Introduction to CNS pharmacology

Dr Caroline Stewartc.a.stewart@dundee.ac.uk

Learning Outcomes

• List the principal neurotransmitters of the central nervous system.

• Be aware of the distribution and function of the major neurotransmitters in the brain.

• Describe the processes involved in chemical transmission at central synapses.

• Explain the mechanisms by which drugs gain access to the central nervous system.

What is the central nervous system?

• PNS:– Autonomic

• Sympathetic• parasympathetic

– Somatic

• CNS:– Brain– Spinal cord

Function of the CNS

• Receive and process information (spinal cord is usually the conduit)

• Initiate and maintain appropriate response

– physical– emotional

Components of the CNS

• Neurones• Glial Cells

– Astrocytes– Oligodendrocytes– Ependymal cells– Microglia

• Extracellular space• Ventricular system (CSF)

Organisation of the CNS

• Sensory system• Motor system• Limbic system

Sensory system

Cortex

Specific projection

Sensoryreceptor

Reticular activating system:Regulates arousaland wakefulness

Motor system

Motor cortex

cerebellumbasal gangliavestibular nuclei

Anterior horn cell

Polysynaptic spinal

interneuronesSkeletal muscle

Sensoryreceptor

CNS sensory system

Corticospinal pathway (pyramidal tract)

Extrapyramidal system(motor coordinationand posture)

Limbic system

Cortex

Limbic system

Hypothalamus

Pituitary

GangliaCentres regulating autonomic function and links to others via

medulla (e.g. BP, HR)

Processing of sensory information

Regulation of emotion and mood

Cingulate gyrus

Para-olfactoryarea

Hypothalamus

UncusAmygdala

Para-hippocampalgyrus

Hippocampus

Mamillary bodies ofhypothalamus

Fornix

Thalamus

Anterior nucleus of thalamus

The synapse

• Transmission of information from one neurone to another

Chemical messengers

• Neurotransmitter (fast and slow synaptic transmission)

• Neuromodulator (diffuse, slower action)

• Neurotrophin (long lasting effects on growth and morphology)

Identifying neurotransmitters

• Localisation• Release

• Synaptic mimicry• Synaptic pharmacology

Types of neurotransmitter

• Small molecules– amino acids (glutamate, GABA)– biogenic amines (ACh, NA, DA, 5-HT)

• Neuropeptides– (cholecystokinin, Substance P, enkephalins)

• Diffusable gases– nitric oxide

• Lipid mediators– (e.g. endocannabinoids)

• Neurotrophins– (e.g. nerve growth factor)

• Steroids

Amino acid neurotransmitters

• Glutamic acid (glutamate): principal excitatory transmitter in the brain

• Gamma amino butyric acid (GABA): main inhibitory transmitter in the brain

• Widely distributed• Target for general anaesthetics,

anti-epileptics, anxiolytics.

NH2

O

HO

NH2

O OH O OH

Cholinergic system

• Acetylcholine• Receptors: muscarinic and nicotinic

N+

O

O

Motor control

Learning and memory

Attentional processes

Noradrenergic system

• Noradrenaline/norepinephrine• Receptors: and -adrenoceptors

HO

OH

NH2

OH

Arousal, emotion

Dopaminergic system

• Dopamine• Receptors:D1 and D2 family

HO

HO NH2

Prolactin release

Motivation/reward

Motor control

Serotonergic (5HT) system

• Serotonin (5-hydroxytryptamine)

• Receptors: many subtypes 5HT1, 5HT2, 5HT3

H —

N

HO

NH2

mood, sleep, feeding behaviour and sensory

perception

Analgesia

Neuropeptides

• Synthesised as large precursor polypeptides• Packaged in large dense core vesicles• Substance P and opioid peptides found in

spinal cord and higher brain centres• Play a role in perception of pain

Synaptic transmission (chemical)

Precursor

nTnT

e.g. decarboxylase

Nerve terminal

nT

Postsynapticreceptor

Presynaptic receptor

nT

Transporter

Metabolites

Enzyme

Targets for drug action

• Ion channels• Receptors• Enzymes

• Transport proteins

Blood brain barrier

Brain receives 25-30% of cardiac output but capillaries have no fenestration (holes)

Entry of drugs into brain

• In general, lipid soluble drugs get in, water soluble drugs kept out

• Brain penetration predicted by oil/water partition coefficient (relative solubility in organic solvent compared to water)

• Specific transporters or carrier molecules present

• In some areas of the brain it is more “leaky”• area postrema of medulla• chemoreceptor trigger zone in hypothalamus

Classification of drugs

• By structure e.g. benzodiazepine• By pharmacological action e.g. monoamine

oxidase inhibitor• By clinical action e.g. antipsychotic

The End