Other Transmitters

In addition to the well-known substances, other chemicals are continually being identified as potential CNS neurotransmitters. Recent evidence has implicated substances such as adenosine and adenosine triphosphate (ATP) as transmitters or modulators of neural transmission in specific areas of the brain and in the 

A drug that modifies synaptic transmission must somehow alter the quantity of the neurotransmitter that is released from the presynaptic terminal or affect 

Synthesis of neurotransmitter. Drugs that block the synthesis of neurotransmitter will eventually deplete the presynaptic terminal and impair transmission. For example, metyrosine (Demser) 

FIGURE 5-2 Sites at which drugs can alter transmission at a CNS synapse. 

Storage of neurotransmitter. A certain amount of chemical transmitter is stored in presynaptic vesicles. Drugs that impair this storage will decrease the ability of the synapse to continue to transmit information for extended periods. 

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Neuronal Norepinephrine Depleting Agents. Reserpine (Table 6) is the most active alkaloid derived from Rauwolfia serpentina. The principal antihypertensive mechanism of action primarily results from depletion of norepinephrine from peripheral sympathetic nerves and the brain adrenergic neurons. The result is a drastic decrease in the amount of norepinephrine released from these neurons, leading to decrease in vascular tone and lowering of blood pressure. Reserpine also depletes other transmitters including epinephrine, serotonin [50-67-9] dopamine [51-61-6] ... 

Nitrergic transmission is synaptic transmission by nitric oxide. In contrast to other transmitters, NO is not preformed and stored in synaptic vesicles. When an... 

There are numerous transmitter substances. They include the amino acids glutamate, GABA and glycine acetylcholine the monoamines dopamine, noradrenaline and serotonin the neuropeptides ATP and NO. Many neurones use not a single transmitter but two or even more, a phenomenon called cotransmission. Chemical synaptic transmission hence is diversified. The basic steps, however, are similar across all neurones, irrespective of their transmitter, with the exception of NO transmitter production and vesicular storage transmitter release postsynaptic receptor activation and transmitter inactivation. Figure 1 shows an overview. Nitrergic transmission, i.e. transmission by NO, differs from transmission by other transmitters and is not covered in this essay. 

Many early studies of transmitter release depended on measuring its concentration in the effluent of a stimulated, perfused nerve/end-organ preparation. This technique is still widely used to study drug-induced changes in noradrenaline release from sympathetic neurons and the adrenal medulla. However, it is important to realise that the concentration of transmitter will represent only that proportion of transmitter which escapes into the perfusate ( overflow ) (Fig. 4.2). Monoamines, for instance, are rapidly sequestered by uptake into neuronal and non-neuronal tissue whereas other transmitters, such as acetylcholine, are metabolised extensively within the synapse. Because of these local clearance mechanisms, the amount of transmitter which overflows into the perfusate will depend not only on the frequency of nerve stimulation (i.e. release rate) but also on the dimensions of the synaptic cleft and the density of innervation. 

Unlike other transmitter systems, there are no obvious meehanisms for dampening glutamate release. Presynaptic autoreceptors for glutamate are mostly of the kainate type (see below) and appear to act as positive rather than negative influenees on further release of the amino acid. Although poorly characterised at present, inhibitory autoreceptors of the metabotropic type of receptors may act to inhibit release of glutamate. 

The release of some peptides may differ from that of other transmitters, depending on the firing rate of the neurons. The large vesicles needed to store a peptide may need a greater rate of depolarisation for membrane fusion and release of the contents. In the salivary gland the release of vasoactive intestinal polypeptide requires high-frequency stimulation whereas acetylcholine is released by all stimuli. Due to the complexities and problems of access to CNS synapses it is not known if the same occurs here but there is no reason why this should not. In sensory C-fibres a prolonged stimulus appears to be a prerequisite for the release of substance P. 

An intriguing area of research on opioids has been the accumulating evidence for plasticity in opioid controls. The degree of effectiveness of morphine analgesia is snbject to modulation by other transmitter systems in the spinal cord and by pathological changes induced by peripheral nerve injury. Thus in neuropathic states, pain after nerve injury, morphine analgesia can be reduced (but can still be effective) and tactics other than dose-escalation to circumvent this will be briefly discussed in Chapter 21. 

Neurosteroids differ from nearly all the other transmitters and mediators in that they are lipid-soluble and can easily cross the blood-brain barrier. Thus it is necessary to distinguish those steroids that are produced in the brain from those that find their way there from the circulation after being released from the adrenal cortex or gonads. There are many natural and synthetic steroids that have some effect on neuronal function and can be considered neuroactive but few are actually produced in the brain to act on neurons, i.e. the true neurosteroids. 

The activity of histaminergic neurons is regulated by H3 autoreceptors and by other transmitter receptors 255... 

Histaminergic neurons can regulate and be regulated by other transmitter systems 261... 

TABLE 14-1 Interactions between histamine and other transmitters... 

Experiments investigating the interactions between brain histamine and other transmitters are summarized. Unless otherwise specified, release experiments were performed in vitro with brain slices or synaptosomes. See [71,89,90] for references. 

Histaminergic neurons can regulate and be regulated by other neurotransmitter systems. A number of other transmitter systems can interact with histaminergic neurons (Table 14-1). As mentioned, the H3 receptor is thought to function as an inhibitory heteroreceptor. Thus, activation of brain H3 receptors decreases the release of acetylcholine, dopamine, norepinephrine, serotonin and certain peptides. However, histamine may also increase the activity of some of these systems through H, and/or H2 receptors. Activation of NMDA, p opioid, dopamine D2 and some serotonin receptors can increase the release of neuronal histamine, whereas other transmitter receptors seem to decrease release. Different patterns of interactions may also be found in discrete brain regions. 

Nicotinic cholinergic receptors are located on cells that release a wide variety of transmitters (see chapter by Barik and Wonnacott, in this volume), so that nicotine interacts with multiple neurochemical pathways. The roles of cholinergic, dopaminergic, and endogenous opioid systems in physical dependence and withdrawal have been most thoroughly studied and documented. Research on the role of other transmitters and neurochemical mechanisms is rather scattered. Overall, however, research with rodent models of physical dependence has provided a wealth of potential targets for experimental treatments to aid smoking cessation. 

Medication Means of Increasing Norepinephrine (NE) Activity Prominent Effects on Other Transmitters Clinical Uses... 

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