Drugs and Brain Function

Drug Treatments For Anxiety

Anxiety Chemical

The oldest anti-anxiety agent is undoubtedly alcohol and it is certain that this drug is still routinely self-administered for this purpose. Towards the end of the eighteenth century, bromide salts were used to relieve conditions akin to anxiety despite the risk of a characteristic toxic delirium, known as 'bromism'. Alternative treatments, such as paraldehyde and chloral hydrate, were also widely used but these too had adverse effects the former can cause psychosis but the latter is still used...

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...

Dopamine Receptors Function And Synergism

With the discovery of five distinct DA receptors within two major families, one might hope that the effects of the different DA pathways would be mediated through different receptors. Unfortunately this is not the case. As indicated above, it is generally the D2 receptor that is important. Thus only D2 antagonists have anti-emetic activity and only D2 agonists, like bromocriptine, reduce plasma prolactin levels. In schizophrenia it is again the D2 antagonists that are effective, although D1 and...

Basis For Dependence

The production of dependence (physical) by the depressant drugs is thought to result from an adaptation of the CNS to the altered environment due to chronic drug use. In the case of the depressant drugs the CNS is believed to establish a new homeostatic state by supersensitivity of the pathways involved, counteracting the drug depression. When the drug is discontinued the depressive effect is removed and dramatic withdrawal symptoms result from this supersensitivity. Since opiates act on...

Major Problems Of Drug Dependence And Abuse

(1) Overdose doses are unknown as is purity (2) Crime as a result of need to obtain drug (3) Withdrawal symptoms may be life-threatening with alcohol (5) Acute effects of a particular drug and the chronic pathological effects (6) AIDS, hepatitis, etc. as a result of injections. Injection of tablets The relative importance of these factors will depend on a particular drug, the individual and other factors. Some users are heavily dependent (the prototype addict), others use the drug in very...

Dopamine Receptors

Dopamin Receptors Classification

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...

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,...

NMDA receptors

The NMDA receptors come in four main flavours depending on which NR2 subunit (or subunits) is involved in forming the receptor (Table 3.2). Functional NMDA receptors result from the co-assembly of one or more members of three different subfamilies of subunits NR1, NR2 and NR3. The NR1 family is composed of one subunit with nine different alternatively spliced variants. Block by NMDA channel blockers such as ketamine, MK-801 and phencyclidine is affected by which splice variant of the NR1...

Cholinergic Pathways And Function

Cholinergic Pathways The Brain

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...

Pathways Within The

Drugs And Brain Function

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...

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...

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...

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...

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...

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...

Neurotransmitter Changes In AzD

The NT most consistently implicated in AzD is ACh. It is 20 years since a 50 reduction was noted in the level of choline acetyltransferase (ChAT), the enzyme responsible for ACh synthesis, in the frontal cortex and hippocampus of AzD patients (Bowen et al. 1976). This has since been confirmed by others (see Perry 1986). ACh itself was not easily measured at that time but a reduced synthesis of ACh from 14C glucose was observed in brain tissue from AzD patients. There is in fact a significant...

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)...

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,...

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...

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...

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...

Neuronal Excitability

Drug Use And Brain Function

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...

Recording Neural Activity

Drug Patch Pipette

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...

Voltammetry

Drugs And Brain Function

This can be carried out in vitro (in brain slices, cultured cell preparations) or in vivo and involves penetrating the experimental tissue with a carbon-fibre electrode of 5-30 p,m in diameter (Fig. 4.9). This serves as an oxidising electrode and the Faradaic current generated by the oxidation of solutes on the surface of the electrode is proportional to their concentration. Obviously, only neurotransmitters which can be oxidised can be measured in this way so the technique is mainly limited to...

Vesicular Exocytosis

Brain Function With Heroin

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...

Gabaa receptor pharmacology

Drugs And Brain Function

GABAA receptors are classically defined by their sensitivity to the antagonist bicuculline. Other widely used antagonists include SR-95531 (gabazine), picrotoxin, and cage convulsants such as TBPS (t-butylbicyclophosphorothionate). Like bicucul-line, SR-95531 is a competitive antagonist acting at the GABA binding site while picrotoxin and TBPS are non-competitive, acting at a site which may be more closely associated with the chloride ion channel. Of these antagonists, only bicuculline is...

Therapy Outline

Drugs And Brain Function

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...

Synaptosomes

Synaptosomes are 'pinched-off' nerve terminals which become severed from the parent axon during gentle homogenisation of brain tissue and then subsequently reseal. They Figure 4.1 Turnover of classical neurotransmitters. At normal rates of neuronal activity, endogenous stores of neurotransmitter are maintained at constant (steady-state) levels, indicating that the supply of new neurotransmitter (through synthesis) meets the demand (determined by release and metabolism). Consequently, the rate...

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...

Neurons Structure And Environment

Axo Axonic

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...

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...

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...

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...

Central Events In The Transmission Of Pain

Spinal Cord Laminae And Pain Fiber

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...

References

Attwell, D, Barbour, B and Szatkowski, M (1993) Nonvesicular release of neurotransmitter. Neuron 11 401-407. Basbaum, CB and Heuser, JE (1979) Morphological studies of stimulated adrenergic axon varicosities in the mouse vas deferens. J. Cell Biol. 80 310-325. Benfanati, F, Onofri, F and Giovedi, S (1999) Protein-protein interactions and protein modules in the control of transmitter release. Phil. Trans. Roy. Soc. Lond. B 354 243-257. Burnstock, G (1990) Noradrenaline and ATP as cotransmitters...

Maprotiline

Citalopram Brain Serotonin

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...

Name Of Sleeping Drug In Brain

Names Sleeping Pills

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...

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...

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...

Central Functions

Dopaminergic Pathway Motor Function

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...

Neurotransmitters In Epileptic Activity

Changes in NT levels and function have been (1) Looked for in (b) animals in which convulsions have been induced experimentally (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...

Atypical Neuroleptics

Neuroleptic Drugs And Function

Typical neuroleptics reduce the positive symptoms of schizophrenia at the expense of producing EPSs but the so-called atypical neuroleptics have less tendency to cause EPSs. With most of them, e.g. thioridizine, that is the extent of their atypicality but a few others, such as clozapine (and to a lesser extent risperidone and olanzapine) also reduce negative symptoms. Clozapine can even be effective in patients refractory to other neuroleptics. It is clearly a special drug, so special in fact...

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,...

The Action Potential

Recorded 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...

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...

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...

Pharmacokinetics

Pots Syndrome

This is generally accepted as the term to describe the absorption distribution and metabolism of a drug in vivo and it is these factors which determine how quickly and how much of the administered drug can actually reach its site of action (in the CNS) and be maintained there for the required time (see Fig. 5.4). Experimentally drugs are Figure 5.4 Pharmacokinetics. The absorption distribution and fate of drugs in the body. Routes of administration are shown on the left, excretion in the urine...

Neurochemistry Of Gaba

Gaba Metabolism

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,...

Receptormediated Modulation Of Ca2Dependent Transmitter Release

Regulation of transmitter release does not rest solely on the frequency at which nerve impulses reach the terminals. Early experiments using stimulated sympathetic nerve end-organ preparations in situ, or synaptosomes, indicated that release of 3H noradrenaline was attenuated by exposure to unlabelled, exogenous transmitter. This action was attributed to presynaptic adrenoceptors, designated -adrenoceptors, which were functionally distinct from either a1- or -adrenoceptors. Later experiments...

What Does 5ht Do In The Brain

The final challenge is to define the function of 5-HT in the brain. This is not easy because the actions of drugs that target specific receptors leads us to believe that 5-HT helps to regulate mood, anxiety, sleep, body temperature, appetite, sexual behaviour, movement, intestinal motility, cardiovascular function (central and peripheral) and nociception, at least. While a detailed explanation of the physiology of each of these functions is not possible here, and many are covered in appropriate...

An Overview Of The Neurochemistry Of Depression

Separate lines of research have implicated either the noradrenergic, serotonergic or the HPA axis in depression, and there is more evidence, not covered here, that other neuroendocrine systems are involved as well. Yet, all this effort has so far failed to identify disruption of any single transmitter or hormone system as the sole culprit. This points to disruption of the interactions between these different systems as the cause of the problem. Concentrating on the systems highlighted in this...

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...

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...

Noradrenergic Receptors

The division of adrenoceptors into a- and p-types emerged some 50 years ago and was based on the relative potencies of catecholamines in evoking responses in different peripheral tissues. Further subdivision of p-adrenoceptors followed characterisation of their distinctive actions in the heart (pi), where they enhance the rate and force of myocardial contraction and in the bronchi (p2), where they cause relaxation of smooth muscle. The binding profile of selective agonists and antagonists was...

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...

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....

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...

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...

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...

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...

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...

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...

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...

Neurochemistry Of Glycine

Glycine Receptor And Glia

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...

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...

R A Webster

Everybody suffers some intellectual and memory impairment with age. If it becomes very marked or occurs earlier in life (40+) it is known as dementia. Although it may be caused by alcoholism, cardiovascular disease such as multiple infarcts, and is often seen in the later stages of Parkinsonism, the most common cause is a neurodegenerative one, namely, Alzheimer's disease (AzD). In fact this is the primary and sole cause in over half the cases of dementia and is a contributory cause in a...

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...

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...

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...

Agonists And Antagonists

The Structure Agonist Drugs

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...

Druginduced Sleep

Setting aside the general anaesthetics, which do not directly modify the function of any particular neurotransmitter, all the drugs that are used to induce sleep, i.e. the 'hypnotics', augment the function of GABA and so directly depress neuronal function and probably facilitate cortico-thalamic synchrony. Most of them are benzodiazepines and even those that are not, like zopiclone (a cyclopyrrolone) and Zolpidem (an imidazopyridine), act on the benzodiazepine receptor (see Chapter 19). Many...

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...

Activitystateinfluence

Figure 7.8 Dopamine and motor function. When nigrostriatal dopamine activity is normal so is motor function. Any reduction in this DA activity, as in Parkinson's disease, results in reduced motor activity, i.e. akinesia. By contrast, too much DA activity, as in Huntington's Chorea, produces abnormal motor function, i.e. dyskinesia. The latter may be controlled by neuroleptic drugs (DA antagonists) but they can swing the balance in DA activity sufficiently to produce akinesia (Parkinsonism). DA...

Blockade Of Da Pathways In Schizophrenia

There are three main ascending DA pathways in the brain (Fig. 7.2). (1) The nigrostriatal from substantia nigra (SN), the A9 nucleus (2) The mesolimbic from the ventral tegmentum (VTA, A10) to the nucleus accumbens, olfactory tubercule, amygdala and pyriform cortex (3) The mesocortical also from the VTA (A10) but to the prefrontal cortex (PFC) Sometimes (2) and (3) are grouped together and called the mesocorticolimbic pathway. It is not clear which pathway is responsible for which schizophrenic...

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...

Morphological Correlates Of Synaptic Function

Obviously different NTs have different synaptic actions and it is of interest to see to what extent there are morphological correlates for these differing activities. As mentioned previously, an axon generally makes either an axo-dendritic or axo-somatic synapse with another neuron. Gray (1959) has described subcellular features that distinguish these two main types of synapse. Under the electron microscope, his designated type I synaptic contact is like a disk (1-2 pm long) formed by...

Neurotransmitter Classification

The following substances, listed alphabetically, have been widely implicated and generally accepted as neurotransmitters in the central nervous system (CNS), although some, such as glutamate, are much more important than others, e.g. adrenaline. Some classification is appropriate and the simplest and most commonly used is that based on chemical structure with the substances grouped as follows Dopamine (DA), noradrenaline (NA) (adrenaline) 5-Hydroxytryptamine (5-HT, serotonin) Histamine (HIST)...

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)...