By Z. Rufus. Oregon Health Sciences University.
An interestingpharmacological distinction between these two classes of neuromuscular blockingagents is that the effect of the competitive receptor blockers like curare can be overcome by increasingthe concentration of ACh purchase solian 50 mg without prescription, which is achieved in vivo by giving an anticholinesterase buy solian 50mg low cost, while the blocking action of the depolarisingdrugs is not reversed buy solian 100mg low cost. Drugs that block the nicotinic receptors on autonomic ganglia cheap solian 50mg visa, such as hexamethonium, probably do so by actually blockingthe Na ion channel rather than the receptor. Generally these receptors appear to resemble the central ones more than those at the neuromuscular junction and dihydro-b-erythroidine is one drugthat it is an effective antagonist in both ganglia and the CNS. In contrast to the nicotinic antagonists and indeed both nicotinic and muscarinic agonists, there are a number of muscarinic antagonists, like atropine, hyoscine (scopolamine) and benztropine, that readily cross the blood±brain barrier to produce central effects. Somewhat surprisingly, atropine is a central stimulant while hyoscine is sedative, as least in reasonable doses. This would be the expected effect of a drugthat is blockingthe excitatory effects of ACh on neurons but since the stimulant action of atropine can be reversed by an anticholinesterase it is still presumed to involve ACh in some way. Generally these compounds are effective in the control of motion but not other forms of sickness (especially hyoscine), tend to impair memory (Chapter 18) and reduce some of the symptoms of Parkinsonism (Chapter 15). DRUGS AND THE DIFFERENT MUSCARINIC RECEPTORS While five different muscarinic receptors have now been distinguished, atropine and the other antimuscarinics discussed above show little specificity for any of them, although pirenzapine is most active at the M1 receptor. Much effort has been expended in the search for more specific muscarinic agonists and antagonists and while a few compounds have emerged which, from binding studies at least, show some (but never dramatic) selectivity, the results have been somewhat disappointing. As M1 receptors mediate the postsynaptic excitatory effects of ACh while M2 cause autoinhibition of its release, then augmenting ACh activity requires an M1 agonist coupled with an M2 antagonist capable of crossing the blood±brain barrier as well as an M1 antagonist that will not. Even then the peripheral effects of the M2 antagonist such as dry mouth and blurred vision can be unpleasant. Such possible permutations of agonist and antagonists in the treatment of dementia are considered in more detail in Chapter 18. CHOLINERGIC PATHWAYS AND FUNCTION Three distinct and basic CNS neuronal systems were referred to in Chapter 1, namely: long-axon neurons, intrinsic short-axon neurons and those in brainstem nuclei with extensively branchingand ramifyingascendingaxons. The ubiquitous nature of ACh as a NT is evidenced by it beingemployed as such in all three situations to some extent, although for the first it is mainly confined to the periphery where it is released from long-axon preganglionic fibres and somatic motor nerves to skeletal muscle. In the striatum it is released from intrinsic interneurons and in the cortex from the terminals of ascendingaxons from subcortical neurons in defined nuclei. There are other projections from the medial septum (Ms) and the nucleus of the diagonal band, or diagonalis broco (DB), to the hippocampus and from the magnocellular preoptic nucleus (MPO) and DB to the olfactory bulb (OB). Collectively all these nuclei are known as the magnocellular forebrain nuclei (FN). The paramedian (or pendunculo) pontine tegmental nucleus (PPTN) sends afferents to the paramedian pontine reticular formation and cerebellum but more importantly to the thalamus (lateral geniculate nucleus) and the more cephalic cholinergic neurons in MPO. Activation of neurons in PPTN during REM sleep gives rise to the PGO (ponto±geniculo±occipital) waves (see Chapter 22). There is a smaller lateral and dorsal tegmental nucleus (LDTN) with afferents projections like that of the PPTN, especially to the thalamus, but its role is less clear (see Woolf 1991). In the ventral horn of the spinal cord (b) ACh is released from collaterals of the afferent motor nerves to skeletal muscle to stimulate small interneurons, Renshaw cells (R), that inhibit the motoneurons SPINAL CORD Since ACh is the transmitter at the skeletal neuromuscular junction one might also expect it to be released from any axon collaterals arisingfrom the motor nerve to it. Such collaterals innervate (drive) an interneuron (the Renshaw cell) in the ventral horn of the spinal cord, which provides an inhibitory feedback onto the motoneuron. Not 132 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION only is ACh (and ChAT) concentrated in this part of the cord but its release from antidromically stimulated ventral roots has been demonstrated both in vitro and in vivo. Also the activation of Renshaw cells, by such stimulation, is not only potentiated by anticholinesterases but is also blocked by appropriate antagonists. In fact it illustrates the characteristics associated with both ACh receptors. Stimulation produces an initial rapid and brief excitation (burst of impulses), which is blocked by the nicotinic antagonist dihydro-b-erythroidine, followed, after a pause, by a more prolonged low-frequency discharge that is blocked by muscarinic antagonists and mimicked by muscarinic agonists. Thus in this instance although ACh is excitatory, as in other areas of the CNS, the activation of Renshaw cells actually culminates in inhibition of motoneurons. Pharmacological manipulation of this synapse is not attempted clinically and although administration of nicotinic antagonists that are effective at peripheral autonomic ganglia and can pass into the CNS, such as mecamylamine, may cause tremor and seizures, it cannot be assumed that this results from blockingcholinergic inhibition of spinal motoneurons. STRIATUM The concentration of ACh in the striatum is the highest of any brain region. It is not affected by de-afferentation but is reduced by intrastriatal injections of kainic acid and so the ACh is associated with intrinsic neurons.
Certainly an increase in the number of Na channels on the dendrites of spinal motoneurons discount solian 100 mg mastercard, which would facilitate the occurrence of reactive dendritic Na spikes solian 50 mg, has been seen after axotomy buy solian 100 mg lowest price. Unfortunately since neither of these events is likely to occur in or around a human epileptic focus the results do not tell us much about how focal activity arises and spreads in humans order solian 100 mg otc. This needs to be achieved by the use of human epileptic tissue even though the procedures found to control experimentally induced spiking may well be applicable to humans. There have been a number of observations which show increased excitation and/or reduced inhibition in slices prepared from human epileptic brain tissue. Thus burst discharges can be evoked with stimuli that would not do so in normal animal tissue and these can be blocked by NMDA receptor antagonists. The inhibitory postsynaptic currents (IPSCs) in hippocampal dentate granule cells in slices prepared from temporal lobe epileptic tissue are in fact reduced by stimulation that activates NMDA currents (Isokawa 1996), which are more prolonged than usual and show changes in slope conductance. It is perhaps not surprising that NMDA and AMPA receptor mechanisms are important in epileptogenesis. The summation of EPSPs through activation of recurrent polysynaptic excitatory pathways is necessary to mediate the large depolarisation of neurons in and around a focus and the intense discharge and extracellular field potentials of the interactal EEG spike, although these may only occur if counteracting inhibition is reduced. There is in fact some evidence of morphological changes in human epileptic hippocampal tissue that would facilitate such excitatory circuits with aberrant networks of collaterals from axons of individual mossy fibre neurons ramifying through to the CA3 and other regions (Isokawa et al. Also the increase in extracellular K following increasing neuronal activity may itself reinforce the activity by directly depolarising nerve terminals and neurons. High extracellular K would also counteract K efflux and so initiate a prolonged low depolarisation that would facilitate repetitive firing. From this survey it is clear that just as normal neuronal function requires appro- priately balanced inhibitory and excitatory controls so the generation of interictal spikes depends on disturbances in both. Clearly activity cannot spread without the activation of excitatory circuits, in which NMDA receptors play an important role, but it will be much facilitated by reduced inhibition (Masukawa et al. These obser- vations may help to explain the establishment of a focus and the development of the interictal spike, but why activity can only spread to seizure proportions, at certain times, is less clear. It will, however, again require overactivity of excitatory circuits inadequately controlled by inhibitory processes. Since these controls are mediated by THE EPILEPSIES 335 NTs it is now appropriate to consider what evidence there is for a malfunction of NTactivity in epilepsy, particularly in those responsible for primary excitation and inhibition, i. Before doing so the epileptogenesis of absence seizures (petit mal) justifies separate consideration. ORIGIN OF ABSENCE SEIZURES There is much evidence that absence seizures originate in the thalamus probably due to some malfunction of neuronal Ca2 channels. The sudden synchronous bilateral nature of the slow-wave discharge (SWD) in the EEG which typifies this condition was justifiably considered by Jasper (see Jasper and Drooglewer-Fortuyn 1997) to require a subcortical focus and he was able to reproduce them in anaesthetised cats by 3 Hz stimulation of the intralamina thalamus, which in conscious animals also produced absence-like behavioural symptoms such as staring and unresponsiveness. Also in rats with genetic absence epilepsy (GAER) such symptoms are not only accompanied by a synchronous 7±9 Hz SWD but this coincides with high-amplitude discharges in the lateral part of the thalamus, the lesion of which inhibits SWDs. Within the thalamus the reticular nucleus, which contains predominantly GABA neurons, sends axons to all the other thalamic muclei and although it does not appear to directly drive any thalamic projection to the cortex it receives collaterals from both thalamo-cortical and cortico-thalamic pathways and is well positioned to influence cortico-thalamic activity. If its neurons are stimulated while slightly hyperpolarised they show repetitive burst discharges in rat brain slices followed by a marked after- hyperpolarisation, i. Pharmacological studies in vivo in the genetically prone rat show that this depends on the activity of certain Ca2 and Ca2-activated K conductances and that blocking Ca2 channels just in the reticular nucleus reduces the cortical SWDs. In fact cloning studies in mutant mice strains with features of absence epilepsy show defects in the subunit structure of these channels (Fletcher et al. It may, however, depend on a particular inhibitory control and hyperpolarisation induced locally by GABA, which certainly invokes rhythmic activity when applied to firing neurons and potentiates SWDs in GAERs. In fact this response is probably mediated by GABAB rather than GABAA receptors since not only does baclofen (GABAB agonist) have a similar effect to GABA but when GABA is applied to thalamic neurons it produces a bicuculline-insensitive long-lasting but slight hyperpolarisation which is followed by a low-threshold calcium potential (LTCP) and spike. This T-type Ca2 channel is common in GAERs and larger than normal in thalamic GABA neurons. NEUROTRANSMITTERS IN EPILEPTIC ACTIVITY Changes in NTlevels and function have been (1) Looked for in (a) human epileptic tissue (b) animals in which convulsions have been induced experimentally 336 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION (c) animals with spontaneous (genetically disposed) epilepsy (2) Induced in animals to see how they modify convulsive threshold and intensity These approaches will be considered in respect of the different NTs although most interest has centred on the amino acids not only because of their possible involvement in the pathology, as already emphasised, but because increased neuronal activity in epilepsy must reflect, even if it is not initiated by, augmented glutamate and/or reduced GABA function.
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