Synaptic neurotransmission

Neurotransmitter transporters terminate the time interval of synaptic neurotransmission localization of transporters in the vicinity of exocytotic sites is crucial for their clearance of neurotransmitter molecules following their exocytotic release into the synaptic cleft. 

Finally, perhaps one of the oddest of recent discoveries is that toxic gases, such as nitric oxide (NO) and carbon monoxide (CO), can act as dual first/second messengers in the nervous system (Haley, 1998). Our current ideas of how drugs affect the complex events and regulation of synaptic neurotransmission are very simplistic and the real situation is obviously vastly more complicated. Some of these issues will be addressed in more detail in Chapter 14. 

Outline how psychoactive drugs can modify the five stages of synaptic neurotransmission. 

Finally, an intriguing possible future therapy arises from a radical idea of Horrobin (2001) that schizophrenia is a nutritional disorder linked to a decreased intake of essential polyunsaturated fatty acids. Recent 31P-MRS studies have shown changes in plasma membrane phospholipids in the neocortex of unmedicated schizophrenics, which would have deleterious consequences on synaptic neurotransmission (Fukuzako, 2001). A clinical trial with the co6 fatty acid derivative ethyleicosa-pentaenoic acid (LAX-101) in patients who had been unresponsive to clozapine, reported that a daily dose of 2g LAX-101 gave a 26% improvement in symptoms over 12 weeks compared with 6% with placebo (Peet and Horrobin, 2001). Maybe in... 

The chapter has specifically reviewed how receptors and enzymes are the targets of drag actions in psychopharmacology. We have explored the components of individual receptors and discussed how receptors function as members of a synaptic neurotransmission team, which has the neurotransmitter as captain and receptors as major team players interacting with other players on the team including ions, ion channels, transport carriers, active transport pumps, second-messenger systems, and... 

FIGURE 4—11. Shown here is normal communication between two neurons, with the synapse between the red and the blue neuron magnified. Normal neurotransmission from the red to the blue neuron is being mediated here by neurotransmitter binding to postsynaptic receptors by the usual mechanism of synaptic neurotransmission. 

FIGURE 5—70. Substance P and neurokinin 1 receptors, part 3. Shown here is how substance P is formed from gamma PPT-A. Thus, substance P can be formed from three proteins derived from the PPT-A gene, namely, alpha, beta, and gamma PPT-A (see also Figs. 5-68 and 5-69). When substance P is released from neurons, it prefers to interact selectively with the neurokinin 1 subtype of neurokinin receptor (Figs. 5-68 to 5-70). However, there is a mismatch in the brain between the locations of substance P and the NK-1 receptors, suggesting that substance P acts preferentially by volume neurotransmission at sites remote from its axon terminals rather than by classical synaptic neurotransmission. 

Please indicate which of the following is true for synaptic neurotransmission. 

To understand various ways in which diseases modify synaptic neurotransmission, including molecular neurobiology and psychiatric disorders. 

Synaptic neurotransmission in brain occurs mostly by exocytic release of vesicles filled with chemical substances (neurotransmitters) at presynaptic terminals. Thus, neurotransmitter release can be detected and studied by measuring efflux of neurotransmitters from synapses by biochemical methods. Various methods have been successfully employed to achieve that, including direct measurements of glutamate release by high-performance liquid chromatography of fluorescent derivatives or by enzyme-based continuous fluorescence assay, measurements of radioactive efflux from nerve terminals preloaded with radioactive neurotransmitters, or detection of neuropeptides by RIA or ELISA. Biochemical detection, however, lacks the sensitivity and temporal resolution afforded by electrophysiological and electrochemical approaches. As a result, it is not possible to measure individual synaptic events and apply quantal analysis to verify the vesicular nature of neurotransmitter release. 

The SNAREs involved in the fusion of synaptic vesicles and of secretory granules in neuroendocrine cells, referred to as neuronal SNAREs, have been intensely studied and serve as a paradigm for all SNAREs. They include syntaxin 1A and SNAP-25 at the presynaptic membrane and synaptobrevin 2 (also referred to as VAMP 2) at the vesicle membrane. Their importance for synaptic neurotransmission is documented by the fact that the block in neurotransmitter release caused by botulinum and tetanus neurotoxins is due to proteolysis of the neuronal SNAREs (Schiavo et al. 2000). Genetic deletion of these SNAREs confirmed their essential role in the last steps of neurotransmitter release. Intriguingly, analysis of chromaffin cells from KO mice lacking synaptobrevin or SNAP-25 showed that these proteins can be at least partially substituted by SNAP-23 and cellubrevin, respectively (Sorensen et al. 2003 Borisovska et al. 2005), i.e., the corresponding SNAREs involved in constitutive exocytosis. 

Unspecified endogenous compounds that may modulate synaptic neurotransmission. 

Laruelle M. 2000. Imaging synaptic neurotransmission with in vivo binding competition techniques A critical review. J Cereb Blood FlowMetab 20 423-451. 

In this chapter, we will review the evidence suggesting a role for specific synaptic vesicle-associated proteins in schizophrenia. First, we present a brief overview of the synaptic vesicle cycle in the broader context of synaptic neurotransmission at chemical synapses. We then describe the experimental evidence linking specific molecular components of the synaptic vesicle to schizophrenia. Since not all synaptic vesicle proteins have been studied in relationship to schizophrenia, this review focuses only on those proteins for which such an effort was made. Finally, we describe the potential roles these proteins could play in the context of current etiological theories of schizophrenia, and discuss the relevance of the experimental findings in the context of this enigmatic disorder. 

Comprehensive studies on the synaptic proteome have been rare. Not until quite recently has the mass spectrometric technical momentum developed for detecting and documenting a comprehensive and coherent map of synaptic proteins, currently numbering approximately 1000 unique proteins (Grant 2006). This momentum has been driven by an urgent need in the neuroscientific community for molecular markers of neuropsychiatric and neurodegenerative disorders, as well as a desire to understand the molecular mechanisms underlying synaptic neurotransmission and plasticity. Table 1 presents a compact list of recent proteomic efforts where protein fractions were derived from synapses, and the proteomic methods used to study them. These studies are described further in the text that follows. 

Butyrophenones work primarily by blocking dopamine-mediated synaptic neurotransmission by binding to dopamine receptors. In addition to significant antidopaminergic action, butyrophenones also possess anticholinergic, a-adrenergic blockade, and quinidine-like effects. 

In the case of vertebrates, phenothiazines have also been used as antipsychotic drugs for many years, before the beginning of the investigation of their action on a molecular level. Indeed, recently a number of works have appeared on the influence of phenothiazines on the nicotinic synaptic transmission, indicating that the contribution of cytochrome P-450 isoenzymes to N-demethylation and 5-sulphoxidation reactions was involved. The action of phenothiazine antipsychotics on the pre- and post-synaptic neurotransmission was experimentally examined on the tissues and enzymes extracted from the same neuronal tissues. Some phenothiazines were proposed to treat peripheral neuropathy. A new hope might also arise in the search for novel antipsychotic drugs based on phenothiazines to treat Alzheimer s disease and other taupathies, because these new compounds could inhibit tau filament formation. 

Of the ionotropic receptors, there is a clear distinction between NMDA and non-NMDA receptors (Dingledine et al., 1999). The major differences are seen in the differences in transmission times non-NMDA receptors are thought to mediate fast synaptic neurotransmission, whilst NMDA receptors have a slow rise time, that the NMDA receptor requires a co-agonist glycine, is blocked in a voltage-dependent way by Mg " and modulated by Zn " and polyamines. Non-NMDA receptors exhibit none of the latter characteristics. This separation of NMDA receptors from the others is supported by the finding that there are clear structural differences between them (Barnard, 1997). 

To assess the role of serotonin in synaptic neurotransmission, C-11 McN5652 was developed for assessment of serotonin reuptake sites (Science 226 1393-1396,1984). This PET tracer binds to 5-HT transporters. In male subjects, there was a decline of 46% in 5-HT transporter receptors in the caudate nucleus and a 43% decline in the putamen between the ages of 19 and 73. In females, there was a 25% decline between the ages of 19 and 67. Carbon-11 and fluorine-18 altanserin have a high affinity and selectivity for the 5-HT2 receptors. In PET studies with C-11 altanserin, researchers at the University of Pittsburgh found that 5-HT receptors declined by 55% between the ages of 18 and 76. Post-mortem studies also have shown a decrease in serotonin neurons with age. 

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