Neuronal excitability

As we shall see immediately, this condition, together with the linearity of the neuronal excitations in the threshold condition, allows us to determine a finite system s fate almost entirely) analytically. 

It should be pointed out that most anticonvulsants have more than one effect on neuronal excitability or... 

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. 

Generally, anticonvulsants reduce the excitability of the neurons (nerve cells) of the brain. When neuron excitability is decreased, seizures are theoretically reduced in intensity and frequency of occurrence or, in some instances, are virtually eliminated. For some patients, only partial control of the seizure disorder may be obtained with anticonvulsant drug therapy. 

Suggest a synthesis for amine (5), needed to make the potent neuronal excitant a-kainic acid. ... 

After an overview of neurotransmitter systems and function and a consideration of which substances can be classified as neurotransmitters, section A deals with their release, effects on neuronal excitability and receptor interaction. The synaptic physiology and pharmacology and possible brain function of each neurotransmitter is then covered in some detail (section B). Special attention is given to acetylcholine, glutamate, GABA, noradrenaline, dopamine, 5-hydroxytryptamine and the peptides but the purines, histamine, steroids and nitric oxide are not forgotten and there is a brief overview of appropriate basic pharmacology. 

Like other cells, a neuron has a nucleus with genetic DNA, although nerve cells cannot divide (replicate) after maturity, and a prominent nucleolus for ribosome synthesis. There are also mitochondria for energy supply as well as a smooth and a rough endoplasmic reticulum for lipid and protein synthesis, and a Golgi apparatus. These are all in a fluid cytosol (cytoplasm), containing enzymes for cell metabolism and NT synthesis and which is surrounded by a phospholipid plasma membrane, impermeable to ions and water-soluble substances. In order to cross the membrane, substances either have to be very lipid soluble or transported by special carrier proteins. It is also the site for NT receptors and the various ion channels important in the control of neuronal excitability. 

Metabotropic Those not directly linked to ion channels but initiating biochemical processes that mediate more long-term effects and modify the responsiveness of the neuron. With these the first messenger of synaptic transmission, the NT, activates a second messenger to effect the change in neuron excitability. They are normally associated with reduced membrance conductance and ion flux (unless secondary to... 

These two basic mechanisms could provide a further classification for NTs, namely fast and slow acting, although one NT can work through both mechanisms using different receptors. The slow effects can also range from many milliseconds to seconds, minutes, hours or even to include longer trophic influences. What will become clear is that while one NT can modify a number of different membrane ion currents through different mechanisms and receptors, one current can also be affected by a number of different NTs. The control of neuronal excitability is discussed in more detail in Chapter 2. 

Brown, DA (1983) Slow cholinergic excitation — a mechanism for increasing neuronal excitability. Trends Neurosci. 6 302-307. 

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. 

Two separate lines of research led to the proposal that transmitter released in response to neuronal excitation is derived from a vesicle-bound pool rather than from the neuronal cytoplasm. One piece of evidence came from electron microscopy which... 

Although ACh does not have a primary excitatory role like glutamate in the CNS, it does increase neuronal excitability and responsiveness, through activation of muscarinic receptors. It achieves this in two ways, both of which involve closure of K+ charmels (see Chapter 2 and Brown 1983 Brown et al. 1996). The first is a voltage-dependent K+ conductance called the M conductance, Gm or Im. It is activated by any... 

Studies of release of noradrenaline from sympathetic neurons provided the first convincing evidence that impulse (Ca +)-dependent release of any transmitter depended on vesicular exocytosis. Landmark studies carried out in the 1960s, using the perfused cat spleen preparation, showed that stimulation of the splenic nerve not only led to the detection of noradrenaline in the effluent perfusate but the vesicular enzyme, DpH, was also present. As mentioned above, this enzyme is found only within the noradrenaline storage vesicles and so its appearance along with noradrenaline indicated that both these factors were released from the vesicles. By contrast, there was no sign in the perfusate of any lactate dehydrogenase, an enzyme that is found only in the cell cytosol. The processes by which neuronal excitation increases transmitter release were described in Chapter 4. 

The exact process(es) by which a2-adrenoceptors blunt release of transmitter from the terminals is still controversial but a reduction in the synthesis of the second messenger, cAMP, contributes to this process. a2-Adrenoceptors are negatively coupled to adenylyl cyclase, through a Pertussis toxin-sensitive Gi-like protein, and so their activation will reduce the cAMP production which is vital for several stages of the chemical cascade that culminates in vesicular exocytosis (see Chapter 4). The reduction in cAMP also indirectly reduces Ca + influx into the terminal and increases K+ conductance, thereby reducing neuronal excitability (reviewed by Starke 1987). Whichever of these releasecontrolling processes predominates is uncertain but it is likely that their relative importance depends on the type (or location) of the neuron. 

It is the a2A/D-adrenoceptor that predominates in the locus coeruleus and this subtype seems to be responsible for reducing neuronal excitability and transmitter release. Strangely, immunocytochemical studies suggest that most a2c-receptors are intracellular. The explanation for this finding and its functional implications are as yet unknown but it could reflect differences in intracellular trafficking of different receptor subtypes. 

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). 

The mu, delta and kappa opioid receptors are coupled to G° and G proteins and the inhibitory actions of the opioids occur from the closing of calcium channels (in the case of the K receptor) and the opening of potassium channels (for /i, d and ORL-1). These actions result in either reductions in transmitter release or depression of neuronal excitability depending on the pre- or postsynaptic location of the receptors. Excitatory effects can also occur via indirect mechanisms such as disinhibition, which have been reported in the substantia gelatinosa and the hippocampus. Flere, the activation of opioid receptors on GABA neurons results in removal of GABA-mediated inhibition and so leads to facilitation. 

These observations, while implicating steroids in brain function and behaviour, cannot be taken as a reliable indicator of their actual effect on neuronal function. Nevertheless, some neurosteroids produce CNS depression with a rapid inhibition of neuronal excitability and one progesterone derivative, alphaxalone (3a-hydroxy-5a pregnane-11, 20 dione, see Fig. 13.5) has been used effectively as an intravenous anaesthetic in humans. 

Phenobarbitone was the first AED and was introduced in 1912. It was largely replaced in 1932 by phenytoin for the management of tonic-xilonic seizures and partial and secondary epilepsy. Carbamazepine followed, then ethosuximide for absence seizures and valproic acid. These remained, apart from the introduction of the benzodiazepines, the mainstay of therapy until the last decade. They were introduced solely on their ability to control experimentally induced seizures. Their mechanisms of action were unknown and no thought was given to the possibility of NT modification and in fact subsequent research has shown that with the exception of the benzodiazepines none of them work primarily through NT manipulation. They act directly on neuronal excitability. 

Some neuroleptics, including clozapine, are potent 5-HT-receptor antagonists and the possible role of 5-HT in the action of neuroleptics and the development of schizophrenia has recently generated much interest (Busatto and Kerwin 1997). This has centred primarily on 5-HT2A receptors found in the limbic cortex, which are linked to neuronal excitation and believed to mediate the hallucinogenic effects of drugs such as lysergic acid diethylamide (LSD). 

Fibres from 5-HT neurons in the raphe nucleus innervate and yet, despite the observed 5-HT2A receptor link with neuronal excitation, appear to inhibit DA neurons in the SN (A9). Thus antagonism of 5-HT released onto them would increase their firing and so reduce the likelihood of EPSs, although how 5-HT2A antagonists can... 

Mechanism of Action The mechanism of action of carbamazepine is not well understood. It blocks ion channels and inhibits sustained repetitive neuronal excitation, but whether this explains its effect as a mood-stabilizing drug is not known.32... 

Catteral, W. A., The molecular basis of neuronal excitability, Science, 223, 653 (1984). 

McCarley, R. W. Hobson, J. A. (1975). Neuronal excitability modulation over the sleep cycle a structural and mathematical model. Science 189, 58-60. 

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