Subject transmittance

Impulse-evoked release of 5-HT, like that of noradrenaline, is subject to fine control by a system of autoreceptors, in particular 5-HTia receptors on the cell bodies of neurons in the Raphe nuclei and 5-HTib/id receptors on their terminals. Because these are all G /o protein-coupled receptors, their activation reduces the synthesis of cAMP so that 5-HTia agonists (or 5-HT itself) decrease neuronal excitability and the firing of Raphe neurons whereas activation of 5-HTib/id receptors seems to disrupt the molecular cascade that links the receptor with transmitter release (see Chapter 4). 

Recent evidence indicates that the 5-HT transporter is subject to post-translational regulatory changes in much the same way as neurotransmitter receptors (Blakeley et al. 1998). Protein kinase A and protein kinase C (PKC), at least, are known to be involved in this process. Phosphorylation of the transporter by PKC reduces the Fmax for 5-HT uptake and leads to sequestration of the transporter into the cell, suggesting that this enzyme has a key role in its intracellular trafficking. Since this phosphorylation is reduced when substrates that are themselves transported across the membrane bind to the transporter (e.g. 5-HT and fi -amphetamine), it seems that the transport of 5-HT is itself linked with the phosphorylation process. Possibly, this process serves as a homeostatic mechanism which ensures that the supply of functional transporters matches the demand for transmitter uptake. By contrast, ligands that are not transported (e.g. cocaine and the selective serotonin reuptake inhibitors (SSRIs)) prevent the inhibition of phosphorylation by transported ligands. Thus, such inhibitors would reduce 5-HT uptake both by their direct inhibition of the transporter and by disinhibition of its phosphorylation (Ramamoorthy and Blakely 1999). 

A peptide, once released, is not subject to reuptake like most transmitters, but is broken down by membrane peptidases. There are no known peptide transporters so that reuptake and re-use are not likely. The peptidases are predominantly membrane bound at the synapse and many are metalloproteases in that they have a metal moiety, most often zinc, near the active site. These enzymes are generally selective for particular... 

Purifying the Benzene. Occasionally a drum of technical grade benzene is encountered, the contents of which will develop a pronounced pink color when subjected to the analytical procedure. A typical transmittance-wave-length curve from a 250-ml. specimen of such processed benzene is shown in Figure 4. By comparison with... 

A more sophisticated implementation is full metering control (Fig. 10.6). In this case, we send the signals from the fuel gas controller (FC in the fuel gas loop) and the air flow transmitter (FT) to the ratio controller (RC), which takes the desired flow ratio (R) as the set point. This controller calculates the proper air flow rate, which in turn becomes the set point to the air flow controller (FC in the air flow loop). If we take away the secondary flow control loops on both the fuel gas and air flow rates, what we have is called parallel positioning control. In this simpler case, of course, the performance of the furnace is subject to fluctuations in fuel and air supply lines. 

Innovative methodologies for in vivo microdialysis in immature subjects have facilitated research in multiple areas. Clinically driven experimentation on neonatal anoxia, hypoxia, or ischemia indicates that perinatal manipulations of oxygen and blood flow result in acute and chronic disruptions of neurotransmission and transmitter turnover (Chen et al., 1997 Nakajima et al, 1999 Ogasawara et al., 1999). Recently, a role for toxic free radicals in brain damage induced by prenatal infection was also delineated by in vivo microdialysis in rat pups (Cambonie et al, 2000, 2004). More subtle neonatal manipulations, such as maternal separation or periodic neonatal isolation, coupled with subsequent in... 

Both clinical and experimental studies have shown that a number of transmitter receptors and amine transport processes show circadian changes. It is well established that depression is associated with a disruption of the circadian rhythm as shown by changes in a number of behavioural, autonomic and neuroendocrine aspects. One of the main consequences of effective treatment is a return of the circadian rhythm to normality. For example, it has been shown that the 5-HT uptake into the platelets of depressed patients is largely unchanged between 0600 and 1200 hours, whereas the 5-HT transport in control subjects shows a significant decrease over this period. The normal rhythm in 5-HT transport is only reestablished when the depressed patient responds to treatment. Thus it may be hypothesized that the mode of action of antidepressants is to normalize disrupted circadian rhythms. Only when the circadian rhythm has returned to normal can full clinical recovery be established. 

The mechanism of action of valproate is complex and still the subject of uncertainty. The drug appears to act by enhancing GABAergic function. Thus it increases GABA release, inhibits catabolism and increases the density of GABA-B receptors in the brain. There is also evidence that it increases the sensitivity of GABA receptors to the action of the inhibitory transmitter. Other actions that may contribute to its therapeutic effects include a decrease in dopamine turnover, a decrease in the activity of the NMDA-glutamate receptors and also a decrease in the concentration of... 

New insights into neural networks involved in such alterations in consciousness are likely to arise from in vivo imaging in the presence and absence of plant extracts correlated with subjective reports. As recently reported for psilocybin, chemical imaging provides key information on brain areas and transmitter receptors involved. 

Two transmitters have been the subject of most studies in mental retardation serotonin and dopamine and this section focuses on abnormalities in the function of these transmitters, and effects of serotonin- and dopamine-altering drugs. 

Adrenaline and noradrenaline are unstable in aqueous solution where they are subjected to spontaneous oxidation. In vivo this mechanism is only relevant under pathophysiological conditions of an catecholamine excess, since two enzymes, the catechol-O-methyltransferase (COMT) and the monoamineoxidase (MAO), inactivate physiological amounts of the transmitters. There are at least two subtypes of the enzyme MAO, A and B, which can be inhibited selectively for therapeutic purposes, for example by moclobemide and selegiline. 

However, the exact problem in CNS amine neurotransmission remains a subject of much debate. One leading theory is that depression may be caused by an increased sensitivity of the presynaptic or postsynaptic receptors for these transmitters. That is, the neurochemistry of the brain has been changed in some way to make the amine receptors more sensitive to their respective amine neurotransmitters (norepinephrine, serotonin, and to a lesser extent, dopamine).21 This theory is based primarily on the finding that antidepressant drugs prolong the activity of amine neurotransmission in the brain, thereby causing a compensatory decrease in the sensitivity of the amine receptors.21,47... 

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