Brain Function

Department of Pharmacology, University College London, UK Chichester New York Weinheim Brisbane Singapore Toronto Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright 2001 John Wiley & Sons Ltd ISBN Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Copyright 2001 by John Wiley & Sons Ltd. Baffins Lane, Chichester, West Sussex P019 1UD, UK National 01243 779777 International ( + 44) 1243 779777 e-mail (for orders and customer service enquiries)...

Therapy Outline

In 1952 reserpine, an alkaloid extract from the Indian snakewort plant, Rauwolfia serpentina, which had been used in that country to treat 'madness', was first tried in schizophrenia. The beneficial impact on patients and the hospital wards was dramatic, as was that a year later of chlorpromazine, a phenothiazine derivative and haloperidol, a butyrophenone. These latter two drugs and closely related derivatives remained the mainstay of therapy for almost 40 years. Chlorpromazine had been shown...

Where Does The Released Transmitter Come From

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 showed that nerve terminals were packed with vesicle-like organelles (Fig. 4.10). Using differential centrifugation, these vesicles were soon identified as the major storage sites for neurotransmitters. The second was electrophysiological evidence...

Inactivation

As with other monoamines, the actions of 5-HT are terminated by its reuptake from the synapse by another member of the family of Na+ Cl -dependent transporters. The 5-HT transporter has many features in common with its catecholamine equivalent (described fully in Chapter 8 see Fig. 8.7), including its presumed 12 transmembrane-spanning domains. However, the cloned 5-HT transporter has a Km for 5-HT of about 450 nM whereas its Ki for both noradrenaline and dopamine is some ten thousand-fold...

Dopamine Receptors

The original discovery and classification of DA receptors was based on the results of three distinct studies (1) Stimulation of adenylate cyclase (3) Inhibition of prolactin release The adenylate cyclase discovered originally in bovine superior cervical ganglia, and then found in homogenates of rat striatum, was specific to DA, in that it was activated by other DA agonists like ADTN, but not greatly by NA or 5-HT. Some other drugs with established DA-like effects proved, however, to be either...

Pathways Within The

The cell bodies of central noradrenergic neurons are all clustered within two bilateral groups of nuclei (numbered A1 to A7) in the brainstem (Fig. 8.2). These comprise the locus coeruleus complex and the lateral tegmental nuclei. The locus coeruleus proper (nucleus A6) has attracted most interest because it accounts for approximately 45 of all the noradrenergic neurons in the brain. In the rat, there are only about 1500 noradrenergic cell bodies in the locus coeruleus of each hemisphere but...

The Neural Basis Of Orcadian Rhythms

It is most probable that sleep and waking stem from an inherent cycle of neuronal activity that can be influenced dramatically by changes in sensory stimulation. This is demonstrable not only in humans and laboratory animals, but also in invertebrates. Thus, while we cannot be sure that other animals sleep in the same way that we do, they do show a circadian cycle of motor activity. In some (nocturnal) species, such as the rat, this activity is actually highest during darkness. Even aplysia,...

Measurement Of Transmitter Release

ESTIMATION OF TRANSMITTER TURNOVER EX VIVO Until the development of sensitive assays and sophisticated collection techniques, release studies relied on measuring changes in the concentration of neurotransmitters in whole organs, or dissected brain regions, following nerve stimulation. However, under resting conditions, the transmitter content of any given organ or brain region is remarkably constant. The store of classical transmitters (monoamines and acetylcho-line) in nerve terminals is...

Pathology

It was known for most of the twentieth century that the brains of PD patients lacked the dark pigmentation characteristic of neurons in the substantia nigra. Such colouring is caused by melanin granules in their cell bodies and although its role is uncertain it is only found in humans and primates and they alone can develop the symptoms of PD. The substantia nigra (SN) is also characterised by round eosinophilic intraneuronal inclusions known as Lewy bodies, which are increased in PD. Neither...

Peptides

Many peptidergic and amino acid receptors have been suggested as potential targets for anti-anxiety drugs. The outcome of preclinical and clinical investigations (together with further references) are detailed in Jackson and Nutt (1996). So far, no compounds have emerged as clear candidates for the clinic, not least because pharmacokinetic considerations and adverse effects in the periphery are common confounding factors. How any of the peptides could actually influence the neuronal networks...

Neuronal Excitability

The neuronal membrane normally has a resting membrane potential around 70 mV (inside negative in respect of outside) with Na+ and Cl concentrated on the outside and K+ on the inside prepared to move down their concentration gradients when the appropriate ion channels are opened (Fig. 1.4). On arrival of an excitatory impulse the Na+ channels are opened and there is an increased influx of Na+ so that the resting potential moves towards the so-called equilibrium potential for Na+ (+50 mV) when...

Ion Channels Affecting The Pattern And Frequency Of Action Potential Discharges

The opening of Na+ ion channels for the initiation of neuronal depolarisation and action potential generation, as described above, can be induced by excitatory neuro-transmitters acting on receptors that are directly linked to cation channels. These include glutamate AMPA receptors (Chapters 3 and 10) and ACh nicotinic receptors (Chapter 6). The inhibitory neurotransmitter GABA has an opposing effect through receptors (GABAa) that are directly linked to the opening of chloride channels,...

Neurobiological Changes Induced By Chronic Administration Of Antidepressants

Bupropion Reeptor Profile

The actions of all the compounds described so far seem to underpin the monoamine hypothesis. Yet an outstanding problem in treating depression is that the therapeutic response is both slow and progressive a significant improvement usually takes at least 2-3 weeks and sometimes much longer. Obviously, if we are to explain the therapeutic effects of antidepressants, we must search for long-term neurochemical changes that occur after their prolonged administration. The first indication that some...

D A Brown

The task of nerve cells is to communicate. They do this using a combination of electrical signals (action potentials) and chemical signals (transmission). However, even the chemical signal has to be transduced to an electrical signal (the synaptic potential) in order to continue the process of communication from one neuron to another. Information is then coded in the frequency and pattern of action potential discharges. This chapter considers the question of how these electrical signals are...

Chemical Transmission

We might start by considering what we understand by the term 'neurotransmitter'. According to the Oxford English Dictionary (2nd edition) it is A substance which is released at the end of a nerve fibre by the arrival of a nerve impulse and by diffusing across the synapse or junction effects the transfer of the impulse to another nerve fibre (or muscle fibre or some receptor). Other dictionaries carry similar definitions. Based on this definition a neurotransmitter could be exemplified by...

Drugreceptor Interactions

The effect of an agonist drug whether it is measured as the ability to fire a neuron, inhibit an enzyme or reduce motor function, increases with the concentration of the drug and the number of receptors it occupies. In fact the magnitude of the response, like that of a chemical reaction, is proportional to the product of the concentration of the reactants, in this case the drug and its receptors, and as such obeys the law of Mass Action. Thus the rate at which a drug D combines with the...

Neurotransmitter Organisation And Utilisation

In the periphery at the mammalian neuromuscular junction each muscle fibre is generally influenced by only one nerve terminal and the one NT acts on one type of receptor localised to a specific (end-plate) area of the muscle. The system is fitted for the induction of the rapid short postsynaptic event of skeletal muscle fibre contraction and while the study of this synapse has been of immense value in elucidating some basic concepts of neurochemical transmission it would be unwise to use it as...

Sleep

Defining sleep is not at all straightforward but its general features comprise (see Hendricks, Sehgal and Pack 2000) (1) a sterotypical, species-specific posture (2) an absence of voluntary movements (3) elevated threshold for arousing stimuli (4) reversibility on stimulation of the individual (or organism). The following sections outline what is known about how these changes come about and how they are regulated. Probably the most important breakthrough in sleep research came in the mid-1930s...

Neurons Structure And Environment

The neurons from which NTs are released number more than 7 billion in the human brain. Each (Fig. 1.2) consists of a cell body, the soma or perikaryon, with one major cytoplasmic process termed the axon, which projects variable distances to other neurons, e.g. from a cortical pyramidal cell to adjacent cortical neurons, or to striatal neurons or to spinal cord motoneurons. Thus by giving off a number of branches from its axon one neuron can influence a number of others. All neurons, except...

Agonists And Antagonists

Many drugs bind to cholinergic receptors but few of them enter the brain and those that do are not noted for their effects. Some agonists, such as methacholine, carbachol and bethanecol are structurally very similar to ACh (Fig. 6.6). They are all more resistant to attack by cholinesterase than ACh and so longer acting, especially the non-acetylated carbamyl derivatives carbachol and bethanecol. Carbachol retains both nicotinic and muscarinic effects but the presence of a methyl (CH3) group on...

Neurochemistry

The release (calcium-dependent) and receptor actions of peptides resemble those of the 'classical' transmitters, the receptors being seven transmembrane-spanning receptors Neurotransmitters, Drugs and Brain Function. Edited by R. A. Webster 2001 John Wiley & Sons Ltd Figure 12.1 A comparison of the production, release and fate of 'classical transmitters' such as glutamate and the monoamines and a peptide. (Most neurons use both classical and peptide transmitters) coupled to second...

Sideeffects Of Opiates

The large numbers of opioid receptors in areas of the brainstem such as the solitary tract and adjacent areas are probably related to respiratory effects of opiates, cough suppression and nausea and vomiting. Opiates acting in the brainstem reduce the sensitivity of the respiratory centres to pCO2 and this is the most common cause of death from overdose with street use of opiates. Opiates activate the chemoreceptor trigger zone in the medulla (by disinhibition) to cause nausea and vomiting, and...

Supraspinal Opiate Analgesia

There are other important sites of opiate actions located in the 5-HT and noradrenergic nuclei of the brainstem and midbrain including the raphe nuclei, the periaquaductal grey matter and the locus coeruleus. Opiate receptors in these zones (mu, delta and kappa) when activated alter the level of activity in descending pathways from these zones to the spinal cord. The mechanisms of action of opioids at supraspinal levels are still poorly understood. One idea is that descending controls filter...

Vesicular Exocytosis

Once vesicles detach from the cytoskeleton they are free to participate in the release process but our understanding of precisely how this is brought about is still sketchy, despite the wealth of information which has accumulated over recent years. What is clear is that it involves a complex cascade of regulatory processes focusing on proteins bound to vesicle membranes, the axolemma and some cytoplasmic factors (see Calakos Figure 4.11 Dephosphorylated synapsin, associated with SSVs, is...

Pharmacology Of The Dopamine Synapse

The sites of action of drugs affecting the dopamine synapse are indicated in Fig. 7.3. Those modifying the synthesis, storage, release, uptake and metabolism of DA have been covered above in the appropriate sections on neurochemistry. The actions and uses of agonists and antagonists are outlined in Table 7.4 and covered in detail in appropriate chapters. Their structures are given in Fig. 7.6. Those for the D2 receptor (e.g. bromocriptine) have a particular value in the treatment of Parkinson's...

Subunit transmembrane topology

Pnr Medication Chart

The ligand-gated ion channel receptors form three distinct super-families based on the number of times the receptor subunits are predicted to cross the cell membrane (Fig. 3.2). For the nicotinic acetylcholine receptors, GABAa, GABAc, 5-HT3 and glycine receptors each subunit is predicted to cross the cell membrane four times (Fig. 3.2(a)). The exact transmembrane topology is only known with certainty for the nAChR (Unwin 1995). For the other 4-TM domain receptors (and for those in the 3-TM...

Neurotransmitter Systems

Ips Drug Screening

Based on the above account of the neuronal pathways thought to be responsible for the basic sleep-wake cycle, the neurotransmitters that are most likely to be involved in the cycle are those which (1) Are released either in the cortex or the non-specific thalamic nuclei. (2) Augment, or more probably, break up thalamic-cortico synchrony and its tendency to promote slow-wave EEG activity and non-REM sleep. Whether this results in full arousal, or merely a temporary disruption of sleep to give...

Manipulation Of Neurotransmitters

Primitive Brain Function

Since ACh appears to be important in memory processing and as its concentration is significantly reduced in appropriate brain areas in AzD then augmenting its action should at least improve memory function. ACh activity may be increased by (1) Enhancing its synthesis (and presumed release) through giving the precursor choline (2) Stopping its degradation by cholinesterase with anticholinesterase drugs (3) Reproducing its action with appropriate agonists (a) muscarinic, (b) nicotinic Approaches...

Benzodiazepines And Benzodiazepine Receptors

Extreme Cases Animal Abuse

MOLECULAR TARGETS FOR THE GABAa RECEPTOR The first clues to the mechanism of action of benzodiazepines came from landmark experiments (Squires and Braestrup 1977 Moehler and Okada 1977) which showed that Loss of consciousness Muscle relaxation Hypnosis Sedation Ataxia Anti-epileptic Anti-anxiety Dose of benzodiazepine Low M- High Figure 19.4 The activity spectrum of the benzodiazepines. Motor impairment and CNS depression increases with drug dose. (Based on data for chlordiazepoxide (Sternbach,...

The Action Potential

This is the basic unit ('bit') of information processing in the nervous system. It is a transient electrical signal generated by the opening of voltage-gated Na+ channels. These are normally shut at rest (or largely so), but are opened when the nerve cell membrane is depolarised by (e.g.) an excitatory transmitter. Since the entry of Na+ ions further depolarises the membrane, so opening more Na+ channels, the process becomes regenerative once the threshold potential is exceeded this is the...

Microdialysis

This is a modification of the earlier push-pull cannula which could be used in anaesthetised animals only. The microdialysis probe which has an outside diameter of about 250 pm (Fig. 4.6) is implanted into the brain under anaesthesia and then subsequently perfused with aCSF. Solutes (including neurotransmitters) in the extracellular fluid of the brain diffuse down their concentration gradient into the probe. By taking samples of the effluent dialysate at regular intervals it is possible to...

Neurotransmitter Identification

Magic Mushrooms Species

To achieve NT status a substance must fulfil three main criteria (1) Presence. It perhaps goes without saying that the proposed transmitter must be shown to be present in the CNS and preferably in the area and at the synapses where it is thought to act. (2) Release. Stimulation of the appropriate nerves should evoke a measurable release of NT. (3) Identity of action. The proposed NT must produce effects postsynaptically which are identical physiologically (appropriate membrane potential...

Neurochemistry Of Glycine

The details of glycine metabolism within neural tissue are poorly understood, and it is unclear to what extent neurons depend on de novo synthesis or uptake of glycine. Two enzymes are important in glycine metabolism serine hydroxymethyltransferase (SHMT), which is thought to be present in the mitochondria of both neurons and glia, and the four-enzyme complex known as the glycine cleavage system (GCS), present in glia. SHMT catalyses the interconversion of L-serine and glycine while GCS...

Synthesis

Steps Synthesis Tryptophan Images

The first step in the synthesis of 5-HT is hydroxylation of the essential amino acid, tryptophan, by the enzyme tryptophan hydroxylase (Fig. 9.4). This enzyme has several features in common with tyrosine hydroxylase, which converts tyrosine to -DOPA in Figure 9.4 The synthesis and metabolism of 5-HT. The primary substrate for the pathway is the essential amino acid, tryptophan and its hydroxylation to 5-hydroxytryptophan is the rate-limiting step in the synthesis of 5-HT. The cytoplasmic...

Basal Ganglia Circuitry Fig 152

Corticothalamic Pathway

In order to understand how the symptoms of PD could arise from a loss of striatal DA and what can be done to replace it and treat PD, it is necessary to know something of basal ganglia circuitry and the role of DA in it. The scheme to be outlined should, however, be regarded as a working template rather than fully proven fact but there is much evidence for it (Fig. 15.2). Certainly the striatum, i.e. the putamen and caudate nucleus, is accepted as the main receiving area in motor circuits....

Therapy

Parkinsonism is unique among diseases of the CNS, in that it results from the known loss of a particular NT, i.e. DA, resulting from the degeneration of a particular pathway, the nigrostriatal. Dopamine also has a relatively limited distribution in the brain and few peripheral effects. It should therefore be amenable to therapy based on augmenting its function. Also since the role of DA appears to be to maintain a tonic inhibitory control on GABA output pathways from the striatum, possibly in...

Central Events In The Transmission Of Pain

SENSORY TRANSMISSION IN THE SPINAL CORD Morphology of the spinal cord dorsal horn The spinal cord is arranged in such a way that primary afferents originating from different regions of the body display specific somatotopic organisations upon entry into the cord. Hence in any given segment, there is a definite laterality (ipsilateral contralateral) and a three-dimensional organisation (rostrocaudal, mediolateral, dorsoventral) of the afferent terminations. The spinal cord is classically divided...

Neurochemistry Of Noradrenaline

Phenylalanine Norepinephrine Pathway

The effects of drugs on the synthesis, storage, release and destruction of noradrenaline, summarised in Fig. 8.4, are discussed in the following sections. Plierwliine Irreversible, selective. Dcprcry) (MAO-B) ftEverslble, selective Moclobemid (MAO-A, RIKA) Figure 8.4 The site of action of drugs that modify noradrenergic transmission Plierwliine Irreversible, selective. Dcprcry) (MAO-B) ftEverslble, selective Moclobemid (MAO-A, RIKA) Figure 8.4 The site of action of drugs that modify...

Gabab receptors

GABAB receptors are found in both the peripheral nervous system and CNS. They were first identified in the late 1970s, during studies of noradrenaline release from axon terminals of sympathetic post-ganglionic fibres in rat atria. GABA was found to reduce the evoked release of transmitter but this action was not blocked by the conventional antagonists bicuculline and picrotoxin. The effect of GABA was mimicked not by muscimol but by the compound ( )-4-amino-3-(4-chlorophenyl)butanoic acid...

CBZ 2jjj

Figure 16.8 Cellular action of phenytoin and carbamazepine. Each column shows the response of a spinal cord neuron in culture to four increasing directly applied current pulses (amplitude in nA given at start of each sweep. Under control conditions (CONT)) the progressive depolarisations (bottom to top of each column of traces) induce increasing sustained discharges, whereas in the presence of phenytoin (PTZ) and carbamazepine (CBZ) firing cannot be maintained although the initial action...

Gabab receptor mechanisms

Pathway For Prevention Uti

Depending on cell type and the location of the receptor on neurons, GABAB receptors act via G-proteins to affect the activity of either Ca2+ channels, K+ channels or adenylate cyclase (Bowery and Enna 2000). For example, in dorsal root ganglion (DRG) neurons baclofen was found to inhibit the Ca2+-dependent phase of the DRG action potential, an effect attributed to block of voltage-activated Ca2+ currents. A similar action on presynaptic Ca2+ channels was presumed to underlie the block of...

Regulation of tyrosine hydroxylase activity

Metabolism Noradrenaline

At first, it was thought that control of TH activity depended on inhibition by its end-product, noradrenaline, which competes with the binding of co-factor. According to this scheme, release of noradrenaline would diminish end-product inhibition of the enzyme and so ensure that synthesis is increased to replenish the stores. When the neurons are quiescent, the opposite would occur i.e. intraneuronal accumulation of noradrenaline would automatically blunt synthesis. Much evidence was deemed to...

Aetiology And Prevention

If the symptoms of PD arise when nigra cell loss results in a particular depletion of striatal DA (e.g. 50 or more) and, as is generally assumed, there is a gradual loss of nigra cells during ageing then we should all develop PD if we live long enough. Fortunately this is not the case as many people can reach 90 or 100 years without developing PD. In fact, PM studies show that in normal subjects nigra DA cell loss proceeds at 4-5 per 10 years but in PD sufferers it occurs at almost ten times...

Trace Amines Tryptamine Phenylethylamine Tyramine And Octopamine

Decarboxylation, instead of hydroxylation, of the amino-acid precursors of DA and 5-HT results in the formation of amines that are only found in trace amounts in the CNS but have distinct effects when administered into the brain (Fig. 13.7). Since such decarboxylation can be achieved by the non-specific L-aromatic amino acid decarboxylase there is considerable potential for its occurrence, especially if there is a rise in the concentration of the appropriate precursor or some malfunction in...

Neurochemistry Of Gaba

Brain Neurochemistry

The synthesis and metabolism of GABA is closely linked with that of glutamate and the citric acid or tricarboxylic acid (TCA) cycle (Fig. 11.1). GABA is produced by the decarboxylation of glutamate, a reaction catalysed by the enzyme glutamic acid decarboxylase (GAD). GAD is found in several non-neuronal tissues (including ovary and pancreas) but within the CNS it is a specific marker of GABAergic neurons, where it is present in the cytoplasm as both soluble and membrane-bound forms,...

Neurosteroids

Steroid Synthesis Brain

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...

Fjt XJ

Figure 11.6 Schematic representation of the GABAa receptor complex. Examples of the many structurally diverse compounds that act at different sites Z on the receptor (see text for details). Picrotoxinin, the active component of picrotoxin, and TBPS act as non-competitive antagonists. The barbiturates, Q steroids and anaesthetics are positive allosteric modulators, as are the benzodiazepine site ligands shown, with the exception of DMCM (negative q allosteric modulator) and flumazenil...

Animal Models Of Epilepsy

These are normally based on the use of either electrical stimulation or chemical convulsants. When applied generally, i.e. an electric shock to the whole brain or convulsants injected systemically, the resulting convulsions are indicative of generalised seizures. If they are applied locally to specific brain areas, the same approaches induce activity indicative of partial seizures. Also some animals can be bred in which seizures either occur spontaneously or can be induced easily by appropriate...

Toxification Detoxification

Figure 15.11 Possible scheme for the formation of free radicals from the metabolism of dopamine. Normally hydrogen peroxide formed from the deamination of DA is detoxified to H20 along with the production of oxidised glutathione (GSSG) from its reduced form (GSH), by glutathione peroxidase. This reaction is restricted in the brain, however, because of low levels of the peroxidase. By contrast the formation of the reactive OH-radical (toxification) is enhanced in the substantia nigra because of...

Recording Neural Activity

RECORDING ION CHANNEL CURRENTS THE PATCH-CLAMP Currents through individual ion channels can be recorded using the patch-clamp technique (Fig. 2.10). A fine glass micro-electrode (tip diameter about 1 filled with electrolyte solution is attached to the cell membrane by suction, forming a 'tight seal' (resistance 1 GQ or more, i.e. 109 Q), so that all current flowing through the channel enters the electrode. These currents are very small (a few picoamps, pA) so have to be amplified. The amplifier...

Attenuation Of Degeneration

Even if NT manipulation had provided an effective therapy in AzD it would still be important to stop the progression of degeneration and the disease process itself. The failure of the NT approach makes it even more vital. While the precise cause of AzD remains unknown, the evidence implicating -amyloid is such as to justify attempts to reduce its involvement. The activity of -amyloid might be reduced by (a) stopping its production by reducing the phosphorylation and proteolysis of APP (c)...

Integrated Theories Of Anxiety

Anxiety And Brain Function

The evidence outlined so far does little to explain how monoamines or anti-anxiety drugs might influence anxiety states. To achieve this, an integrated view of the relevant brain systems is required, together with an appreciation of how their function is regulated. One scheme focuses on the roles of the septum and hippocampus. Detailed justification of this theory is beyond the scope of this chapter but can be found in Gray (1987). Briefly, the 'septohippocampal system' is thought to form part...

Central Functions

It is perhaps easier to identify some of the central functions of DA than that of the other monoamines because not only does it have distinctive central pathways associated with particular brain areas, but it has few peripheral actions. Also the actions of its antagonists reveal its central effects. These are summarised in Table 7.4. Table 7.4 Summary of dopamine function Control (inhibition) of prolactin release Nigrostriatal tract from substantia nigra (A9) Mesolimbic pathway to nucleus...

Drug Antagonism

Competitive Surmountable Antagonism

One drug can overcome the effect of another or reduce the activity of an endogenously released and active substance such as a neurotransmitter, either by competing with that substance for its receptor site (receptor antagonism) or stimulating a different receptor to induce an opposing effect (physiological or functional antagonism), The former may be regarded as true antagonism for in the latter case both drugs are actually agonists, It is epitomised by the use in asthma of beta adrenoceptor...

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 branching and ramifying ascending axons. The ubiquitous nature of ACh as a NT is evidenced by it being employed 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...

Maprotiline

Figure 20.4 The chemical structure of mianserin and maprotiline antidepressants is mirtazepine, which is an analogue of mianserin but with fewer pronounced side-effects. SELECTIVE NORADRENALINE REUPTAKE INHIBITORS (NARIs) Once it was realised that the adverse effects of the TCAs were due to their interactions with transmitter receptors, rather than their inhibition of noradrenaline reuptake, one objective in the development of novel drug treatments was to produce a 'clean' and selective...

Distribution In The

Median Raphe Dorsal Raphe Innervation

As with the other monoamines, the distribution of 5-HT-releasing neurons in the brain was first characterised in the 1960s using the Falck-Hillarp histochemical technique whereby 5-HT is converted to a compound that is fluorescent under ultra-violet light. This showed that the cell bodies of 5-HT neurons aggregate around the midline of the upper brainstem, forming distinct clusters (or nuclei) (Fig. 9.2). Since then, 5-HT neurons have been found in the noradrenergic locus coeruleus and the area...

References And Further Reading

Arendt, J, Middleton, B, Stone, B and Skene, D (1999) Complex effects of melatonin Evidence for photoperiodic responses in humans Sleep 22 625-635. Barnes, NM and Sharp, T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38 1083-1152. Berridge, CW (1998) Modulation of forebrain electroencephalographic action and behavioral state by locus coeruleus-noradrenergic system involvement of the medial septal area. Adv. in Pharmacol. 42 744-748. Bjorvatn, B and Ursin, R...

References

Abe, K, Takeyama, C and Yoshimura, K (1998) Effects of S-8510, a novel benzodiazepine receptor partial inverse agonist, on basal forebrain lesioning-induced dysfunction in rats. Eur. J. Pharmacol. 347 145-152. Awad, M and Gavish, M (1987) Binding of 3H Ro 5-4864 and 3H PK 11195 to cerebral cortex and peripheral tissues of various species species differences and heterogeneity in peripheral benzodiazepine binding sites. J. Neurochem. 49 1407-1414. Ballenger, JC (1990) Neurobiology of Panic...

What Is The Function Of Noradrenaline In The Brain

Because central noradrenergic pathways are so diffuse, and the synaptic effects of noradrenaline have a comparatively slow time-course, these neurons could have a wide range of functions, depending on the brain region being targeted and the neurobiological status of the individual. In general terms, however, it is agreed that noradrenergic neurons influence arousal. This encompasses not only the sleep waking cycle see Chapter 22 but also more specific activities, such as selective attention and...

Octodecaneuropeptide Structure

Figure 19.6 The chemical structure of the imidazopyridine and benzodiazepine BZ receptor ligand, zolpidem, and the cyclopyrrolone, zopiclone Whether simple augmentation of GABAa receptor function accounts for the anti-anxiety effects of these compounds remains equivocal. If this was the case then other agents that augment GABAergic transmission such as inhibitors of GABA uptake e.g. vigabatrin or metabolism e.g. tiagabine should also have anti-anxiety effects. Indeed, there are reports of their...

Animal Models Of Anxiety

All preclinical animal models of anxiety involve exposing animals usually rats or mice to environmental stimuli that disrupt their normal pattern of behaviour Table 19.2 . Obviously, it can never be confirmed that animals are actually experiencing the equivalent of human anxiety and so the validity of all preclinical models rests largely on confirming that the change in behaviour is prevented by drugs that have established anti-anxiety effects in humans. An influential theory proposed by Gray...

Calcium Channels Transmitter Release

When an action potential arrives at the axon terminal, it induces the release of a chemical transmitter. Transmitter release is a Ca2 -dependent process see Chapter 4 and requires a charge of Ca2 . This is provided through the action potential-induced Low threshold around 60 mV high threshold around 40 mV. 2s soma d dendrites t axon terminals. Low threshold around 60 mV high threshold around 40 mV. 2s soma d dendrites t axon terminals. opening of voltage-gated Ca2 channels. A variety of Ca2...

Antiepileptic Drugs Aeds

Anticonvulsants Drugs Structures

There is no shortage of AEDs Fig. 16.7 but it is not appropriate to consider them in detail in this text other than to see how their mechanisms of action comply with and illustrate those proposed above Fig. 16.6 for the control of epileptic seizures see Meldrum 1996 Upton 1994 . The decision on which drug to use depends not only on their proven efficacy in a particular type of epilepsy some drugs are inactive in certain forms but also what side-effects they have many are sedative how they...