Department of Pharmacology Yunyang Medical College

1. Drugs for Central Nervous System Department of Pharmacology Yunyang Medical College Wanhong Zhao (赵万红)

2. Mailbox for Answering Questions • Website：Homepage of campus net/Teaching resources/Construction platform of excellent courses/Constructing courses/Pharmacology • yymcyaoli@163.com • zhaowanhong0803@163.com Welcome

3. Chapter 12 General Theory for Central Nervous System Pharmacology Objectives and Requirements • Understanding the metabolic processes and physiological functions of central neurotransmitters and their receptors • Understanding the categories and characteristics of the drugs for CNS

4. CNS:primary conduction and coordination Modes: nerve and/or humoral regulation for maintaining homeostasis and producing response for external environment Humans: dominating intellect and complicated behaviors

5. Section 1 Cytologic Basis of CNS 1.Nerve cell ● Cell body, dendrite and axon ● Inclusion body in cytoplasm: pyknotic body(致密小体) and lipofuscin(脂褐素) etc. ● Basic structure and function unit of CNS ● Major function: transmitting message ● Synapse is the centre of transmitting message

6. 2. Neuroglia • Astrocyte, oligodendrocyte and microglia • Functions：support, insulation, homeostasis, guiding the growth of neuron, and participating the deactivation of transmitter and nerve regeneration etc.

7. 3. Neuronal circuit • Neuron regulation is performed by neuronal circuit (not only one neuron) • Messages are processed and integrated by neuron circuit

8. 4. Synapse and message transmission • Synapse composition: presynaptic membrane, postsynaptic membrane and synaptic cleft • Synapse categories: chemical, electric and mixed • Synaptic transmission: synthesis and storage of transmitter, depolarization of presynaptic membrane and extracellular calcium influx triggering transmitter release, combination of transmitter and receptor producing biological effect, and transmitter elimination and recycle to vesicle • Message may be transmitted by two way at synapse

9. Section 2 Transmitters and Receptors of CNS • Neurotransmitter: transmitting signal quickly, strong action and high selectivity • Neuromodulator：no transmitter action, modulating transmitter releasing and the excitability of postsynaptic cell; its effects are chronic, long and extensive • Neurohormone: being mainly neuropeptides • Several transmitters and modulators may coexist in one nerve terminal • Some neurotrophic and cellular factors impact information transfer by regulating gene expression

10. We have known more than 30 transmitters. 1. Acetylcholine (ACh) Distribution: widespread in CNS Receptors: M (especially M1) and N Functions: involving in motion, memory, alertness and internal organ activities etc Excitatory transmitter, e.g. ACh is released in brain when an animal is infuriated and it is reduced when an animal sleeps

11. 2. γ-aminobutyric acid (GABA) • Widespread and non-uniform in brain, especially in nigra (黑质) and globus pallidus (苍白球) • Receptors: A, B and C, especially A type in brain • Inhibitive transmitter in CNS, e.g. GABA insufficiency of cerebral cortex in epileptics may cause convulsion; valproate sodium can treat various kinds of epileptic seizures because it inhibits the degradation of GABA

12. 3. Excitatory Amino Acids (EAA) • Glu and asp: the maximal content amino acid in mammal’ brain • Receptors: NMDA, AMPA, KA and metabotropic; the former three are ligand-gated ion channel and the final impacts phosphatidylinositol metabolism and adenylcyclase activity • NMDA receptor is the target of many nervous and mental disorders • EAA are related with study and memory, neuron plasticity, epilepsy and CNS degenerative diseases

13. 4. Noradrenaline (NA) • Concentrated distribution in CNS, e.g. in hypothalamus • Receptors: α and β • Functions: alertness, sleep and emotion etc; e.g. when NA neuron activity increases, happiness and agitation appear.

14. 5. Dopamine (DA) Distribution : relative centered; clear projection pathways; centered in striatum (ST, 纹状体), nigra (SN) and globus pallidus (苍白球) ①SN－ST pathway：advanced center of the motion function in extrapyramidal system; function ↓→PD, function ↑→minimal brain dysfunction (多动症) ②Mes－limbic system: emotion and affection ③Mes－cortex pathway: cognition, thinking, sensation and senses ④Tuberculum-funnel pathway：regulating endocrine function of antehypophysis (垂体前叶)

15. Receptors: D1 and D2; five subtypes D1-5; the pharmacological characteristics of D1 and D5 are similar to that of D1, which are called D1-like receptors，the other—D2-like receptors • Relations with diseases： SN-ST pathway ↓→PD; treatment—supplement DA or DA receptor agonists Hyperfunction of D2-like receptor in Mes-limbic system and Mes-cortex pathways causes schizophrenia; treatment—DA antagonists

16. 6. 5－Hydroxytryptamine (5－HT) • Distribution: similar to that of NA • 5-HT transporter is the main target of antidepressants, which participates the regulations of cardiovascular activity, sleep, algesia, affection and endocrine • Functions: inhibition and stabilization 7. Histamine (H) • Maldistribution; more in hypothalamus and reticular formation (网状结构), H1, H2 and H3 receptor • Functions: regulating psychoactivity, decreasing body temperature, participatingdrinking and causing vomit; exciting H1→excitation, exciting H2→inhibition; the lethargy effect of antihistamine drugs may involve in H1 blockage

17. 8. Endopioid Peptide More in ST and HT (下丘脑) Opium (the main active component is morphine) has sedative, hypnosis, preventing cough and inhibiting respiration function etc. 9. Prostaglandin (PG) • Uniformity distribution, many can induce fever and the effect of PGE2 is the strongest. • Central PG synthetase (cycloxygenase) inhibitors, e.g. acetyl salicylic acid reduces PG so that it has antipyretic action

18. Section 3 Pharmacological characteristics of CNS • Excitation: mild to severe—euphoria, insomnia, discomfort, illusion, dilusion (妄想), mania and convulsion etc. • Inhibition: sedative, hypnotic, depression, anesthesia and coma etc. • Drug categories: central stimulants and depressants • Inhibition function is more sensitive to drugs than excitation

19. Sensitivity Differences of Brain Tissue to drugs High evolutive brain tissues have more sensitivity for drugs, e.g. cortex. Vital center in medulla oblongata is lower evolution. Hypotension and respiratory failure appear when brain is inhibited severely. Drugs can impact some functions of CNS selectively, e.g. analgesia and antipsychotic etc.

20. Action modes of CNS drugs Most of drugs impact some courses of synaptic transmission, so cause some homologous function changes, e.g. synthesis, storage, release and deactivation of transmitter, and exciting or blocking receptor etc. Minority impact the energy metabolism or membrane stability---no specific detoxicant, e.g. general anesthetics.

21. Review Subjects • To compare the characteristics of neurotransmitter, neuromodulator and neurohormone. • To state pharmacological features of CNS.