Neurotransmitter systems of the brain and their functions

• Neurotransmitter, drugs and brain function// Ed. By R.Webster. Oxford University Press, London. 2001.

• J.R.Cooper, F.E. Bloom, R.H.Roth. The biochemical basis of Neuropharmacology. / Oxford University Press, USA; 2007.

• Е.И.Белова Основы нейрофармакологии Аспект Пресс. Москва. 2010.

1. All biological functions are the output of complex network of interactions of neurons.

In spite of the fact that similar spikes are the output of any neuron, the result of their team work is the complex of physiological and psychological conditions and functions.

2. Different neurons interact by synapse contacts.

3. The information transmition in the chemical synapses is carried out by neurotransmitters.

Schematic representation of a excitatory synapse in the brain

Schematic representation of a neuron

Different synaptic arrangements of a neuron :

a)axo-dendritic, b)B) axo-somatic, c)C) axo-axonicd)D) dendro-dendritic.

What is neurotransmitter?

Neurotransmitter is a substance which is released at the end of a nerve fiber by the arrival of a nerve impulse and by diffusing across the synapse or junction effects the transfer of the impulse to another nerve fiber. (or muscle fiber or some receptor).

Neuromodulators as opposed to neurotrasmitters:• don't have their own effect, they can only modulate

the effect of neurotransmitters. • Their actions are slow and can take hours.• Their receptors are not always placed in synapses, but

on different membranes inside and outside the neuron.

Postsynaptic eventsIonic basis for excitatory postsynaptic potentials (EPSPs) and inhibitory

postsynaptic potentials (IPSPs)

The action potential: ionic conductances underlying the action potential recorded from a squid axon

Transmitter release

Ionotropic receptor

Transmembrane topology of the subunits of three different families of ion channel receptors denoted as 4-TM, 3-TM and

2-TM receptors

Metabotropic receptor

Metabotropic receptor

Four classes G –protein are known:

• Gs – activates adenylyl cyclase

• Gi – inhibits adenylyl cyclase

• Gq – activates

phospholipase-C

• Go – inhibits

voltage-depended Ca2+ and K+ channels

Cholinergic pathways

•BM – nucleus basalis magnocellularis; Ms – medial septum; DB – diagonalis broco; MPO – magnocellular preoptic nucleus; OB – olfactory bulb; PPTN – pedunculo-pontine tegmental nucleus

The model of a acetylcholine synapse

ACh – acetylcholineChAT - choline acetyltransferase AchE - acetylcholine esterase CT - plasma membrane transporter of cholineVAT – vesicular amine transporter.

Nicotinic receptor of acetilcholine

Schematic representation of muscarinic receptor

What does acetylcholine do in the brain?

Acetylcholine helps to regulate: • movement• cortical excitability• arousal and sleep• cognition and reward

The distribution of noradrenerdic neurons in the brain

Brain areas receiving a prominent noradrenergic innervation

Model of a noradrenaline synapse illustrating the presynaptic and postsynaptic events

NE – noradrenaline; DA – dopamine; DOPA – 3,4-dihydroxyphenylalanineAC – adenylyl cyclase; AR - adrenergic receptor; DAG - diacylglycerol; IP3 – inositol triphosphate; PLC – phospholipase C; NET – plasma membrane noradrenaline transporter, VMAT – vesicular monoamine transporter.

Subdivisions of alpha- and beta-adrenoceptor families

• Adrenoceptor

• alpha- beta-

• alpha-1 alpha-2 beta-1 beta-2

What is the function of noradrenaline in the brain?

• influence arousal• selective attention• emotional behaviour

Dopamine neuronal pathways

• AMYG, amygdala; CN, caudate nucleus; MFB, medial forebrain bundle; NcA, nucleus accumbers; OT, olfactory tubercle; PUT, putamen; SN, substantia nigra.

Schematic model of a dopaminergic nerve terminal

Schematic diagram of the anatomical arrangement of D1 and D2 receptors

Central functions of dopamine

• motor activity• psychoses• reward and reinforcement

Dopamine and motor function

5-HT neuronal pathways

Raphe nucnei projections to the brain regions

The synthesis of 5-HT

Model of a serotonin (5-HT) synapse

AC – adenylyl cyclase; DAG, - diacylglycerol; IPS – inositol triphosphate; PLC - phospholipase C; SERT – plasma membrane serotonin transporter; VMAT – vesicular monoamine transporter

Essential features of 5-HT receptor subtypes

• 5-HT1A - thir activation induces hypothermia, increases food intake and reduces anxiety

• 5-HT2A Well-known agonist at these receptors is LSD. All atypical neuroleptics such as clozapine, risperidone, olanzepine act as antagonists of these receptors.

• 5-HT3 receptors are ionotropic. They are best known for their stimulation of transmitter release (DA, NA, ACh, GABA).

• 5-HT4 – agonists of this receptors are being explored as possible cognitive enhancers.

• 5-HT5 – Many used in clinic antipsychotic agents and some antidepressant drugs have high-affinity to this receptor where they act as antagonists.

What does 5-HT do in the brain?

• 5-HT helps to regulate: • mood • anxiety • sleep• body temperature• appetite• sexual behavior• movement• intestinal motility• cardiovascular function • nociception

Different types of GABA neurons in CNS

Fast inhibitory GABA transmition

Chlorine distribution and the GABAA response

Schematic model of the GABAA receptor structure

Structure of GABAA receptor

• Subunit combinations change receptor function

Metabotropic GABA receptors

Pathways for glutamate utilization and metabolism

Receptors of glutamate

• Ionotropic• –AMPA (predominantly Na+/ K+ conductance)• – Kainate (Na+/K+ /Ca2+ conductance)• –NMDA (predomimantly Ca2+, less Na+ conductance) –

potential-dependent• Play distinctive functional role• Can be targets for different drugs

• Metabotropic• –mGluR groups I, II and III Can be implicated in memory, pain, enxiety

Ionotropic receptors of glutamate

NMDA receptor

Functional roles of glutamate receptors

• Epilepsy• Pain• Memory• Excitotoxicity• Development