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Dr. Joan Heller Brown BIOM 255 2012

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CNS Neurotransmitters. Dr. Joan Heller Brown BIOM 255 2012. Gross anatomy of the human brain. Anatomy of a neuron. Figure 1. Peripheral Nervous System (PNS) Autonomic division : neuron to smooth muscle, cardiac muscle and gland Somatic division : neuron to skeletal muscle

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slide1

CNS Neurotransmitters

Dr. Joan Heller Brown

BIOM 255

2012

slide8
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
multiple sites of cns drug action
Multiple sites of CNS drug action
  • Conduction
  • Synthesis and storage
  • Release and reuptake
  • Degradation
  • Receptors, pre-and post-synaptic
  • Ion channels
  • Second messengers
classes of receptors
Classes of Receptors
  • GPCR=7 transmembrane spanning = metabotropic
  • Ligand gated ion channel=ionotropic
slide21
Neurotransmitter regulation of ion channels affects membrane potential and action potential generation (firing)
principles of cns drug action
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
slide26

Monoamine Biosynthesis

Catecholamines

Indoleamines

important monoamine metabolites formed in the cns
Important monoamine metabolites formed in the CNS
  • NE MAO, COMT MHPG (MOPEG)
  • DA  MAO, COMT HVA
  • 5HT MAO  5HIAA
slide28

Noradrenergic Pathways in the Brain

Locus ceruleus to cortical and subcortical sites

slide29

Serotonergic Pathways in the Brain

Midline raphe nuclei to cortical and subcortical areas

29

cns functions regulated by ne
CNS functions regulated by NE
  • Arousal
  • Mood
  • Blood pressure control
cns functions regulated by 5ht
CNS functions regulated by 5HT

Sleep

Mood

Sexual function

Appetite

31

slide36

Major Dopaminergic (DA) pathways

  • 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)
cns functions regulated by da
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

37

brain amines and disease states
Brain Amines and Disease States

Biogenic amine theory of depression

Dopaminergic theory of schizophrenia

Dopaminergic involvement in Parkinson’s disease

38

brain amines and disease states1
Brain Amines and Disease States
  • Biogenic amine theory of depression
  • Dopaminergic theory of schizophrenia
  • Dopaminergic involvement in Parkinson’s disease
brain amines and disease states2
Brain Amines and Disease States

Biogenic amine theory of depression

Dopaminergic theory of schizophrenia

Dopaminergic involvement in Parkinson’s disease

42

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

DA involvement in Parkinson’s disease (PD)
ach as a cns neurotransmitter
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)
slide47

Cholinergic pathways in the CNS

B

A

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

amino acid neurotransmitters
Amino Acid Neurotransmitters

Inhibitory

GABA and Glycine

Hyperpolarize = don’t fire

Excitatory

Glutamate ( and Aspartate)

Depolarize = fire

50

slide51

GABA Synthesis

Glutamic acid decarboxylase (GAD)

COOH

NH2 – CH – CH2 – CH2 - COOH

NH2 – CH2 – CH2 – CH2 - COOH

Glutamate

GABA

location and cns functions of gaba
Location and CNS functions of GABA

Nigrostriatal pathway

extrapyramidal motor responses

Interneurons throughout the brain

inhibit excitability, stabilize membrane potential, prevent repetitive firing

54

slide55

Synaptic effects of GABAA receptor activation

Inhibitory transmitters (I) hyperpolarize the membrane.

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

55

subunit composition of gaba a receptors
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 β2γ2 is predominant in mammalian brain but there are different combinations in specific brain regions
gaba a receptor pharmacology
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
gaba a receptor involvement in seizure disorders
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
glycine as an inhibitory cns neurotransmitter
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.
the metabotropic gaba b receptor
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

68

glutamate
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
slide71

Glutamate Synthesis

Glutamine (from glia)

COOH

NH2 – CH – CH2 – CH2 - COOH

Glutamate

transaminases

α-ketoglutarate

slide73

Glutamate Receptor Subtypes

GluR 5-7, KA1,2

NR1, NR2A-2D

GluR 1-4

GluN1

GluN2A-D

GluN3A-B

mGlu2

mGlu3

mGlu4

mGlu6-8

mGlu1

mGlu5

GluK1-3

Subunits

GluA1-4

GluK4-5

calcium ca permeability of ampa vs nmda receptors
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

82

properties of nmda receptor
Properties of NMDA Receptor
  • Blocked at resting membrane potential (coincidence detector)
  • Requires glycine binding
  • Permeable to Ca++ as well as Na
nmda receptors involvement in disease seizure disorders learning and memory neuronal cell death
NMDA receptors involvement in disease - seizure disorders - learning and memory - neuronal cell death

85

slide93

Apoptosis

Necrosis

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