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Dr. Joan Heller Brown

BIOM 255

2012

CNS Neurotransmitters

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Gross anatomy of the human brain

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Anatomy of a neuron

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• Peripheral Nervous System (PNS)– Autonomic division : neuron to smooth

muscle, cardiac muscle and gland– Somatic division : neuron to skeletal

muscle

• Central Nervous System ( CNS)– neuron to neuron

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Sites of CNS drug action

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Multiple sites of CNS drug action

• Conduction• Synthesis and storage• Release and reuptake• Degradation• Receptors, pre-and post-synaptic• Ion channels• Second messengers

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CNS neurotransmitters

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Table 1. Classes of CNS Transmitters

Neurotransmitter % of Synapses

BrainConcentration

Function Primary Receptor Class

MonoaminesCatecholamines: DA, NE, EPIIndoleamines: serotonin (5-HT)

2-5 nmol/mg protein(low)

Slow change in excitability (secs)

GPCRs

Acetylcholine (ACh) 5-10 nmol/mg protein(low)

Slow change in excitability (secs)

GPCRs

Amino acidsInhibitory: GABA, glycine

Excitatory: Glutamate, aspartate

15-20

75-80

μmol/mg protein(high)

μmol/mg protein(high)

Rapid inhibition (msecs)

Rapid excitation (msecs)

Ion channels

Ion channels

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Table 1. Classes of CNS Transmitters

Neurotransmitter % of Synapses

BrainConcentration

Function Primary Receptor Class

MonoaminesCatecholamines: DA, NE, EPIIndoleamines: serotonin (5-HT)

2-5 nmol/mg protein(low)

Slow change in excitability (secs)

GPCRs

Acetylcholine (ACh) 5-10 nmol/mg protein(low)

Slow change in excitability (secs)

GPCRs

Amino acidsInhibitory: GABA, glycine

Excitatory: Glutamate, aspartate

15-20

75-80

μmol/mg protein(high)

μmol/mg protein(high)

Rapid inhibition (msecs)

Rapid excitation (msecs)

Ion channels

Ion channels

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Classes of Receptors

• GPCR=7 transmembrane spanning = metabotropic

• Ligand gated ion channel=ionotropic

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Most neurotransmitters can activate multiple receptor

subtypes and receptor classes

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Table 2. Major Neurotransmitter Receptors in the CNS

Neurotransmitter Receptor Subtypes G Protein-Coupled (G) vs. Ligand-Gated Ion Channel (LG)

DA D1

D2

D3

D4

D5

GGGGG

NE/EPI α1

α2

β1

β2

β3

GGGGG

5-HT 5-HT1A

5-HT1B

5-HT1D

5-HT2A

5-HT2B

5-HT2C

5-HT3

5-HT4

GGGGGG

LGG

ACh Muscarinic M1

Muscarinic M2

Muscarinic M3

Muscarinic M4

Nicotinic

GGGG

LG

Glutamate NMDAAMPAKainate

Metabotropic

LGLGLGG

GABA AB

LGG

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Neurotransmitter regulation of ion channels affects membrane potential and action potential

generation (firing)

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Principles of CNS Drug action

• Selectivity for the targeted pathway – Receptor subtypes– Allosteric sites on receptors – Presynaptic and postsynaptic actions– Partial/inverse agonist (activity dependent)

• Plasticity reveals adaptive changes in drug response– Pharmacokinetic: drug metabolism– Pharmacodynamic: cellular

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Monoamine Neurotransmitters

Neurotransmitter Cell Bodies Terminals

Norepinephrine (NE) Locus coeruleusLateral tegmental area

Very widespread: cerebral cortex, thalamus, cerebellum, brainstem nuclei, spinal cordBasal forebrain, thalamus, hypothalamus, brainstem, spinal cord

Epinephrine (EPI) Small, discrete nuclei in medulla

Thalamus, brainstem, spinal cord

Dopamine (DA) Substantia nigra (pars compacta)Ventral tegmental areaArcuate nucleus

StriatumLimbic forebrain, cerebral cortexMedian eminence

Serotonin (5-HT) Raphe nuclei (median and dorsal), pons, medulla

Very widespread: cerebral cortex, thalamus, cerebellum, brainstem nuclei, spinal cord

Table 3. Localization of Monoamines in the Brain

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Catecholamines Indoleamines

Monoamine Biosynthesis

Important monoamine metabolites formed in the CNS

• NE MAO, COMT MHPG (MOPEG)

• DA MAO, COMT HVA

• 5HT MAO 5HIAA

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Noradrenergic Pathways in the Brain

Locus ceruleus to cortical and subcortical sites

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Serotonergic Pathways in the Brain

Midline raphe nuclei to cortical and subcortical areas

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CNS functions regulated by NE

• Arousal

• Mood

• Blood pressure control

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CNS functions regulated by 5HT

• Sleep

• Mood

• Sexual function

• Appetite

Figure 15-1, G&G

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Catecholamines

Monoamine Biosynthesis

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• Nigrostriatal (substantia nigra to striatum)

• Mesolimbic/mesocortical (ventral tegmental midbrain to n.accumbens, hippocampus, and cortex)

• Tuberoinfundibular (arcuate nucleus of hypothalamus to median eminence then anterior pituitary)

Major Dopaminergic (DA) pathways

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CNS functions regulated by DA

• Nigrostriatal (substantia nigra to striatum)

– extrapyramidal motor control

• Mesolimbic/mesocortical (ventral tegmental to n.accumbens, hippocampus, and cortex)

– emotion– cognition

• Tuberoinfundibular (arcuate nucleus of hypothalamus to median eminence then anterior pituitary)

– prolactin release

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Brain Amines and Disease States

• Biogenic amine theory of depression

• Dopaminergic theory of schizophrenia

• Dopaminergic involvement in Parkinson’s disease

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Brain Amines and Disease States

• Biogenic amine theory of depression

• Dopaminergic theory of schizophrenia

• Dopaminergic involvement in Parkinson’s disease

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Brain Amines and Disease States

• Biogenic amine theory of depression

• Dopaminergic theory of schizophrenia

• Dopaminergic involvement in Parkinson’s disease

DA involvement in Parkinson’s disease (PD)

• Pathology of disease: DA neurons in nigrostriatal pathway degenerate

• Replacing DA is a therapeutic approach to treat PD

• Parkinson like symptoms are side effects of DA receptor blockade with antipsychotic drugs

• MPTP, a neurotoxin, destroys DA neurons and induces PD

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ACh as a CNS neurotransmitter

• Memory (ChEI in Alzheimers disease) – Basal forebrain to cortex/hippocampus (A)

• Extrapyramidal motor responses (benztropine for Parkinsonian symptoms)– Striatum (B)

• Vestibular control (scopolamine patch for motion sickness)

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B

A

Cholinergic pathways in the CNS

Nucleus basalis to cortex (A) and interneurons in striatum ( B)

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Amino Acid Neurotransmitters

• Inhibitory – GABA and Glycine– Hyperpolarize = don’t fire

• Excitatory– Glutamate ( and Aspartate)– Depolarize = fire

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NH2 – CH – CH2 – CH2 - COOH

COOH

NH2 – CH2 – CH2 – CH2 - COOH

Glutamic acid decarboxylase (GAD)

Glutamate GABA

GABA Synthesis

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Location and CNS functions of GABA

• Nigrostriatal pathway– extrapyramidal motor responses

• Interneurons throughout the brain– inhibit excitability, stabilize membrane

potential, prevent repetitive firing

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Synaptic effects of GABAA receptor activation

Inhibitory transmitters (I) hyperpolarize the membrane.

The IPSP stabilizes against excitatory (E) depolarization and action potential generation

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The ionotropic GABAA

receptor

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Subunit composition of GABAA receptors

• Five subunits, each with four transmembrane domains (like nAChR)

• Most have two alpha (α),two beta (β), one gamma (γ) subunit

• α1 β2 γ2 is predominant in mammalian brain but there are different combinations in specific brain regions

58Modified from nAChR, G and G 2011

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Pharmacology of the GABAA

receptor

GABAA receptor pharmacology

• There are two GABA binding sites per receptor.

• Benzodiazepines and the newer hypnotic drugs bind to allosteric sites on the receptor to potentiate GABA mediated channel opening.

• Babiturates act at a distinct allosteric site to also potentiate GABA inhibition.

• These drugs act as CNS depressants

• Picrotoxin blocks the GABA-gated chloride channel

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GABAA receptor involvement in seizure disorders

• Loss of GABA-ergic transmission contributes to excessive excitability and impulse spread in epilepsy.

• Picrotoxin and bicuculline ( GABA receptor blocker) inhibit GABAA receptor function and are convulsants.

• BDZs and barbiturates increase GABAA receptor function and are anticonvulsants.

• Drugs that block GABA reuptake (GAT) and metabolism ( GABA-T) to increase available GABA are anticonvulsants

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Glycine as an inhibitory CNS neurotransmitter

• Major role is in the spinal cord

• Glycine receptor is an ionotropic chloride channel analagous to the GABAA receptor.

• Strychnine, a competitive antagonist of glycine, removes spinal inhibition to skeletal muscle and induces a violent motor response.

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The metabotropic GABAB receptor

• These receptors are GPCRS

• Largely presynaptic, inhibit transmitter release

• Most important role is in the spinal cord

• Baclofen, an agonist at this receptor, is a muscle relaxant

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Glutamate as a CNS neurotransmitter

Glutamate• Neurotransmitter at 75-80% of CNS

synapses

• Synthesized within the brain from – Glucose (via KREBS cycle/α-ketoglutarate)– Glutamine (from glial cells)

• Actions terminated by uptake through excitatory amino acid transporters (EAATs) in neurons and astrocytes

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NH2 – CH – CH2 – CH2 - COOH

COOH

Glutamate Synthesis

Glutamate

α-ketoglutarate

Glutamine (from glia)

transaminases

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GluA1-4 GluK1-3 GluN1GluN2A-DGluN3A-B

mGlu1

mGlu5

SubunitsmGlu2

mGlu3

mGlu4

mGlu6-8GluK4-5

Glutamate Receptor Subtypes

GluR 1-4 GluR 5-7, KA1,2

NR1, NR2A-2D

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Ionotropic glutamate receptors: ligand gated

sodium channels

Glutamate

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Pharmacology of NMDA

receptors

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NMDA receptor as a coincidence detector : requirement for membrane depolarization

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NMDA receptor uses glycine as a co-agonist

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NMDA receptor channel is blocked by phencyclidine (PCP)

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NMDA receptor is Ca++ permeable

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Calcium (Ca++) permeability of AMPA vs NMDA receptors

• It is the GluR2 subunit that makes most AMPA receptors Ca++ impermeant

• The GluR2 subunit contains one amino acid substitution : arginine (R) versus glutamine (Q) in all other GluRs

RNA editing of GluR subunits

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Properties of NMDA Receptor

• Blocked at resting membrane potential (coincidence detector)

• Requires glycine binding

• Permeable to Ca++ as well as Na

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NMDA receptors involvement in disease

- seizure disorders - learning and memory

- neuronal cell death

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NMDA receptors in seizure disorders

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NMDA receptors in long term potentiation

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NMDA receptors in excitotoxic cell death

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Necrosis Apoptosis

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End of CNS NT lecture slides

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Extra stuff

Drugs acting on serotonergic neurons

Drugs acting on noradrenergic neurons

Drugs acting on serotonergic neurons