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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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CNS Neurotransmitters

Dr. Joan Heller Brown

BIOM 255

2012





  • 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




20 subtypes and receptor classes


Neurotransmitter regulation of ion channels affects membrane potential and action potential generation (firing)


Principles of cns drug action
Principles of CNS Drug action potential and action potential generation (firing)

  • 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


Monoamine neurotransmitters
Monoamine Neurotransmitters potential and action potential generation (firing)


Table 3. Localization of Monoamines in the Brain potential and action potential generation (firing)


Monoamine Biosynthesis potential and action potential generation (firing)

Catecholamines

Indoleamines


Important monoamine metabolites formed in the cns
Important monoamine metabolites formed in the CNS potential and action potential generation (firing)

  • NE MAO, COMT MHPG (MOPEG)

  • DA  MAO, COMT HVA

  • 5HT MAO  5HIAA


Noradrenergic Pathways in the Brain potential and action potential generation (firing)

Locus ceruleus to cortical and subcortical sites


Serotonergic Pathways in the Brain potential and action potential generation (firing)

Midline raphe nuclei to cortical and subcortical areas

29


Cns functions regulated by ne
CNS functions regulated by NE potential and action potential generation (firing)

  • Arousal

  • Mood

  • Blood pressure control


Cns functions regulated by 5ht
CNS functions regulated by 5HT potential and action potential generation (firing)

Sleep

Mood

Sexual function

Appetite

31


Figure 15-1, G&G potential and action potential generation (firing)


Monoamine Biosynthesis potential and action potential generation (firing)

Catecholamines


Major Dopaminergic (DA) pathways potential and action potential generation (firing)

  • 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 potential and action potential generation (firing)

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 potential and action potential generation (firing)

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 potential and action potential generation (firing)

  • 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 potential and action potential generation (firing)

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 degenerate

  • 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)


Cholinergic pathways in the CNS degenerate

B

A

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


Amino acid neurotransmitters
Amino Acid Neurotransmitters degenerate

Inhibitory

GABA and Glycine

Hyperpolarize = don’t fire

Excitatory

Glutamate ( and Aspartate)

Depolarize = fire

50


GABA Synthesis degenerate

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 degenerate

Nigrostriatal pathway

extrapyramidal motor responses

Interneurons throughout the brain

inhibit excitability, stabilize membrane potential, prevent repetitive firing

54


Synaptic effects of GABA degenerateA receptor activation

Inhibitory transmitters (I) hyperpolarize the membrane.

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

55


The ionotropic gaba a receptor
The ionotropic GABA degenerateAreceptor

56


Subunit composition of gaba a receptors
Subunit composition of GABA degenerateA 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



Pharmacology of the GABA degenerateAreceptor


Gaba a receptor pharmacology
GABA degenerateA 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


64 degenerate


Gaba a receptor involvement in seizure disorders
GABA degenerateA 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 degenerate

  • 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 GABA degenerateB 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 degenerate

  • 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


Glutamate Synthesis degenerate

Glutamine (from glia)

COOH

NH2 – CH – CH2 – CH2 - COOH

Glutamate

transaminases

α-ketoglutarate


Figure 24. degenerate


Glutamate Receptor Subtypes degenerate

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



Glutamate degenerate


Figure 20A. degenerate


Pharmacology of NMDA degeneratereceptors





NMDA receptor is Ca membrane depolarization ++ permeable

81


Calcium ca permeability of ampa vs nmda receptors
Calcium (Ca membrane depolarization ++) 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


RNA editing of GluR subunits membrane depolarization


Properties of nmda receptor
Properties of NMDA Receptor membrane depolarization

  • 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 membrane depolarization - seizure disorders - learning and memory - neuronal cell death

85


Nmda receptors in seizure disorders
NMDA receptors in seizure disorders membrane depolarization

86


87 membrane depolarization



89 membrane depolarization


90 membrane depolarization


Figure 32. membrane depolarization



Apoptosis membrane depolarization

Necrosis


End of CNS NT lecture slides membrane depolarization


Extra stuff membrane depolarization



Drugs acting on noradrenergic neurons membrane depolarization



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