life (QoL).

Methods

Twenty-four patients who received bilateral STN DBS and had follow-up evaluations one year after surgery were included in this study. Patients’ motor function was evaluated with the Unified Parkinson’s Disease Rating Scale, non-motor symptoms were assessed with the Non-Motor Symptom questionnaire (NMSQuest) and quality of life was assessed with the PDQ-39.

Results

There was a mean of 12 non-motor symptoms reported prior to surgery which was significantly reduced to a mean of 7 symptoms one year after surgery. Autonomic symptoms were the most frequently reported and demonstrated the greatest reductions following surgery. Twenty-seven of the 30 items represented in the NMSQuest were reported less frequently one year after surgery compared to before surgery. The reduction in non-motor symptoms was significantly correlated with total QoL scores and the subscales of mobility, activities of daily living, cognition and bodily discomfort.

Conclusions

Non-motor symptoms are common in patients with advanced PD. The number of non-motor symptoms was significantly decreased one year following bilateral STN DBS which was associated with a significant improvement in QoL. Further studies focused on specific non-motor symptoms are warranted in order to fully understand the impact and mechanisms of STN DBS on these symptoms.     

The type 3 serotonin receptor is expressed in a subpopulation of GABAergic neurons in the rat neocortex and hippocampus

We used in situ hybridization and immunocytochemistry to investigate the presence of GABA in neurons that express the type 3 serotonin receptor (5-HT₃R). Quantitative analysis indicated that more than 90% of 5-HT₃R expressing cells are GABAergic in the neocortex and hippocampus. The co-existence of 5-HT₃R and GABA in cortical and hippocampal neurons indicates that serotonin, via 5-HT₃R, can affect GABA release and suggests the participation of 5-HT₃R in the inhibitory regulation of forebrain neurons.     

Neuropsychological changes 1-year after subthalamic DBS in PD patients: A prospective controlled study

ObjectiveThis study aimed at investigating the neuropsychological effect of DBS of the Subthalamic Nucleus in patients with advanced Parkinson's disease (PD).MethodsA standardized neuropsychological test battery, assessing reasoning, memory and executive functions, was administered to 27 PD patients who underwent DBS-STN (DBS group) and to a matched control group of 31 PD patients under optimal medical treatment (MED group). Patients were evaluated at baseline and at the end of 1 year.ResultsChange score analysis (T1 minus T0 scores) demonstrated a significant decline in phonemic verbal fluency in the DBS group compared with the MED group (p < 0.005), while there were no significant changes between the two groups for the other cognitive tests. Single cases analysis by means of multivariate normative comparisons revealed that 4 out of 27 DBS patients (15%) showed cognitive deterioration one year post surgery. These patients were significantly more compromised from a motor standpoint (UPDRS, section III) than the 23 DBS PD patients who had no cognitive decline post surgery.ConclusionResults of this prospective controlled-study showed that phonemic verbal fluency declined one year after DBS-STN, while the other cognitive domains did not change significantly. Nevertheless, single case analysis highlighted the fact that a subgroup comprising 15% of DBS-STN patients (4/27) showed significant cognitive decline 1 year after surgery.     

Serotonin 5-HT3 receptor binding kinetics in the cortex of suicide victims are normal

Summary Serotonergic abnormalities have been identified in the brain of suicide victims independent of psychiatric diagnosis. We report the first study of serotonin 5-HT₃ receptors in the brain of suicide victims. There were no differences in the number (B_max) or affinity (K _d ) of 5-HT₃ receptors in the temporal cortex of suicide victims compared to matched controls. There was a negative correlation between brain serotonin levels and receptor number (r=–0.5, p=0.04) in both groups. This study indicates that alterations in serotonergic function in the brain of suicide victims do not appear to directly involve the 5-HT₃ receptor.     

Cerebral 5-HT2A receptor and serotonin transporter binding in humans are not affected by the val66met BDNF polymorphism status or blood BDNF levels

Recent studies have proposed an interrelation between the brain-derived neurotrophic factor (BDNF) val66met polymorphism and the serotonin system. In this study, we investigated whether the BDNF val66met polymorphism or blood BDNF levels are associated with cerebral 5-hydroxytryptamine 2A (5-HT_2A) receptor or serotonin transporter (SERT) binding in healthy subjects. No statistically significant differences in 5-HT_2A receptor or SERT binding were found between the val/val and met carriers, nor were blood BDNF values associated with SERT binding or 5-HT_2A receptor binding. In conclusion, val66met BDNF polymorphism status is not associated with changes in the serotonergic system. Moreover, BDNF levels in blood do not correlate with either 5-HT_2A or SERT binding.     

Deep brain stimulation outcomes in the malignant end of Parkinson's disease spectrum

BackgroundHeterogeneity of Parkinson's Disease (PD) phenotype may influence deep brain stimulation (DBS) outcome. However, DBS response in the malignant end of the PD spectrum has been poorly investigated.ObjectiveTo evaluate and compare DBS outcomes in malignant and benign PD patients, defined according to motor and non-motor symptom presentation at the presurgical selection.MethodsWe categorized a cohort of 154 parkinsonian patients fulfilling criteria for subthalamic nucleus (STN)-DBS into malignant, benign, and intermediate subtypes, according to a recently validated clinical PD classification. DBS efficacy on daily living independence (Schwab and England –S&E-score ≥70%), motor symptoms, and motor fluctuations (Unified Parkinson's Disease Rating Scale -UPDRS- part-III and -IV, and Ambulatory Capacity Measure) were compared between malignant and benign patients, using corrected binary logistic regressions and repeated measure general linear model.ResultsOne year after surgery, the probability of losing daily life independence was 16-fold higher in malignant patients, even after adjusting for age at PD onset, PD duration, and percentage of motor improvement after STN-DBS (OR: 16.233; p: 0.035). Conversely, malignant and benign patients showed a similar extent of improvement after STN-DBS (p > 0.05) in motor symptoms, motor fluctuations, and ambulatory capacity, both in medication-ON and medication-OFF conditions.ConclusionDBS candidates in the malignant end of the PD spectrum may profit from a similar improvement of motor symptoms and fluctuations after STN-DBS when compared to benign PD. However, patients of the malignant group have a lower probability of maintaining independence in daily life early after surgery.     

Chronic subthalamic deep brain stimulation improves pain in Parkinson disease

Background   

Pain is a well recognized feature of Parkinson disease (PD). Like motor fluctuations, pain in PD may fluctuate as ‘non-motor fluctuations’. Subthalamic deep brain stimulation (STN DBS) is an established treatment for motor fluctuations in PD. However, the effect of STN DBS on the pain in PD is only partially investigated.