Chapter 21: CNS Pharmacology HLSC 3P19 PDF

Chapter 21: Introduction to CNS Pharmacology HLSC 3P19 Instructor: Hui Di Wang HLSC3P19 Dr. Hui Di Wang 1  Objectives: Discuss the significance of the BBB. Study synapse and synaptic potentials Study Synapse and Sites of drug action (Hierarchical system and N...

Chapter 21: Introduction to CNS Pharmacology HLSC 3P19 Instructor: Hui Di Wang HLSC3P19 Dr. Hui Di Wang 1  Objectives: Discuss the significance of the BBB. Study synapse and synaptic potentials Study Synapse and Sites of drug action (Hierarchical system and Nonspecific or Diffuse neuronal systems are not included in the final exam) Identify the major receptor subtypes of CNS neurotransmitters and receptor regulation: HLSC3P19 Dr. Hui Di Wang 2  Objectives: Presynaptic receptors (Chapter 6) Postsynaptic receptors  Ionotropic—ligand-gated ion channels Composed of subunits containing 4 membrane spanning domains Different combinations of subunits form heterogeneous receptors with slightly different properties. Metabotropic (linked to G-proteins). G-protein- coupled receptors have seven transmembrane spanning domains. Study the major exciting central neurotransmitters (glutamate and aspartate). HLSC3P19 Dr. Hui Di Wang 3  Objectives: Study the following neurotransmitters of the CNS, including types, receptor subtypes, mechanisms, preferred agonists, (and receptor antagonists): Acetylcholine, Dopamine, GABA, Glutamate, Glycine, Serotonin, Norepinephrine, and Orexins. Discuss CNS adaptation to prolonged drug exposure. HLSC3P19 Dr. Hui Di Wang 4  The Human Nervous System Peripheral Central Afferent Efferent Brain Spinal cord Somatic Autonomic (Control the (Control the muscles of internal skeletal muscle) organs and the glands) Sympathetic Parasympathetic (expends energy) (conserves energy) HLSC3P19 Dr. Hui Di Wang 5 Physiology of CNS – Brain and Spine – CNS starts at the spinal cord and connects the afferent and efferent neurons of the PNS with the brain, which provides higher processing and executive control – control of motor and cognitive activity – control of emotional and intellectual functions HLSC3P19 Dr. Hui Di Wang 6 Blood-brain barrier (BBB) Fig. 5-8 HLSC3P19 Dr. Hui Di Wang 7  Organization of the CNS Neurons Neuroglia Blood-Brain Barrier HLSC3P19 Dr. Hui Di Wang 8 Neurons Nerve cells Composed of – Cell Body – Axon – Dendrites – Synapses which are the basis of neurochemical communication HLSC3P19 Dr. Hui Di Wang 9 Types of ion channels and neurotransmitter receptors in the CNS Figure 21-2 HLSC3P19 Dr. Hui Di Wang 10 The Synapse – Axon terminal of the presynaptic neuron – Dendrite of the postsynaptic neuron – Synaptic cleft (gap between the 2 structures listed above) HLSC3P19 Dr. Hui Di Wang 11 FIGURE 21–4 HLSC3P19 Dr. Hui Di Wang 12 Neurotransmitters at CNS (1) Neurotransmitters serve as messengers that enable neurons to communicate with one another. Present in higher concentration at the synaptic area. Released by electrical or chemical stimulation via a calcium dependent manner. Must exhibit synaptic mimicry. HLSC3P19 Dr. Hui Di Wang 13 Neurotransmitters at CNS (2) Neurotransmitters serve as messengers that enable neurons to communicate with one another. Synthesized in Presynaptic neuronal cell body or terminals. Stored in neuronal vesicles. electrical or chemical stimulation increase [Ca2+]I, which result in fusion of storage vesicles with presynaptic membrane. HLSC3P19 Dr. Hui Di Wang 14 Neurotransmitters at CNS (2) Synaptic Cleft: Neurotransmitters are released from vesicles into cleft and diffused to… Postsynaptic: Receptor activation. HLSC3P19 Dr. Hui Di Wang 15 FIGURE 21–3 Postsynaptic potentials and action potential generation HLSC3P19 Dr. Hui Di Wang 16  Examples of Major neurotransmitters in the CNS Amino Acid: Glutamate, GABA and Glycine Acetylcholine Monoamine: Dopamine, Norepinephrine, Serotonin, Histamine Neuropeptides: Orexin HLSC3P19 Dr. Hui Di Wang 18  Excitatory Neurotransmitters Glutamate is a major excitatory neurotransmitters. Amino acid Acts on N-methyl D-aspartate (NMDA) receptors (Ca2+, ionotropic). Acts on α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) Ionotropic Excitatory ↑ cation conductance Acts on metabotropic receptors (mGluR) on the postsynapticHLSC3P19 cell Dr. Hui Di Wang 19 HLSC3P19 Dr. Hui Di Wang 20 Inhibitory Neurotransmitters GABA (γ-Amino-butryic acid) is a major inhibitory neurotransmitters. Amino acid Acts on GABAA and GABAB receptors – GABAA is receptor-operated Cl- channel- Ionotropic – GABAB receptors are couple to G proteins: Metabotropic Barbiturates, benzodiazepines and some anticonvulsants influence GABAergic system. HLSC3P19 Dr. Hui Di Wang 23 Amines Neurotransmitters Dopamine (In general, inhibitory) Norepinephrine Serotonin (5HT) Substance P HLSC3P19 Dr. Hui Di Wang 24  27 HLSC3P19 Dr. Hui Di Wang Neurotransmitter Receptors metabotropic receptors: a type of membrane receptor that acts through a secondary messenger. Ionotropic receptors: form an ion channel pore. HLSC3P19 Dr. Hui Di Wang 28  -A given neuron cell most commonly releases only one type of neurotransmitter, but most cells contain receptors for multiple neurotransmitters. -In addition, neurotransmitters commonly have multiple receptor subtypes (e.g. up to 2 different GABA & many glutamate receptor subtypes have been identified). 29 HLSC3P19 Dr. Hui Di Wang Neurotransmitter Receptors Presynaptic receptors. Postsynaptic receptors HLSC3P19 Dr. Hui Di Wang 30 Presynaptic regulation Presynaptic receptors –Autoreceptors: activated by same NT that is released by the neuron (alpha2-receptor) –Heteroreceptors: activated by a different NT.. Postsynaptic receptors HLSC3P19 Dr. Hui Di Wang 31 Postsynaptic regulation: Receptor sensitization – Up regulation – Number of receptors may be increased – Sustained reduction in NT release or long term use of antagonist Receptor desensitization – Down-regulation – Number of receptors may be decreased – Sustained increase of NT release, a sustained blockade of NT reuptake, or long-term activation by a drug HLSC3P19 Dr. Hui Di Wang 32 Receptor regulation is one of the primary mechanisms associated with drug tolerance HLSC3P19 Dr. Hui Di Wang 33  Sites of drug action See Textbook, Figure 21-4 HLSC3P19 Dr. Hui Di Wang 34 HLSC3P19 Dr. Hui Di Wang 35