Feasibility and Safety of Multicenter Tissue and Biofluid Sampling for α-Synuclein in Parkinson's Disease: The Systemic Synuclein Sampling Study (S4).

BACKGROUND: α-synuclein is a lead Parkinson's disease (PD) biomarker. There are conflicting reports regarding accuracy of α-synuclein in different tissues and biofluids as a PD biomarker, and the within-subject anatomical distribution of α-synuclein is not well described. The Systemic Synuclein Sampling Study (S4) aims to address these gaps in knowledge. The S4 is a multicenter, cross-sectional, observational study evaluating α-synuclein in multiple tissues and biofluids in PD and healthy controls (HC). OBJECTIVE: To describe the baseline characteristics of the S4 cohort and safety and feasibility of this study. METHODS: Participants underwent motor and non-motor clinical assessments, dopamine transporter SPECT, biofluid collection (cerebrospinal fluid, saliva, and blood), and tissue biopsies (skin, sigmoid colon, and submandibular gland). Biopsy adequacy was determined based on presence of adequate target tissue. Tissue sections were stained with the 5C12 monoclonal antibody against unmodified α-synuclein. All specimens were acquired and processed in a standardized manner. Adverse events were systematically recorded. RESULTS: The final cohort consists of 82 participants (61 PD, 21 HC). In 68 subjects (83%), all types of specimens were obtained but only 50 (61%) of subjects had all specimens both collected and evaluable for α-synuclein. Mild adverse events were common, especially for submandibular gland biopsy, but only 1 severe adverse event occurred. CONCLUSION: Multicenter tissue and biofluid sampling for α-synuclein is feasible and generally safe. S4 will inform understanding of the concurrent distribution of α-synuclein pathology and biomarkers in biofluids and peripheral nervous system in PD.

Effect of serotonin depletion on 5-HT2A-mediated learning in the rabbit: evidence for constitutive activity of the 5-HT2A receptor in vivo.

RATIONALE: Associative learning during Pavlovian eyeblink conditioning has been shown to be regulated by 5-HT2A receptors. The existence of inverse agonists that retard learning through an action at the 5-HT2A receptor suggests the existence of constitutive activity at that receptor and that depletion of serotonin should have minimal effects on learning. OBJECTIVES: We examined whether depletion of serotonin would impair trace eyeblink conditioning or the enhancement of conditioning produced by the agonist lysergic acid diethylamide (LSD) and the retardation of conditioning produced by the inverse agonist MDL11,939. METHODS: Animals received bilateral intraventricular injections of 5,7-dihydroxytryptamine (5,7-DHT) at doses of 760 or 1,140 microg/side (1.88 or 2.82 micromol/side) and were later exposed to eight daily conditioning sessions. RESULTS: Serotonin depletion produced by the lower dose of 5,7-DHT was 71 and 72% in cortex and hippocampus, respectively, with no change in 5-HT2A receptor density, no effect on learning, and no effect on the ability of LSD to enhance and MDL11,939 to retard learning. The higher dose of 5,7-DHT produced serotonin decreases of 85 and 90% in cortex and hippocampus, respectively, accompanied by a 96% decrease in the density of the serotonin transporter, but no significant effect on learning. CONCLUSIONS: Pavlovian trace eyeblink conditioning is regulated predominantly by the constitutive activity of the 5-HT2A receptor rather than by serotonin release onto the receptor during learning. It was suggested that the 5-HT2A receptor regulates learning by modulating the release of dopamine, acetylcholine, and glutamate, transmitters known to affect eyeblink conditioning.

Selective and divergent regulation of cortical 5-HT(2A) receptors in rabbit.

It is well established that repeated administration of both 5-hydroxytryptamine(2) (5-HT(2)) receptor agonists and antagonists decreases the density of 5-HT(2A) and 5-HT(2C) receptors. However, the regulation of these two receptors has not been studied in the same tissue. Therefore, we examined the effects of repeated daily injections of the 5-HT(2) receptor agonists (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and D-lysergic acid diethylamide (LSD) and the antagonists d-2-bromolysergic acid diethylamide hydrogen tartrate (BOL) and alpha-phenyl-2-(2-phenylethyl)-4-piperidinemethanol (MDL 11,939) on rabbit cortical 5-HT(2A) and 5-HT(2C) receptors. Repeated administration of DOI, LSD, or BOL decreased cortical 5-HT(2A) receptor density but had no effect on the density of cortical 5-HT(2C) receptors. Repeated administration of the selective 5-HT(2A) receptor antagonist MDL 11,939 significantly increased 5-HT(2A) receptor density. This unexpected outcome also occurred without any change in cortical 5-HT(2C) receptor density. The down-regulation of 5-HT(2A) receptors produced by chronic administration of BOL was associated with a decrease in DOI-elicited head bobs, whereas 5-HT(2A) receptor up-regulation produced by MDL 11,939 was associated with an increase in DOI-elicited head bobs compared with controls. These studies demonstrate that 5-HT(2A) receptor antagonists can both down- and up-regulate the density of cortical 5-HT(2A) receptors and these changes in receptor density have functional consequences for 5-HT(2A) receptor-mediated behaviors. Furthermore, because DOI, LSD, and BOL have approximately equal affinities for the 5-HT(2A) and 5-HT(2C) receptors, these results suggest that different mechanisms regulate 5-HT(2A) and 5-HT(2C) receptor density, in that chronic occupation of 5-HT(2C) receptors does not modulate their density in rabbit frontal cortex.