Neurotransmitter activity, control

There have been many references in this book to the role of neurotransmitters in the control of CNS excitability. It is therefore appropriate, but possibly foolhardy, to see if the two natural extremes of that excitability, namely sleep and waking, can be explained in terms of neurotransmitter activity. Of course, these states are not constant our sleep can be deep or light and, even when we are awake, our attention and vigilance fluctuate, as the reading of these pages will no doubt demonstrate. Also, the fact that we sleep does not mean that our neurotransmitters are inactive this would imply that sleep is a totally passive state, whereas all the evidence suggests that it is an actively induced process, subject to refined physiological control. 

The more synchronised the activity of the cortical neurons, the greater the summation of currents and the larger and slower the EEG wave, as in the sleep pattern (Fig. 22.4). While there are some dissociations between EEG pattern and behavioural states, the EEG offers one way of determining experimentally the pathways (and neurotransmitters) that control arousal and sleep, and can be regarded as an important objective measurement of the cortical correlates of sleep and waking. 

Naturally Occurring Compounds. Many derivatives of iadole are found ia plants and animals where they are derived from the amino acid tryptophan. Several of these have important biological function or activity. Serotonin [50-67-9] (12) functions as a neurotransmitter and vasoconstrictor (35). Melatonin [73-31-4] (13) production is controlled daily by the circadian cycle and its physiological level iafluences, and seasonal rhythms ia humans and other species (36). Indole-3-acetic acid [87-51-4] (14) is a plant growth stimulant used ia several horticultural appHcations (37). 

Populations of receptors that are excluded from synaptic junctions. These may be distributed over neuronal cell bodies or located around but not directly beneath synapses (perisynaptic). Some receptors have become specialised to setve an extrasynaptic function producing a tonic level of activity in response to ambient levels of neurotransmitter. This tonic current can be used to maintain homeostatic control over neuronal excitation. 

As to be expected from a peptide that has been highly conserved during evolution, NPY has many effects, e.g. in the central and peripheral nervous system, in the cardiovascular, metabolic and reproductive system. Central effects include a potent stimulation of food intake and appetite control [2], anxiolytic effects, anti-seizure activity and various forms of neuroendocrine modulation. In the central and peripheral nervous system NPY receptors (mostly Y2 subtype) mediate prejunctional inhibition of neurotransmitter release. In the periphery NPY is a potent direct vasoconstrictor, and it potentiates vasoconstriction by other agents (mostly via Yi receptors) despite reductions of renal blood flow, NPY enhances diuresis and natriuresis. NPY can inhibit pancreatic insulin release and inhibit lipolysis in adipocytes. It also can regulate gut motility and gastrointestinal and renal epithelial secretion. 

The membranes of nerve cells contain well-studied ion channels that are responsible for the action potentials generated across the membrane. The activity of some of these channels is controlled by neurotransmitters hence, channel activity can be regulated. One ion can regulate the activity of the channel of another ion. For example, a decrease of Ca + concentration in the extracellular fluid increases membrane permeability and increases the diffusion of Na+. This depolarizes the membrane and triggers nerve discharge, which may explain the numbness, tinghng, and muscle cramps symptomatic of a low level of plasma Ca. ... 

Because of their strategic localization, astrocytes play a crucial role in maintaining the extracellular ionic homeostasis, provide energetic metabolites to neurons and remove excess of neurotransmitter in schedule with synaptic activity. In addition, the strategic location of astrocytes allows them to carefully monitor and control the level of synaptic activity. Indeed, number of papers during the last 15 years have shown that cultured astrocytes can respond to a variety of neurotransmitters with a variety of different patterns of intracellular calcium increases (Verkhratsky et al. 1998). Later on, studies performed in intact tissue preparations (acute brain slices) further established that the plasma membrane receptors can sense external inputs (such as the spillover of neurotransmitters during intense synaptic activity) and transduce them as intracellular calcium elevations, mostly via release of calcium from internal stores (Dani et al. 1992 Murphy et al. 1993 Porter and McCarthy... 

Figure 1.8 Some basic neuronal systems. The three different brain areas shown (I, II and III) are hypothetical but could correspond to cortex, brainstem and cord while the neurons and pathways are intended to represent broad generalisations rather than recognisable tracts. A represents large neurons which have long axons that pass directly from one brain region to another, as in the cortico spinal or cortico striatal tracts. Such axons have a restricted influence often only synapsing on one or a few distal neurons. B are smaller inter or intrinsic neurons that have their cell bodies, axons and terminals in the same brain area. They can occur in any region and control (depress or sensitise) adjacent neurons. C are neurons that cluster in specific nuclei and although their axons can form distinct pathways their influence is a modulating one, often on numerous neurons rather than directly controlling activity, as with A . Each type of neuron and system uses neurotransmitters with properties that facilitate their role...

While this chapter is concerned primarily with the neurochemical mechanisms which bring about and control impulse-evoked release of neurotransmitter, some of the methods used to measure transmitter release are described first. This is because important findings have emerged from studies of the effects of nerve stimulation on gross changes in transmitter release and intraneuronal stores. The actual processes that link neuronal excitation and release of transmitter from nerve terminals have been studied only relatively recently. The neurochemical basis of this stimulus-secretion coupling, which is still not fully understood, is described next. The final sections will deal with evidence that, under certain conditions, appreciable amounts of transmitter can be released through Ca +-independent mechanisms which do not depend on neuronal activation. 

Even more sophisticated control of neurotransmitter release is suggested by the possibility of heteroceptors . These receptors are thought to be located on the terminals of, and to modulate transmitter release from, one type of neuron, but are activated by transmitter released from a different type of neuron (Laduron 1985). For example, noradrenaline has been proposed to modulate release of a wide range of transmitters (e.g. dopamine, 5-HT and glutamate) through activation of a2-heteroceptors on the terminals of each of these different types of neuron. However, one factor that should be borne in mind is that most of the evidence for heteroceptors comes from studies of... 

The major inhibitory neurotransmitter in the cerebral cortex is y-aminobutyric acid (GABA). It attaches to neuronal membranes and opens chloride channels. When chloride flows into the neuron, it becomes hyperpolarized and less excitable. This mechanism is probably critical for shutting off seizure activity by controlling the excessive neuronal firing. Some antiepileptic drugs, primarily barbiturates and benzodiazepines, work by enhancing the action of GABA. 

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