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Neurotransmitters Flashcards

1
Q

What are the two families of ligand-gated ion (ionotropic) receptors?

A

Cys-loop family and glutamate receptor family

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2
Q

what is the difference between the two ionotropic receptor families, and what is the similarity in their structures?

A

-Cys-loop receptor have a pentameric subunit structure
-Glutamate receptors have four subunits
-In both, the subunits are clustered around a central pore

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3
Q

How is it possible to get receptors with distinct pharmacology and physiology?

A

There are numerous subunit isoforms and receptos can be assembled from several subunit combinations

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4
Q

In the cys-loop family, what does each subunit consist of?

A

Extracellular N and C terminals and four transmembrane alpha-helical segments (M1-M4).

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5
Q

In the cys-loop family, what do receptors have for agonist binding ?

A

Alpha subunits. A disulphide bond between two cysteine residues at the N-terminus forms a loop required for binding

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6
Q

What forms the ion pore of the cys-loop receptors?

A

The M2 domains of the alpha subunits

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7
Q

Nicotinic receptors are divided into which two types? what is the structural differences?

A

Muscle types (assembled from alpha-1, beta-1, delta, y or e subunits in a 2:1:1:1 stoichiometry) and neuronal types (various combinations of 12 subunits alpha2-alpha10 and beta2-beta4)

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8
Q

What do the nicotinic receptors bind?

A

Each receptor binds two molecules of acetylcholine

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9
Q

What is allostery?

A

Binding of one molecule ACh to receptor makes binding of the second one easier.

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10
Q

What cations do nicotinic receptors conduct and in which direction?

A

they allow Na influx, K efflux, some configurations (homomeric alpa7) are calcium conductances. The net current is inward, so ACH is excitatory at nicotinic receptors.

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11
Q

GABA receptor activation opens a channel selective for chloride, usually resulting in ipsps, when is it excitatory?

A

In some neurons, especially in the embryo, the internal chloride concentration is so high that the chloride reversal potential is closer to zero than the resting potential.

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12
Q

How many GABA receptors have been identified?

A

11

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13
Q

GABA receptors contain binding sites for which endogenous agents and which drugs?

A

Endogenous: Endozepines and neurosteroids
Drugs: Benzos, Barbiturates, ethanol and volatile anaesthetics

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14
Q

Where do compounds, other than GABA bind on the GABA receptors, how do they act on these receptors?

A

they bind to a variety of sites distinct from the GABA-binding site. They act by allosterically altering the binding of GABA and thereby modulating the chloride current.

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15
Q

What is the effect of typical benzodiazepines on the GABA receptors?

A

They increase the affinity of the receptor for GABA, which causes the chloride channel to open more frequently. It potentiates the GABA effect without prolonging it.

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16
Q

On which receptors does diazepam act on to exert different effects?

A

it exerts its anti-anxiety and muscle relaxant effects via receptors containing alpha-2 subunits but its sedative and anti-convulsant effects through alpha-1 containing receptors

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17
Q

What do inverse agonists go to GABA receptors?

A

They bind the benzodiazpine-binding site and decrease channel opening

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18
Q

What are endogenous inverse agonists of GABA receptors?

A

Endozepines- peptides released by astrocytes

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19
Q

What are the effects of endozepines at different receptors

A

GABA- Increase anxiety. They bind to Gprotein coupled receptors. NPY/AgRP- anorexigenic effects. act on POMC/CART neurons in the hypothalamus

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20
Q

What are neurosteroids?

A

Endogenous steroids active in the brain. they include pregnenolone and dehydroepiandosterone and their sulphates.

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21
Q

Where are neurosteroids produced?

A

In the peripheral and central nervous system by glial cells and neurons, supplemented by gonadal and adrenal steroids which easily cross the BBB. They are produced during stress, the luteal phase of the menstrual cycle and reach high levels during pregnancy

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22
Q

What do neurosteroids act on ?

A

GABA receptors: the potentiate GABA activated currents, and NMDA receptors

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23
Q

What is the effect of neurosteroids?

A

Anxiolytic, anticonvulsant, possibly antidepressant

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24
Q

What is the structure of inotropic glutamate receptors

A

Tetrameric, quaternary structure and share weak homologies with the cys-loop family

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25
Q

What are the three populations of glutamate receptors (defined by selective agonists)?

A

AMPA receptors, kainate receptors an NMDA receptors. All are nonselective cation channels, though NMDA and AMPA favour calcium permeation

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26
Q

What is the secondary structure for the AMPA and kainate receptor subunits?

A

4 membrane spanning segments, one of which (MII) is on a re-entrant loop which contributes to the core.

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27
Q

Four subunits, Glur1-Glur4, contribute to AMPA receptors, what are the special roles of Glur2 subunits in AMPA receptors?

A

-control voltage gating of the receptor
-Come in two forms that differ in their MII region (changes cation preference)
- Control transport of receptor to the Post synaptic membrane
-stimulates the growth of dendritic spines on cortical pyramidal cells.

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28
Q

What is the NMDA receptor named after

A

N-methyl-D-aspartate

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29
Q

What are the natural agonists of NMDA receptors?

A

Glutamate and aspartate

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30
Q

what is the importance of NMDA receptors?

A

implicated in key aspects of brain function such as development, learning and memory, and pathologies, for example stroke and epilepsy

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31
Q

What is the structure of NMDA receptors subunits?

A

They are heterotetramers containing two NR1 and two NR2 subunits. There are 8 NR1 isoforms (expressed ubiquitously in the brain) and 4 NR2 isoforms (expressed in a region specific way). There are 2 NR3 isoforms that confer inhibitory properties

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32
Q

Where do the neurotransmitters and co-agonists bind on the NMDA receptors?

A

The extracellular N-terminal domain of the NR2 subunits bind the neurotransmitter while the extracellular domain between MIII and MIV is a modulatory domain that binds the co-agonists glycine or serine. The extensive cytoplasmic domain has phosphorylation sites and regions for binding structural proteins

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33
Q

Where is D-serine released from?

A

It is synthesized and released by astrocytes co-localized with neurons containing NMDA receptors. May also be released by neurons.

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34
Q

What is required for the opening of the ion channel in NMDA receptors?

A

Glutamate has to bind and receptor must experience depolarisation at the same time. The blockade of the channel by Mg2+ will then be lifted.

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35
Q

What is the NMDA ion channel permeable to?

A

Calcium, potassium and sodium

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36
Q

What feature of NMDA receptors is critical for long term potentiation and long term depression of a neuron?

A

Activation of the NMDA receptors raises intracellular calcium concentrations, this can activate several second messenger cascades, many of which alter AMPA receptor functions.

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37
Q

What are most NMDA receptor types inhibited by?

A

H+, and show partial inhibition at physiological pH.
It is also blocked by Zn2+ ions and Pb2+ is a potent antagonist.

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38
Q

What site on the NMDA receptors is presumably the target for endogenous redox agents such as glutathione?

A

A redox modulatory site, where reductants enhance and oxidants depress NMDA channel activity

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39
Q

What drugs target NMDA receptors?

A

Dissociative anesthetics, nitrous oxide, several opiates and phencyclidine

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40
Q

What is the iconic feature of G-protein coupled receptors

A

the seven membrane spanning segments (MI-MVII). The third cytoplasmic loop between MVI and MV couples to G proteins that are critical for signal transduction.

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41
Q

What do GPCRs bind?

A

Small molecules (amines and glutamate) and a wide variety of peptides

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42
Q

What is the structure of G proteins?

A

They are trimers, consisting of alpha, beta and y- subunits . the alpha subunit binds GTP.

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43
Q

Binding of a neurotransmitter to GPCRs activate their associated G protein which may lead to what?

A

-They may interact directly with ion channels causing them to open or close OR
- They may interact with enzymes to switch on or off second messenger cascades that regulate ion channels and other proteins by phosphorylation

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44
Q

Binding of the transmitter allows the G protein and receptor to couple, what happens at the G protein next?

A

GDP leaves the alpha subunit in exchange for GTP –> G protein dissociates into alpha and B/y subunits. The alpha subunit activates a second messenger enzyme.

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45
Q

How does the second messenger enzyme activated by the GPCR return to basal activity?

A

The alpha subunit cleaves the terminal phosphodiester bond in the GTP converting to GDP. the alpha subunit in this form uncouples from the enzyme

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46
Q

How does the GPCR cycle amplify the effect of a small signal?

A

A single transmitter-binding event results in several cycles of G protein shuttling between receptor and enzyme. The enzyme will catalyse the synthesis of hundreds of second messenger molecules before it is switched off by the hydrolysis of GTP.

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47
Q

Which family of G receptors activate adenyl cyclase?

A

Gs Proteins.

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48
Q

What does adenyl cyclase catalyse?`

A

The conversion of ATP to cAMP –> diffuses freely through cytoplasm and binds to a kinase enzyme Protein Kinase A (PKA), which is switched on

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49
Q

What does protein kinase A do?

A

Phosphorylates target proteins that have the appropriate amino acid sequence to recognise the kinase. Targets include ion channels and transcription factors

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50
Q

How does the cAMP system turn off the second messenger systems?

A

-cAMP in hydrolysed to AMP by the action of a phosphodiesterase in the cytoplasm
-Phosphatases responsible for dephosphorylating target proteins
-Prolonged occupation of the receptor by transmitter causes it to desensitise.

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51
Q

What is the process of GPCR desensitisation?

A

-Phosphorylation of a specific kinase that recognises the agonist-bound form of the receptor followed by the binding of an arrestin protein. the resulting complex is unable to recognise the G protein

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52
Q

Which GPCRs inhibit the activity of adenyl cyclase?

A

G1 receptors

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53
Q

Gq Coupled receptors activate what enzyme?

A

Phospholipase C

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54
Q

What process does phospholipase C catalyse?

A

The enzyme cleaves a minor phospholipid in the inner leaflet of the plasma membrane (PIP2) to give diacylglycerol and IP3

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55
Q

What does diacylglycerol activate?

A

Protein Kinase A

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56
Q

What is the target of IP3?

A

IP3 receptor, and IP3 gated calcium channel in the membrane of the smooth endoplasmic reticulum and sarcoplasmic reticulum that acts as an intracellular calcium store.

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57
Q

What is the effect of IP3 binding to IP3 receptors?

A

Calcium channels open –> calcium flows out of the SER into the cytosol

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58
Q

Neurons contain a calcium binding protein called calmodulin, what is its function?

A

On binding calcium, it activates a number of enzymes including CaMKII–>mediate the effects of raised intracellular calcium such as changes in membrane permeability and gene expression

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59
Q

What are the major excitatory neurotranmsitters

A

Glutamate and Aspartate

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60
Q

How and where is glutamate synthesised?

A

It is synthesised in neurons from glutamine, a reaction catalysed by glutaminase. Glutamate is then pumped into vesicles

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61
Q

After leaving the synaptic cleft, what happens to glutamate?

A

In neurons, it is proably metabolised although some may be recycled as a transmitter. In glia glutamate is converted by glutamine synthetase to glutamine which then gets into extracellular space for uptake by neurons

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62
Q

What receptors does glutamate act on?

A

AMPA, kainate and NMDA, and on metabotropic receptors (GPCRs)

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62
Q

What receptors does glutamate act on?

A

AMPA, kainate and NMDA, and on metabotropic receptors (GPCRs)

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63
Q

What are the major inhibitory neurotransmitters

A

Gamma-amino butyrate and glycine

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64
Q

Where does glycine have a higher abundance?

A

Brainstem and spinal cord

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65
Q

How is GABA synthesised?

A

It is synthesized from glutamate by glutamic acid decarboxylase

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66
Q

What happens after GABA re uptake?

A

It is catabolized to succinic semi-aldehyde by the mitchondrial enzyme GABA transaminase

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67
Q

Which receptors does GABA act on

A

GABAa- Ligand-gated chloride channels
GABAb- GPCRs

68
Q

How can the responses of the two classes of GABA receptor be discriminated?

A

GABAa antagonist bicuculiline and GABAb agonist baclofen

69
Q

How is glycine synthesised

A

From serine by mitochondrial serine transhydroxymethylase

70
Q

Which cells use glycine as a transmitter and what is its overall effect?

A

Renshaw cells inhibit motor neurons that excite them (recurrent inhibition). It serves to dampen the output of the motor neurons

71
Q

What does the glycine receptor resemble?

A

the GABAa receptors, and is a chloride channel

72
Q

what are the glycine receptors blocked by?

A

strychnine, tetanus toxin blocks glycine release. both are convulsants as they remove renshaw cell inhibition

73
Q

Where are dopamine neurons generally found?

A

Retinal amacrine cells, olfactory bulb and autonomic ganglia. Most are confined to a few nuclei in the brainstem sending axons to many regions in the forebrain. 80% are found in the zona compacta of the Substantia Nigra (A9 group of catecholaminergic cells)

74
Q

Where do Dopamine neurons in the substantia nigra project to, what is their function?

A

to the striatum as the nigrostriatal pathway. Involved in the basal ganglia regulation of movement.

75
Q

Where do dopamine cell clusters (A8 and A10) in the ventral tegmentum project to? What are they implicated in?

A

To limbic structures or to associated cortical areas (Medial prefrontal and cingulate cortex), giving rise to the mesolimbic and mesocortical systems. They are implicated in motivation, drug addiction and Schizophrenia

76
Q

Where do dopaminergic cells in the hypothalamus project axons to? What is its function?

A

To the pituitary in the tuberoinfundibular pathway, to inhibit secretion of prolactin or growth hormone

77
Q

What is the structure of dopaminergic neurons?

A

Small, with a thin unmyelinated axon, which arises from one of the dendrites, which bears numerous varicosities along its length

78
Q

What are the properties of action potentials generated in dopamine neurons?

A

They are long lasting (2-5ms) and propagated very slowly (0.5 m.s-1)

79
Q

What is the precursor for the catecholamine transmitters?

A

The amino acid L-tyrosine

80
Q

How is L-tyrosine converted to dopamine

A

it is hydroxylated by tyrosine hydroxylase to give 3,4-dihydroxy phenylalanine (L-dopa) which is decarboxylated by L-aromatic amino acid decarboxylase to give dopamine

81
Q

What is the rate-limiting step of catecholamine synthesis?

A

The hydroxylation of tyrosine

82
Q

How is tyrosine hydroxylase regulated?

A
  • Increased expression of TH genes, leading to de novo synthesis of the enzyme
    -Phosphorylation by protein kinases which increases its activity
    -End point inhibition by catecholamines
83
Q

How is dopamine taken into vesicles?

A

It is taken by a vesicular monoamine transporter, which actively transports catecholamines and serotonin using the co-transport of protons from the vesicle to provide the energy

84
Q

What are VMATs blocked by, and what is the effect?

A

The drug reserpine, by preventing vesicular storage, drastically impairs monoamine neurotransmission

85
Q

How is dopamine inactivated?

A

Inactivation is by diffusion and reuptake into the nerve cell by a high affinity Na/Cl dependant dopamine transporter. This transporter is competitively inhibited by cocaine and amphetamines. Neurons releasing dopamine into the hypothalamic-pituitary portal system lack the transporters

86
Q

What are the primary dopamine metabolites in the CNS?

A

Homovanillic acid and dihydroxyphenyl acetic acid

87
Q

What is the fate of dopamine released into the cleft which escapes reuptake?

A

It is catabolised to homovanillic acid via the sequential action of catechol-O-methyl transferase (COMT) and monamine oxidase (MOA). Both of which are present in neuronal membranes

88
Q

What happens to cytoplasmic dopamine that is not transported into vesicles?

A

Remains free in axon where it is catabolized by MAO located on the outer membrane of mitochondria, then by aldehyde dehydrogenase, to dihydroxyphenyl acetic acid

89
Q

What are the two families of of dopamine receptors (GPCRs)?

A

the D1 family (D1 and D5) are coupled to Gs and activate adenylyl cyclase to increase cAMP synthesis. The D2 family (D2,D3,D4) are coupled to Gi and inhibit adenylyl cyclase

90
Q

Where are D1 receptors mostly located?

A

In the striatum and substantia nigra.

91
Q

There are two variants of the D(2) receptors?

A

The short variant is an autoreceptor on nigrostriatal and ventral tegmental neurons, where it regulates dopamine synthesis by lowering cAMP [] and phosphorylation of TH. The long variant is postsynaptic in the striatum.

92
Q

What is the function of D(3) receptors?

A

They are presynaptic autoreceptors and reduce dopamine release by closing presynaptic calcium channels

93
Q

Where are D(4) and D(5) receptors located?

A

D4 are more abundant in the cortex than striatum. D5 receptors are widely distributed in the brain

94
Q

Which receptors does bromocriptine have a higher affinity to, and haloperidol block more strongly?

A

D2 more strongly than D1

95
Q

What is the target for clozapine ?

A

It is a fairly selective D4 receptor antagonist

96
Q

Where are cell bodies of noradrenergic neurons located?

A

In the pons and medulla (cell groups A1-A6, except A3).

97
Q

Where do noradrenergic neurons send their axons to?

A

The most caudal groups (A1 and A2) send their axons into the spinal cord where they form synapses with the terminals of primary afferents. The others project in two bundles, the dorsal and ventral bundle which unite to form the medial forebrain bundle –> hypothalamus, amygdala, thalamus, limbic structures, hippocampus and neocortex

98
Q

Which is the major noradrenergic cell group?

A

Locus coeruleus (group A6), contributes to the dorsal noradrenergic bundle and projects to the cerebellum.

99
Q

What is the structure of noradrenergic neurons?

A

They are small with fine, highly branched axons that ramify widely. The axons bear varicosities along their length, but they do not form synaptic contacts, so noradrenaline is able to diffuse to reach widespread targets (volume transmission)

100
Q

What is an important function of noradrenaline?

A

It is implicated in sleep-wake cycles and in maintaining arousal, firing of noradrenergic cells is low in sleeping animals and increases with arousal level. It increases the signal-to-noise ratio of cortical processing

101
Q

What are the steps of noradrenaline synthesis?

A

First steps require the synthesis of dopamine from tyrosine. Dopamine-b-hydroxylase, present in the vesicle membrane, catlyzes the synthesis of noradrenaline

102
Q

How is noradrenaline converted to adrenaline

A

Phenyletholamine N-methyltransferase catalyses the N-methylation of noradrenaline to adrenaline

103
Q

What is the rate-limiting step in NA synthesis and why is this the case?

A

Dopamine-Beta-hydroxylase, as high activity in the locus coerulus results in increases expression of the tyrosine hydroxylase genes and de novo synthesis of the genes

104
Q

What are the key mechanisms of removing NA from the synapse?

A

Diffusion and reuptake

105
Q

What is the structure of the NA transporter?

A

It is a saturable NA/CL dependent transporter, it shares homology with the dopamine receptor. It is inhibited by TCAs.

106
Q

What is the process of metabolic degradation of NA in the CNS?

A

MOA catalyses formation of 3,4-dihydroxy phenylglycoaldehyde which is reduced to the corresponding alcohol (DOPEG)–> methylated by COMT to give MOPEG–> excreted in urine

107
Q

What are the properties of alpha1 NA receptors?

A

Typically postsynaptic and coupled via Gq to phosphlipase C

108
Q

What is the effect of activating alpha1 and beta NA receptors?

A

They are excitatory by increasing the concentration of second messenger inositol triphosphate and diacylglycerol concentrations. Beta receptors are coupled to Gs proteins and raise cAMP levels

109
Q

What is the structure and function of alpha2 receptors in the CNS

A

Presynaptic autoreceptors, reducing NA release by lowering cAMP-mediated phosphorylation of calcium channels

110
Q

What is the effect of presynaptic beta NA receptors found on noradrenergic terminals in the brain?

A

Facilitate NA release by increasing cAMP mediated phosphorylation and opening calcium channels

111
Q

What important drugs act on NA receptors, and which are they selective for?

A

Phenylephrine, clonidine and isoproterenol act as fairly selective agonists of alpha1, alpha2 and beta receptors respectively. Prasozin blocks alpha responses. beta blockers are selective beta antagonists

112
Q

Where are serotonin neurons found?

A

Clusters of neurons (B1-B9) are scattered throughout the brainstem, mostly towards the midline in the raphe nuclei

113
Q

Where do serotonin neurons projecting to the spinal cord terminate and what is the function?

A

Terminate in the dorsal horn, they reduce nociceptor input into the spinothalamic tract

114
Q

Where do forward projections of serotonin neurons project to? What is their function and What are they inhibited by?

A

They run in the medial forebrain bundle to go to the hypothalamus, amygdala, striatum, thalamus, hippocampus and neocortex. They are involved in the expression of anxiety, inhibited by GABAergic neurons.

115
Q

What is serotonin transmission modulated by?

A

Social status

116
Q

What effects does serotonin have?

A

Effects Mood. Deficits are associated with depression and increased risk of suicide. Serotonin is also involved in sleep, satiety and regulation of CSF secretion and cerebral blood flow.

117
Q

What is the precursor of serotonin?

A

Tryptophan, therefore plasma concentration of tryptophan, which varies according to dietary intake, can alter brain serotonin levels

118
Q

What is the rate limiting step of serotonin synthesis

A

Tryptophan is hydroxylated by tryptophan hydroxylase to give 5-hydroxytryptophan (5-HTP)

119
Q

What is the final step of serotonin synthesis?

A

Decarboxylation of 5-HTP by L-aromatic amino acid decarboxylase gives serotonin or 5-hydroxytryptamine (5-HT)

120
Q

What is serotonin synthesis matched to?

A

Firing frequency of the neuron. Higher firing rates allow increased Ca2+-dependent phosphorylation of tryptophan hydroxylase, the activity of which goes up

121
Q

What terminates the action of serotonin?

A

Diffusion and reuptake via a saturable Na/Cl dependent transporter.

122
Q

Oxidative deamination produces of serotonin by MOA yields which metabolite?

A

5-hydroxyindoleacetic acid (5-HIAA)

123
Q

All serotonin receptors are GPCRs except for which one?

A

5-HT3

124
Q

Which serotonin receptor subtypes decrease cAMP?

A

5-HT1

125
Q

Which serotonin receptor subtypes increase cAMP?

A

5-HT4; 5-HT7

126
Q

What is the effect of the 5HT2 subtypes of serotonin receptors?

A

they are coupled via Gq to phospholipase C, so are excitatory by increasing inositol triphosphate and diacylglycerol

127
Q

Which serotonin receptor subtypes are putative ?

A

5-ht5, 5-ht6

128
Q

What is the structure of 5-HT3 receptors?

A

These are ligand-gated channels similar to the nicotinic receptor and form pentamers. There are several isoforms

129
Q

What is the function of 5-HT3 receptors?

A

As cation conductances they mediate fast depolarisation and are distributed widely in the nervous system

130
Q

A number of drugs that bind to nicotinic receptors, also bind to 5-HT3 receptors, but there are selective antagonists at some isoforms, what is an example of this?

A

Anti-emetics (eg odansetron) block 5-HT3 receptors in the area postrema, the chemosensitive cells of which trigger vomiting in response to toxins in the blood

131
Q

Which serotonin receptor subtypes are autoreceptors that inhibit the release of serotonin?

A

5-HT1A

132
Q

Agents that have proved to be anti-anxiety agents work on which serotonin receptors?

A

5-HT2 and 5-HT3 antagonists and 5-HT1A agonists

133
Q

Where are cholinergic neurons usually found?

A

Motor neurons in the motor nuclei of cranial nerves and ventral horn of the spinal cord, preganglionic autonomic neurons, interneurons in the striatum and nucleus accumbens, pontine reticular formation, nucelues basalis of Meynert and the medial septum giving rise to the septohippocampal pathway

134
Q

Where does the pontine reticular formation project to and what is its functions?

A

Sends axons to the spinal cord or forward to the amygdala, thalamus and basal forebrain. These are important in regulating sleep and wakefulness.

135
Q

What do lesions in the nucleus basalis of Meynert produce?

A

Impairment in recall for tasks learnt before the surgery and in acquisition of new learning

136
Q

How do ACH neurons produce long-term facilitation of neurons in the neocortex and hippocampus?

A

Act at muscarinic receptors to close potassium channels, making the cells more likely to fire in response to excitatory inputs, hence the forebrain cholinergic system seems to be selective arousal system, activated by rewarding or salient events, which facilitates learning

137
Q

How is acetylcholine synthesised?

A

From choline and acetyl coA, catalysed by choline acetyl transferase (ChAT). Acetyl coA is derived from glycolysis and must be transported out of the mitochondria of neurons (rate-limiting step)Choline is taken up Via a Na dependant choline transporter that is saturated at plasma choline concentrations.

138
Q

How is Ach loaded into vesicles?

A

Via a transporter that is related to the vesicular monoamine transporters.

139
Q

How is the action of Ach terminated?

A

By hydrolysis in the cleft to choline and acetate by acetylcholinesterase (AChE)

140
Q

Nicotininic Ach receptors are ligand-gated channels, what are some of the functions?

A

-Mediate fast ACH transmission from septum to GABAergic interneurons in the hippocampus, helping to synchronize the rhythmic firing of pyramidal cells
-Mediate fast Ach transmission from the brainstem to the ventral tegmental area, stimulating dopamine reward pathways
Presynaptic nicotinic receptors enhance NT release at many sites. Mediate fast transmission at the NMJ between motor neurons and skeletal muscle.

141
Q

What suggests that nicotinic receptors play a role in memory?

A

They potentiate glutamate transmission at NMDA but not AMPA receptors

142
Q

Slow cholinergic transmission is mediated by muscarinic receptors (5 Subtypes), what are the effects of these receptors?

A

M1, M3, M5, are coupled via Gq to phospholipase second messenger system so are excitatory by elevating inositol trisphosphate and diacylglycerol. M2 and M4 decrease cAMP. M1 receptors also facilitate cortical neuron responses to excitatory input (by closing Km potassium channels) and learning

143
Q

What drugs act on muscarinic receptors?

A

All muscarinic receptor responses can be blocked by atropine. M1 receptors (post synaptic) blocked by pirenzipine. M2 (presynaptic autoreceptors) blocked by methoctamine.

144
Q

Which acetylcholine receptors are found in the autonomic system?

A

In the PNS, both nicotinic and mucarinic receptors are involved in cholinergic transmission in the autonomic ganglia, only muscarinic receptors in the neuroeffector junctions of the ANS.

145
Q

Which are the purine transmitters?

A

ATP and adenosine

146
Q

Where is ATP stored?

A

In synaptic vesicles

147
Q

Where is ATP co-released from ?

A

Co-released with classical transmitters for postganglionic autonomic fibers and central synapses.

148
Q

What are the two families of receptor for ATP?

A

P2x receptors, ligand-gated ion channels permeable to Na, K, Ca2+ and exert excitatory effects. P2y receptors, GPCRs excitatory by stimulating phospholipase C and/or adenylyl cyclase.

149
Q

What is ATP synaptically inactivated by?

A

ecto-5-nucleotidase

150
Q

4 examples of ATP transmission?

A

1.Fast phase of smooth muscle contraction in response to sympathetic stimulation
2.Excitation of dorsal horn cells and motor neurons in the spinal cord by ATP release from primary afferents
3.CA3 region of the hippocampus
4. Nociceptor signalling at numerous sites

151
Q

Why is adenosine an atypical transmitter?

A

Not stored in a vesicle or released in a calcium-dependant way

152
Q

How is adenosine generated?

A

Locally by enzyme-catalysed breakdown of released ADP and ATP.

153
Q

What is the effect of adenosine receptors?

A

GPCRs that modulate cAMP

154
Q

How are the synaptic actions of adenosine inactivated

A

By a nucleoside transporter

155
Q

2 examples of adenosine transmission?

A

-Terminate epileptic seizures
- Protects neurons from oxidative stress

156
Q

How are peptides grouped into families?

A

Similarities in their amino acid sequence, being derived from a common large precursor polypeptide encoded by a single mRNA molecule (different cells may process the same precursor or its mRNA in different ways).

157
Q

The first peptide transmitter to be discovered was substance P (SP). It is an excitatory transmitter in which regions of the brain?

A

Cerebral cortex, striatum and substantia nigra

158
Q

Where is substance P released from, and what are the effects?

A

It is released by both central and peripheral terminals of C fiber primary afferents. Central terminals synapse with dorsal horns to convey information about pain and temperature. Rela

159
Q

Where is substance P released from, and what are the effects?

A

It is released by both central and peripheral terminals of C fiber primary afferents. Central terminals synapse with dorsal horns to convey information about pain and temperature. Release from peripheral terminals results in neurogenic inflammation. S-P containing terminals also found adjacent to cerebral blood vessels and may play a role in migraine and other headaches

160
Q

The gene which codes for substance P encodes which other transmitters of the tachykinin family?

A

Substance K, Neurokinins A and B

161
Q

What are the three tachykinin receptors?

A

GPCRs (NK1, NK2, NK3) coupled to phospholipase C and (for NK1 and NK2)
increase in cAMP.

162
Q

Which receptor is Substance P the preferred ligand for?

A

Nk1

163
Q

Which classical transmitters are opioids typically released with

A

GABA and serotonin

164
Q

Which three precursor genes encode for opioids?

A

Enkephalin precursor–> met-enkephalin and leu-enkephalin (expressed mainly in short interneurons throughout the brain)
Pro-opiomelanocortin–> beta-endorphin (expressed in the hypothalamus)
Dynorphin –> leu-enkephalin and dynorphins

165
Q

What is the effect of the opioid GPCRs?

A

They allow direct coupling of G proteins to ion channels. By opening potassium channels and closing calcium channels, they hyperpolarize neurons

166
Q

What are the two peptides that have a high affinity and specificity for u opioid receptors?

A

Endomorphins (no gene or precursor protein has been found)

167
Q

What other receptors do opioids interact with?

A

NMDA receptors and o (sigma) receptors

Neuroscience (15 decks)

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