1. Introduction to CNS pharmacology
This introductory powerpoint presentation is to give you the background to enable the later sessions that deal with drugs affecting cognition and emotion.
Dr Caroline Stewart

2. 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.

3. What is the central nervous system?
PNS:
Autonomic
Sympathetic
parasympathetic
Somatic
CNS:
Brain
Spinal cord
The brain and spinal cord constitute the central nervous system. Many different cell types exist (more than in other organs), different receptors and interconnecting pathways. This makes it difficult to predict action of an individual drug/compound.
FOR MORE DETAILS SEE Overview of Nervous System Lecture BY Paul Felts

4. Function of the CNS
Receive and process information (spinal cord is usually the conduit)
Initiate and maintain appropriate response
physical
emotional
The brain is the command centre of the body. Information from the outside world and inside the body has to be interpreted and the appropriate response initiated e.g. muscular or glandular. Complex pathways link specific areas together

5. Components of the CNS Neurones Glial Cells Extracellular space
Astrocytes
Oligodendrocytes
Ependymal cells
Microglia
Extracellular space
Ventricular system (CSF)
There are the working units of the central nervous system. In post-mortem or some forms of imaging: cell bodies – grey matter; axons – white matter
Neurones are highly assymetric polarised cells. Vast array of shapes and sizes for specialised uses. They receive and transmit information.
FOR MORE DETAILS SEE NEUROLOGY LECTURE BY SANDY HARPER (Introduction to neurones, nerve conduction, synaptic transmission, muscle contraction)
Glial cells have a supportive role both in structure and function
Astrocytes outnumber neurones by about 10 to 1. They hold neurones in place, regulate nutrients, modify neuronal signals and can regulate local blood flow.
Oligodendrocytes are responsible for the myelin sheath to permit rapid electrical conduction
Ependymal cells line cerebral ventricles and are responsible for the manufacture of cerebrospinal fluid
Microglia are the defense mechanism. Phagocytic cells of the brain. Excessive activation could lead to inflammation.

6. Organisation of the CNS
Sensory system
Motor system
Limbic system
Please refer back to Paul Felts lecture on the detailed anatomy of the brain and the regional specialisation of some functions. We will try and consider the function of the CNS under 3 main systems to cover the drugs used in psychiatric conditions but also to understand their possible side effects on other brain functions.

7. Sensory system Cortex Reticular activating system: Regulates arousal
and wakefulness
Specific projection
In the somatosensory cortex certain areas of the body are disproportionately represented according to their importance.
FOR MORE DETAIL SEE NEUROANATOMY LECTURE BY PAUL FELTS
Examples of sensory receptors are retinal cell or cochlear hair cell
There is a direct pathway to cortex
There is also an indirect pathway via the RETICULAR FORMATION
Nuclei in the brain stem and thalamus are involved in arousal levels. At one extreme is unconsiousness. Emotions like fear require vigilance. Different neurotransmitters are involved.
Smelling salts are thought to stimulate the trigeminal nerve which actives the Reticular Activating System (RAS).
Sensory
receptor

8. Polysynaptic spinal interneurones
Motor system
Extrapyramidal system
(motor coordination
and posture)
Motor cortex
Corticospinal pathway (pyramidal tract)
cerebellum
basal ganglia
vestibular nuclei
CNS sensory system
Sensoryreceptor
Controls movement
Voluntary actions start in the motor cortex
Two systems described although it is difficult to entirely separate them by structure or function
Pyramidal tract named due to appearance in pathological sections and is more involved in carrying out a detailed task e.g. stitching by a surgeon
FOR MORE DETAIL SEE NEUROANATOMY LECTURE BY PAUL FELTS
Extrapyramidal system results in smooth movements, inhibits inappropriate or unwanted activity, initiates movement and the learning of motor skills
Polysynaptic spinal interneurones
Skeletal muscle
Anterior horn cell

9. Processing of sensory information Regulation of emotion and mood
Limbic system
Processing of sensory information
Cortex
Limbic system
Regulation of emotion and mood
Hypothalamus
Pituitary
This is an even more diffuse collection of different brain areas
Emotions can activate behavioural repertoires AND physiological outcomes that may be adaptive to outside or inside stimuli
EMOTION = transient e.g.happy, sad, fear, anger or disgust
MOOD = predominant state over time e.g. depression, mania
What kind of biological responses do you feel when you are afraid?
Centres regulating autonomic function and links to others via medulla (e.g. BP, HR)
Ganglia

10. Cingulate gyrus Anterior nucleus of thalamus Thalamus Para-olfactory
area
Fornix
Here is more detail of structures that are part of the limbic system
Hippocampus – major role in memory formation
Amygdala – important in regulating fear responses
The olfactory cortex is well represented, smells are good at stimulating memories or emotions.
FOR MORE DETAILS SEE NEUROANATOMY LECTURES BY PAUL FELTS
Mamillary bodies of
hypothalamus
Hypothalamus
Hippocampus
Uncus
Amygdala
Para-hippocampal
gyrus

11. The synapse Transmission of information from one neurone to another
Derived from Greek word for clasp. Neurones can form thousands of synapses with other neurones. The majority of synapses in the brain are chemical. What other type of communication is there between neurones?
FOR ANSWER SEE NEUROLOGY LECTURE “Introduction to neurones, nerve conduction, synaptic transmission, muscle contraction” BY SANDY HARPER

12. Chemical messengers
Neurotransmitter (fast and slow synaptic transmission)
Neuromodulator (diffuse, slower action)
Neurotrophin (long lasting effects on growth and morphology)
There are many types of chemical messenger. We will focus most on neurotransmitters. These are released by a neurone and act over a short distance on receptors of another neurone.
Neuromodulator is a term that describes action that is more diffuse, e.g. it may come from glial cells and can have short or longer term effects. Includes neuropeptides and things like nitric oxide.
Neurotropins can affect growth and survival of neurones and also functional properties

13. Identifying neurotransmitters
Localisation
Release
Synaptic mimicry
Synaptic pharmacology
Many substances have been identified from small gaseous molecules like nitric oxide to larger pepties.
They should be found in presynaptic terminals or dendrites/soma
Their release should be dependent on extracellular Ca2+
Exogenous application of substance should have the same effect
If action of the substance can be blocked by a known antagonist this is strongly suggestive of it being a neurotransmitter

14. 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
Neurotransmitters can be classified into groups but as nearly all drugs used clinically target the first two we will focus on them.
There is future potential for the other mediators and receptors, especially for possible repair in CNS?

15. Amino acid neurotransmitters
NH2 O OH
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
Glutamate mediates most of the fast excitatory transmission in the brain and is present in most neuronal circuits. Aspartate may also play a role in some areas.
Overactivity has been linked to various disorders, especially those related to excitotoxicity
GABA is the most common neurotransmitter and is probably released at up to 40% of brain synapses. Glycine also plays a role, especially in the spinal cord.
As they do not cross the blood brain barrier they need to be synthesised from glucose and other precursors

16. Attentional processes
Cholinergic system N+ O
Acetylcholine
Receptors: muscarinic and nicotinic
Motor control
Acetylcloline was the first molecule to be indentified as a neurotransmitter and is also found in peripheral nervous system
Unlike the amino acid neurotransmitters, it has a much more localised distribution. Neurones containing ACh are only found in certain areas.
Intrinsic interneurones e.g. Striatum - role in motor control (relevant to some treatments for Parkinson’s disease)
Longer projection systems with roles in attention, cognitive function (learning & memory – relevant to Alzheimer’s disease):
Nucleus Basalis of Meynert to cortex, thalamus, amygdala and…
Septohippocampal system - Brain stem projections
Learning and memory
Attentional processes

17. Noradrenergic system Noradrenaline/norepinephrineHO OH
NH2
Noradrenergic system
Noradrenaline/norepinephrine
Receptors: and -adrenoceptors
Arousal, emotion
This neurotransmitter is also found in the sympathetic nervous system. Receptors are G-protein linked.
Two main projecting nuclei in locus coeruleus (LC) and brain stem (pons/medulla)
Each noradrenaline (NA) containing neurone has many terminals and innervates many other cells
LC neurones may be involved in arousal (silent during sleep) but NA has also been implicated in mood regulation, cells are particularly sensitive to noxious or stressful stimuli
Control of blood pressure through NE synapses in the medulla

18. Dopaminergic system Dopamine Receptors:D1 and D2 family Motor controlHO
NH2
Dopamine
Receptors:D1 and D2 family
Motor control
Motivation/reward
Nigrostriatal pathway contains 70% of all brain dopamine and is involved in motor control. It degenerates in Parkinson’s disease
Mesocortical/mesolimbic involved in motivation (exploratory activity in the rat and reward)
Minor projection to pituitary control hormone release
Prolactin release

19. Serotonergic (5HT) system
H — N HO
NH2
Serotonergic (5HT) system
Serotonin (5-hydroxytryptamine)
Receptors: many subtypes 5HT1, 5HT2, 5HT3
mood, sleep, feeding behaviour and sensory perception
Happy nT? Ecstasy?
Many subtypes of receptor, most of them G-protein linked apart from the 5-HT3 receptor
Nuclei confined almost exclusively to the midline or raphe of brain stem.
Virtually every neurone in the brain may be contacted by a serotonergic fibre.
Plays a role in mood, sleep, feeding behaviour and sensory perception CLICK (hallucinations and analgesia)
Analgesia

20. 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
Small proteins that can act as neurotransmitters
Extensive posttranslational processing and cleavage
Biogenic amines and animo acids are stored in small synaptic vesicles
First peptide neurotransmitter was Substance P which is a tachykinin

21. Synaptic transmission (chemical)
Nerve terminal
Metabolites
Enzyme nT
e.g. decarboxylase
Precursor nT
Transporter nT
Common mechanisms:
Formation: in this case (small molecule) in the nerve terminal. Peptides are usually made in the cell body and transported down the axon to the release site.
Storage: inside vesicles, small synaptic or dense core
Release: an action potential invades the terminal and causes a rise in intracellular calcium. The vesicles fuse with the terminal membrane to allow the neurotransmitter into the synaptic space.
Action: dependent on the receptor present. Ligand gated ion channel or G protein linked
Inactivation: Usually uptake into glia or neurone where it is restored or metabolised. Occasionally there is metabolism in the synaptic cleft. nT
Postsynaptic
receptor
Presynaptic receptor

22. Targets for drug action
Ion channels
Receptors
Enzymes
Transport proteins
Drugs normally interact with protein molecules in or on neurones in order to alter synaptic transmission. Refer back to the blue labelled targets on the previous slide.
Receptor types include
Ionotropic (ligand gated ion channel)
Metabotropic (G protein linked)
Kinase-linked receptors
Nuclear receptors
Only 1 and 2 tend to be targetted in the CNS
Some exceptions in the periphery e.g. therapeutic antibodies or chemotherapeutic drugs (target the DNA)

23. Blood brain barrier
Brain receives 25-30% of cardiac output but capillaries have no fenestration (holes)
Many substances do not penetrate the brain as easily as other organs or tissues. In the periphery capillaries have holes called fenestrations to allow substances through. The brain doesn’t as there are tight junctions between cells. Drugs have to get from aqueous plasma into cell membranes (phospholipid bilayers).
The blood brain barier (BBB) is a control system to preserve homeostasis in the nervous system, facilitating the entry of necessary metabolites, but blocking the entry or facilitating the removal of unnecessary metabolites or toxic substances.

24. 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
Lipid soluble drugs can pass through the phospholipid bilayers more easily. High olive oil/water coefficient means that a substances will pass through more easily.
Some anticancer or antibiotic drugs cannot normally get in.
Some essential molecules cannot get in e.g. glucose (highly water soluble). These have to be taken in by active transport or carrier molecules (requires energy). Some drugs can hi-jack these to get into the brain.
In certain areas the BBB is more “leaky”
Area postrema of medulla
Hypothalamic areas
This allows the brain to sample the general homeostatic milieu. Some drugs cause nausea by stimulating the chemoreceptor trigger zone in the hypothalamus. Domperidone (DA antagonist) helps prevent this.

25. Classification of drugs
By structure e.g. benzodiazepine
By pharmacological action e.g. monoamine oxidase inhibitor
By clinical action e.g. antipsychotic
Drug group names is a confusing minefield and can depend on:
What they look like
What they do pharmacologically
What they do behaviourally

26. The End