Introduction to CNS pharmacology

By S.Bohlooli, PhD

School of Medicine, Ardabil University of Medical Sciences

Ion channels & neurotransmitter receptors

Voltage gated channels Ligand gated channels

Ionotropic receptors Metabotropic receptors

Membrane delimited Diffusible second messenger

Nicotinic acetylcholine receptor

The synapse & synaptic potentials

Excitatory Excitatory post-synaptic potential (EPSP) Ionotropic receptor

Inhibitory Inhibitory post-synaptic potential (IPSP) Presynaptic inhibition

Table 21-1. Some toxins used to characterize ion channels.

Channel Types Mode of Toxin Action Source

Voltage-gated

  Sodium channels    

    Tetrodotoxin (TTX) Blocks channel from outside Puffer fish

    Batrachotoxin (BTX) Slows inactivation, shifts activation Colombian frog

  Potassium channels    

    Apamin Blocks "small Ca-activated" K channel Honeybee

    Charybdotoxin Blocks "big Ca-activated" K channel Scorpion

  Calcium channels    

    Omega conotoxin (-CTX-GVIA)

Blocks N-type channel Pacific cone snail

    Agatoxin (-AGA-IVA) Blocks P-type channel Funnel web spider

Ligand-gated

  Nicotinic ACh receptor    

    -Bungarotoxin Irreversible antagonist Marine snake

  GABAA receptor    

    Picrotoxin Blocks channel South Pacific plant

  Glycine receptor    

    Strychnine Competitive antagonist Indian plant

  AMPA receptor    

    Philanthotoxin Blocks channel Wasp

Site of drug action

Identification of central neurotransmitters

More difficult for CNS Anatomic complexity Limitation of available techniques

Criteria for neurotransmitter identification

Localization Microcytochemical immonocytochemical

Release Simulation of Brain slices Calcium dependency of release

Synaptic mimicry Microiontophoresis Physiological view Pharmacological view

Cellular organization of the brain

Hierarchical systems Sensory perception, motor control Phasic information, delineated pathways Two types of neurons

Projection or relay Local circuit neurons

Limited number of transmitters Nonspecific or diffuse neuronal systems

Affecting global function of CNS Small number of neurons, projections to wide

area of CNS

Central neurotransmitters Amino acids

Neutral amino acids Acidic amino acids

Acetylcholine Monoamines

Dopamine Norepinephrine 5-hydroxytryptamine

Peptides Nitric oxide endocananbiniods

Table 21-2. Summary of neurotransmitter pharmacology in the central nervous system. (Many other central transmitters have been identified [see text].)

Transmitter Anatomy

Receptor Subtypes and

Preferred Agonists

Receptor Antagonists

Mechanisms

Acetylcholine

Cell bodies at all levels; long and short connections

Muscarinic (M1):

muscarine

Pirenzepine, atropine

Excitatory: in K+ conductance; ↑ IP3,

DAG

   

Muscarinic (M2):

muscarine, bethanechol

Atropine, methoctramine

Inhibitory: ↑ K+ conductance; cAMP

 Motoneuron-Renshaw cell synapse

Nicotinic: nicotine

Dihydro--erythroidine, -bungarotoxin

Excitatory: ↑ cation conductance

Dopamine Cell bodies at all levels; short, medium, and long connections

D1

 

Phenothiazines Inhibitory (?): cAMP

    D2: bromocriptine

 

Phenothiazines, butyrophenones

Inhibitory (presynaptic): Ca2+; Inhibitory (postsynaptic): in K+

conductance, cAMP 

GABA Supraspinal and spinal interneurons involved in pre- and postsynaptic inhibition

GABAA: muscimol

 

Bicuculline, picrotoxin

Inhibitory: Cl–conductance 

    GABAB: baclofen

 

2-OH saclofen Inhibitory (presynaptic): Ca2+ conductance; Inhibitory (postsynaptic): K+ conductance 

Transmitter Anatomy Receptor Subtypes and Preferred Agonists

Receptor Antagonists

Mechanisms

Glutamate Relay neurons at all levels and some interneurons

N-Methyl-D-aspartate (NMDA): NMDA 

2-Amino-5-phosphonovalerate, dizocilpine

Excitatory: cation conductance, particularly Ca2+

 

    AMPA: AMPA CNQX Excitatory: cation conductance

    Kainate: kainic acid, domoic acid

   

    Metabotropic: ACPD, quisqualate

MCPG Inhibitory (presynaptic): Ca2+ conductance cAMP; Excitatory: K+ conductance, IP3, DAG

 

Glycine Spinal interneurons and some brain stem interneurons

Taurine, -alanine Strychnine Inhibitory: Cl–conductance 

Transmitter Anatomy Receptor Subtypes and Preferred Agonists

Receptor Antagonists

Mechanisms

5-Hydroxytryptamine (serotonin)

Cell bodies in midbrain and pons project to all levels

5-HT1A: LSD

 

Metergoline, spiperone

Inhibitory: K+ conductance, cAMP 

    5-HT2A: LSD

 

Ketanserin Excitatory: K+ conductance, IP3,

DAG 

    5-HT3: 2-methyl-5-

HT 

Ondansetron Excitatory: cation conductance

    5-HT4

 

  Excitatory: K+ conductance 

Transmitter Anatomy Receptor Subtypes and Preferred Agonists

Receptor Antagonists

Mechanisms

Norepinephrine Cell bodies in pons and brain stem project to all levels

1: phenylephrine

 

Prazosin Excitatory: K+ conductance, IP3, DAG

 

    2: clonidine

 

Yohimbine Inhibitory (presynaptic): Ca2+ conductance; Inhibitory: K+ conductance, cAMP 

    1: isoproterenol,

dobutamine 

Atenolol, practolol Excitatory: K+ conductance, cAMP 

    2: albuterol

 

Butoxamine Inhibitory: may involve in electrogenic sodium pump; cAMP

Transmitter Anatomy Receptor Subtypes and Preferred Agonists

Receptor Antagonists

Mechanisms

Transmitter Anatomy Receptor Subtypes and Preferred Agonists

Receptor Antagonists

Mechanisms

Histamine Cells in ventral posterior hypothalamus

H1: 2(m-

fluorophenyl)-histamine  

Mepyramine Excitatory: K+ conductance, IP3, DAG

 

    H2: dimaprit

 

Ranitidine Excitatory: K+ conductance, cAMP 

    H3: R--methyl-

histamine  

Thioperamide Inhibitory autoreceptors

Transmitter Anatomy Receptor Subtypes and Preferred Agonists

Receptor Antagonists

Mechanisms

Opioid peptides Cell bodies at all levels; long and short connections

Mu: bendorphin Naloxone Inhibitory (presynaptic): Ca2+ conductance, cAMP 

    Delta: enkephalin Naloxone Inhibitory (postsynaptic): K+ conductance, cAMP 

    Kappa: dynorphin Naloxone  

Tachykinins   Primary sensory neurons, cell bodies at all levels; long and short connections

NK1: Substance P methylester, aprepitant

Aprepitant   Excitatory: K+ conductance, IP3,

DAG 

    NK2    

    NK3    

Endocannabinoids

Widely distributed CB1: Anandamide, 2-arachidonyglycerol

Rimonabant Inhibitory (presynaptic): Ca2+ conductance, cAMP 

Schematic diagram of a glutamate synapse