1 Dr. Joan Heller Brown BIOM CNS Neurotransmitters

2 Gross anatomy of the human brain

3

4 Anatomy of a neuron

5 Figure 1.

6

8 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

9 Sites of CNS drug action

10

Multiple sites of CNS drug action Conduction Synthesis and storage Release and reuptake Degradation Receptors, pre-and post-synaptic Ion channels Second messengers

12

13 CNS neurotransmitters

14 Table 1. Classes of CNS Transmitters Neurotransmitter% of Synapses Brain Concentration FunctionPrimary Receptor Class Monoamines Catecholamines: DA, NE, EPI Indoleamines: serotonin (5-HT) 2-5nmol/mg protein (low) Slow change in excitability (secs) GPCRs Acetylcholine (ACh)5-10nmol/mg protein (low) Slow change in excitability (secs) GPCRs Amino acids Inhibitory: GABA, glycine Excitatory: Glutamate, aspartate μmol/mg protein (high) μmol/mg protein (high) Rapid inhibition (msecs) Rapid excitation (msecs) Ion channels

16 Table 1. Classes of CNS Transmitters Neurotransmitter% of Synapses Brain Concentration FunctionPrimary Receptor Class Monoamines Catecholamines: DA, NE, EPI Indoleamines: serotonin (5-HT) 2-5nmol/mg protein (low) Slow change in excitability (secs) GPCRs Acetylcholine (ACh)5-10nmol/mg protein (low) Slow change in excitability (secs) GPCRs Amino acids Inhibitory: GABA, glycine Excitatory: Glutamate, aspartate μmol/mg protein (high) μmol/mg protein (high) Rapid inhibition (msecs) Rapid excitation (msecs) Ion channels

17 Classes of Receptors GPCR=7 transmembrane spanning = metabotropic Ligand gated ion channel=ionotropic

18 Most neurotransmitters can activate multiple receptor subtypes and receptor classes

19 Table 2. Major Neurotransmitter Receptors in the CNS NeurotransmitterReceptor SubtypesG Protein-Coupled (G) vs. Ligand-Gated Ion Channel (LG) DAD1D2D3D4D5D1D2D3D4D5 GGGGGGGGGG NE/EPIα1α2β1β2β3α1α2β1β2β3 GGGGGGGGGG 5-HT5-HT 1A 5-HT 1B 5-HT 1D 5-HT 2A 5-HT 2B 5-HT 2C 5-HT 3 5-HT 4 G LG G AChMuscarinic M 1 Muscarinic M 2 Muscarinic M 3 Muscarinic M 4 Nicotinic G LG GlutamateNMDA AMPA Kainate Metabotropic LG G GABAABAB LG G

20

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

22

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

24 Monoamine Neurotransmitters

NeurotransmitterCell BodiesTerminals Norepinephrine (NE)Locus coeruleus Lateral tegmental area Very widespread: cerebral cortex, thalamus, cerebellum, brainstem nuclei, spinal cord Basal 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 area Arcuate nucleus Striatum Limbic forebrain, cerebral cortex Median 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

26 CatecholaminesIndoleamines Monoamine Biosynthesis

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

28 Noradrenergic Pathways in the Brain Locus ceruleus to cortical and subcortical sites

29 Serotonergic Pathways in the Brain Midline raphe nuclei to cortical and subcortical areas

30 CNS functions regulated by NE Arousal Mood Blood pressure control

31 CNS functions regulated by 5HT Sleep Mood Sexual function Appetite

Figure 15-1, G&G

33 Catecholamines Monoamine Biosynthesis

34

35

36 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

37 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

38 Brain Amines and Disease States Biogenic amine theory of depression Dopaminergic theory of schizophrenia Dopaminergic involvement in Parkinson’s disease

40 Brain Amines and Disease States Biogenic amine theory of depression Dopaminergic theory of schizophrenia Dopaminergic involvement in Parkinson’s disease

42 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

45

46 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)

47 B A Cholinergic pathways in the CNS Nucleus basalis to cortex (A) and interneurons in striatum ( B)

48

49

50 Amino Acid Neurotransmitters Inhibitory –GABA and Glycine –Hyperpolarize = don’t fire Excitatory –Glutamate ( and Aspartate) –Depolarize = fire

51 NH 2 – CH – CH 2 – CH 2 - COOH COOH NH 2 – CH 2 – CH 2 – CH 2 - COOH Glutamic acid decarboxylase (GAD) GlutamateGABA GABA Synthesis

52

53

54 Location and CNS functions of GABA Nigrostriatal pathway –extrapyramidal motor responses Interneurons throughout the brain –inhibit excitability, stabilize membrane potential, prevent repetitive firing

55 Synaptic effects of GABA A receptor activation Inhibitory transmitters (I) hyperpolarize the membrane. The IPSP stabilizes against excitatory (E) depolarization and action potential generation

56 The ionotropic GABA A receptor

57 Subunit composition of GABA A receptors Five subunits, each with four transmembrane domains (like nAChR) Most have two alpha (α),two beta (β), one gamma (γ) subunit α 1 β 2 γ 2 is predominant in mammalian brain but there are different combinations in specific brain regions

58 Modified from nAChR, G and G 2011

60 Pharmacology of the GABA A receptor

GABA A 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

62

64

GABA A 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 GABA A receptor function and are convulsants. BDZs and barbiturates increase GABA A receptor function and are anticonvulsants. Drugs that block GABA reuptake (GAT) and metabolism ( GABA-T) to increase available GABA are anticonvulsants

66

Glycine as an inhibitory CNS neurotransmitter Major role is in the spinal cord Glycine receptor is an ionotropic chloride channel analagous to the GABA A receptor. Strychnine, a competitive antagonist of glycine, removes spinal inhibition to skeletal muscle and induces a violent motor response.

68 The metabotropic GABA B 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

69 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

71 NH 2 – CH – CH 2 – CH 2 - COOH COOH Glutamate Synthesis Glutamate α-ketoglutarate Glutamine (from glia) transaminases

72 Figure 24.

GluA1-4 GluK1-3 GluN1 GluN2A-D GluN3A-B mGlu 1 mGlu 5 Subunits mGlu 2 mGlu 3 mGlu 4 mGlu 6-8 GluK4-5 Glutamate Receptor Subtypes GluR 1-4 GluR 5-7, KA1,2 NR1, NR2A-2D

74 Ionotropic glutamate receptors: ligand gated sodium channels

Glutamate

76 Figure 20A.

77 Pharmacology of NMDA receptors

78 NMDA receptor as a coincidence detector : requirement for membrane depolarization

79 NMDA receptor uses glycine as a co-agonist

80 NMDA receptor channel is blocked by phencyclidine (PCP)

81 NMDA receptor is Ca ++ permeable

82 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

84 Properties of NMDA Receptor Blocked at resting membrane potential (coincidence detector) Requires glycine binding Permeable to Ca ++ as well as Na

85 NMDA receptors involvement in disease - seizure disorders - learning and memory - neuronal cell death

86 NMDA receptors in seizure disorders

87

88 NMDA receptors in long term potentiation

89

90

91 Figure 32.

92 NMDA receptors in excitotoxic cell death

93 Necrosis Apoptosis

94 End of CNS NT lecture slides

95 Extra stuff

Drugs acting on serotonergic neurons

Drugs acting on noradrenergic neurons

Drugs acting on serotonergic neurons