Radiopharmaceuticals for Diagnostics
Michael Ljungberg in Handbook of Nuclear Medicine and Molecular Imaging for Physicists, 2022
The function of the dopamine transporter is reuptake of dopamine released into the synapse into vesicles in the presynaptic nerve terminal. The dopamine transporter can be imaged with an 123I-labelled analogue of cocaine, ioflupane (fluoropropyl carbomethoxy iodophenyl nortropane, FP-CIT, Datscan, Striascan). Ioflupane binds to the transporter to give an indication of the density of presynaptic nerve terminals. SPECT imaging is performed at a fixed time, 3-6 h after injection [16]. In normal individuals there is bilateral homogeneous accumulation of activity in the basal ganglia (striatum; caudate nucleus and putamen). Parkinson’s disease involves degeneration of the nigrostriatal pathway with loss of dopaminergic nerve terminals. Thus, dopamine transporter imaging can be used to diagnose Parkinson’s disease and to differentiate it from other causes of Parkinsonian tremor, such as essential tremor (i.e. non-degenerative) or that caused by certain neuroleptic drugs. In early Parkinson’s disease there tends to be asymmetry, particularly in the putamen, while in advanced disease there is bilateral degeneration. Ioflupane is also useful in diagnosis of Lewy body disease [17].
Homeostasis of Dopamine
Nira Ben-Jonathan in Dopamine, 2020
Common to all monoaminergic neurotransmitters are reuptake mechanisms in which the released neurotransmitter is taken back into the secreting cell by membrane-embedded transporters. Reuptake fulfills two important functions: (1) guarding against neuronal overstimulation through the removal of the released messenger from the synaptic cleft, resulting in the rapid termination of its actions, and (2) enabling energy conservation by recycling and reutilizing existing molecules rather than producing energy-costly new transmitters [37]. Once the released molecule is brought back into the secreting cell, the next step is its repackaging into storage/secretory vesicles (Figure 1.6). Repackaging is accomplished by two vesicular monoamine transporters, VMAT1 and VMAT2, whose main roles are to (1) protect the transmitter from degradation by intracellular MAO, (2) maintain an adequate intraneuronal storage/secretory capacity to ensure prompt responses to subsequent stimuli, and (3) enable a regulated release of the neurotransmitter from storage vesicles rather than its unregulated release by diffusion [38].
ENTRIES A–Z
Philip Winn in Dictionary of Biological Psychology, 2003
One of the ways in which a NEURON can save energy is by re-accumulating the NEUROTRANSMITTERS (or parts of transmitters) it releases. The neurotransmitter DOPAMINE for example is recaptured whole; ACETYLCHOLINE is broken down in the SYNAPTIC CLEFT, but one of the products of this breakdown, CHOLINE, is taken back up by neuronal terminals. This process—known as REUPTAKE, or more simply as UPTAKE—requires energy and the presence of SODIUM but is nevertheless not as costly as synthesizing molecules de novo. There are four points of interest about reuptake processes. (1) Reuptake is often described as being HIGH or LOW AFFINITY. High affinity reuptake processes will collect molecules when they are in a relatively low concentration; low affinity uptake requires molecules to be in higher concentrations to be effective. (2) Reuptake sites can exist at many different sites on neurons, at terminals as well as on axons and at other places, and are found on GLIAL CELLS as well as on neurons. (3) Reuptake is achieved by specialized transporter mechanisms in neuronal membranes (and within neurons, specialized transporters—VESICULAR TRANSPORTERS—exist to capture molecules from the CYTOPLASM and package them into VESICLES). (4) Reuptake mechanisms have functional importance. Experimental and therapeutic drugs can act by blocking reuptake, thereby increasing the concentrations of neurotransmitter within the synaptic cleft. The neurotoxins 6- HYDROXYDO PAMINE, 5,7-DIHYDROXYTRYPTAMINE and AF-64A all act through reuptake processes, using these transport mechanisms to gain entry to specific types of neurons. Once inside a cell they produce toxic metabolites.
The neurosciences at the Max Planck Institute for Biophysical Chemistry in Göttingen
Published in Journal of the History of the Neurosciences, 2023
Heinz Wässle, Sascha Topp
Whittaker and his colleagues were able to show that the neurotransmitters were not released from the cytoplasmic pool, but through fusion of the vesicle with the presynaptic membrane. They were also able to demonstrate that vesicles are “created” in the cell body and are then transported to the synapse in Fast Axonal Transport. Following vesicle fusion with the presynaptic membrane when the neurotransmitters are released, there is a reuptake of the vesicle, which is once again loaded with neurotransmitters. Whittaker and his colleagues studied this vesicle cycle with radioactive marker substances (e.g., Dextran) and with antibodies against specific proteoglycanes they had identified in the vesicle membranes. They also identified and localized other elements of the vesicle membrane. Figure 4 shows how far their knowledge had reached in the year 1984 (Whittaker 1984).
Machine learning, pharmacogenomics, and clinical psychiatry: predicting antidepressant response in patients with major depressive disorder
Published in Expert Review of Clinical Pharmacology, 2022
William V. Bobo, Bailey Van Ommeren, Arjun P. Athreya
Kautzky and colleagues similarly leveraged clustering and RFs to predict response after 4 weeks of treatment with antidepressants or electroconvulsive therapy (ECT) using 12 SNPs in or near HTR2A (rs643627, rs6313), COMT (rs4680), ST8SIA2 (rs8035760, rs3784723), PPP3CC (rs7430, rs10108011), and BDNF (rs6265, rs11030101, rs11030104, and rs12273363) in 225 depressed participants in the Group for the Study of Resistant Depression (GSRD) cohort [59,60]. MDD diagnoses were confirmed using a modified version of the Mini-International Neuropsychiatric Interview (MINI), version 5.0.0 [61]. SNPs were selected based on literature review. Study drugs included selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), noradrenaline reuptake inhibitors (NARIs), tricyclic and tetracyclic antidepressants, and monoamine reuptake inhibitors (MAOIs). There was no stratification based on antidepressants or intervention types. Response to treatment was defined as achieving a HAMD score ≤17 after one or two adequate trials of antidepressants. The RF model was trained using 10-fold cross-validation, and the trained models were not validated in an external dataset. A four-factor RF model incorporating three SNPs (rs6265, rs6313, and rs7430) and melancholic depressive subtype was associated with a 4-fold higher chance of positive treatment response compared with other patients (OR 4.22, 95% CI 1.43–12.49).
Datumetine exposure alters hippocampal neurotransmitters system in C57BL/6 mice
Published in Drug and Chemical Toxicology, 2022
Azeez Olakunle Ishola, Aminu Imam, Moyosore Salihu Ajao
Electron microscopy studies on the synapse revealed that datumetine exposed animals showed a reduction in the number of viable synapses with 1.0 mg/kg Datumetine animals showing the greatest reduction compared to controls. It is on record that overactivation of NMDAR leads to synaptic loss (Talantova et al.2013, Zhou et al.2013, Lewerenz and Maher 2015). This observation may be due to the persistent interaction of datumetine with NMDAR (Ishola et al.2020). The postsynaptic density was thicker in datumetine exposed animals with a great reduction in presynaptic vesicles. Chemical neurotransmission is through the release of synaptic vesicles (Trkanjec and Demarin 2001, Ikeda and Bekkers 2009) which are tightly regulated by re-uptake back to the presynaptic neurons (Piedras-Renteria et al.2004, Dickman et al.2012, Davis and Muller 2015). Datumetine greatly reducing the number of synaptic vesicles showed that either reuptake of the vesicles is altered, or rate of production is not balanced with the rate of release (Wang et al.2016, Li and Kavalali 2017). Another possible explanation may be that NMDAR binding with datumetine increases the affinity of presynaptic NMDAR for glutamate thereby increasing the release of neurotransmitters (Reimer et al.1998, Takamori 2016).
Related Knowledge Centers
- Action Potential
- Axon Terminal
- Glia
- Synapse
- Cell Membrane
- Dopamine
- Neurotransmitter
- Neurotransmitter Transporter
- Neuron
- Membrane Transport Protein