Chemicals neuromodulation

The second is that the most potent means of experimentally driving waking consciousness in the direction of dream consciousness in humans is to introduce drugs that directly interact with the specific chemical neuromodulators that change naturally in the wake to dream consciousness alterations. 

Nitric Oxide. Nitric oxide [10102-43-9] NO, is a ubiquitous intracellular and intercellular messenger serving a variety of functions including vasodilation, cytotoxicity, neurotransmission, and neuromodulation (9). NO is a paramagnetic diatomic molecule that readily diffuses through aqueous and hpid compartments. Its locus of action is dictated by its chemical reactivity and the local environment. NO represents the first identified member of a series of gaseous second messengers that also includes CO. 

Various experimental criteria are used to formally differentiate among hormones, neurotransmitters and neuromodulators. However, for behavior it often is difficult to discriminate among these categories of function, since a given chemical compound may act at several locations and have more than one mode of action (Brown, 1994). For the pur-... 

In order to review these putative relationships it is first useful to define a subset of well-characterized hormones and neurotransmitters that have been implicated in behavior. The chemicals selected for discussion here are among those for which a robust relationship with behavior has been proposed, including steroids (estrogens, progestins, androgens and glucocorticoids), proteins (prolactin) and the neuropeptides (oxytocin and vasopressin). All of these chemicals may act as hormones, neurotransmitters and/or neuromodulators. In addition, to understand the action of these hormones, it is helpful to be familiar with some of the more common neurotransmitters (described below). Space does not permit a discussion of the behavioral effects of many additional compounds with endocrine or paracrine properties. 

The billions of individual neurones within the nervous system communicate with each other and with the target tissues via chemical neurotransmitters. There is a bewildering array of chemicals which act as neurotransmitters or neuromodulators in peripheral or central nervous systems. These compounds fall into four major groups and some examples are shown in Table 4.3. 

Pharmacology Acamprosate is a synthetic compound with a chemical structure similar to that of the endogenous amino acid homotaurine, which is a structural analogue of the amino acid neurotransmitter -aminobutyric acid and the amino acid neuromodulator taurine. 

A neurotransmitter is a chemical messenger that mediates the passage of electrical information from one neuron to an adjacent neuron. To be defined as a classical neurotransmitter, a molecule must be synthesized and stored in a neuron, released from that neuron in a Ca dependent process, diffuse to an adjacent neuron, specifically dock with a receptor on that adjacent neuron, and have its binding to this receptor blocked by a competitive antagonist. A neuromodulator, on the other hand, is a molecule which is present in the synaptic cleft and which modifies either the frequency or the efficiency of the neurotransmitter molecule, thereby either amplifying or attenuating the neurotransmitter action. 

With respect to the possible contribution of differential neuromodulation to the cognitive differences between sleeping and waking, we unfortunately have as yet very little direct evidence in humans. The indirect evidence constitutes the balance of this book. The psychopharmacological data from both medical and recreational drug sources generally supports the hypothesis, but there are many important exceptions that constitute problems for this aspect of the model. Two complementary facts at this chemical level of analysis strengthen the model ... 

Nature is economical in her means. She uses many of the same chemicals to accomplish her nervous purposes within the brain that she has already used to the same ends throughout the body. The good news is that once you have worked out the biochemistry and pharmacology of a neuromodulator in the body, you can apply a lot of what you know to its action in the brain. The bad news is that every time you target, for example, the acetylcholine system of the brain, you also hit the body. That means that the heart, the bowel, the salivary glands, and all the rest of the organs innervated by the autonomic nervous system are influenced. What is worse, the target sites within the brain may not only be as spatially dispersed as in the periphery, but may also be as functionally differentiated ... 

The reader should now appreciate that chemical neurotransmission is the foundation of psychopharmacology. It has three dimensions, namely, space, time, and function. The spatial dimension is both that of hard wiring as the anatomically addressed nervous system and that of a chemical soup as the chemically addressed nervous system. The time dimension reveals that neurotransmission can be fast (milliseconds) or slow (up to several seconds) in onset, depending on the neurotransmitter or neuromodulator, of which there are dozens. Neurotransmission can also cause actions... 

Information transfer between two neurons or between neurons and effector cells involves the release of chemical substances, which then act on the target cell by binding to appropriate receptors embedded in the plasma membrane. This process, as originally described by Otto Loewi (Loewi 1921), is termed chemical neurotransmission and occurs at contact sites known as synapses. Neurotransmitters exert their effects via members of two major families of receptors ionotropic and metabotropic neurotransmitter receptors. Activation of ionotropic receptors leads to an increase in the ion conductance of the membrane within a time scale of milliseconds or even less, whereas activation of metabotropic receptors results in slow effects (within seconds or even minutes) which involve more or less complex signaling cascades. Accordingly, information transfer via ionotropic receptors is called fast synaptic transmission, whereas the slow counterpart is called neuromodulation (Kaczmarek and Levitan 1987). 

None of this explains why memory is pre-empted. Nor does it explain how PGO waves arise in REM sleep. To unlock those puzzles, we needed the key provided by the discovery of control by neurons, i.e. neuromodulation, a special kind of chemical neurotransmission by which the brain is able to change its state... 

For the enantiopure production of human rhinovirus protease inhibitors scientists from Pfizer developed a kinetic resolution and recycling sequence (Scheme 6.14 A). The undesired enantiomer of the ester is hydrolysed and can be racemised under mild conditions with DBU. This enzymatic kinetic resolution plus racemisation replaced a significantly more expensive chemical approach [52]. An enzymatic kinetic resolution, in combination with an efficient chemically catalysed racemisation, is the basis for a chiral building block for the synthesis of Talsaclidine and Revatropate, neuromodulators acting on cholinergic muscarinic receptors (Scheme 6.14B). In this case a protease was the key to success [53]. Recently a kinetic resolution based on a Burkholderia cepacia lipase-catalysed reaction leading to the fungicide Mefenoxam was described [54]. Immobilisation of the enzyme ensured >20 cycles of use without loss of activity (Scheme 6.14 C). 

Modern psychopharmacology has built its strongest base on the power of mind-altering drugs to influence the neuromodulatory system of the subcortical brain. One general rule that emerges from our studies of neuromodulators in health and disease is that of chemical balance. In many parts of the brain, acetylcholine tends to have a reciprocal relationship... 

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