Neuropharmacology course (year 1, MSc);
Vilnius University Lithuania.

Contact : Hab.Dr.P.Gaidelis, Dept of Pharmacology and Microbiology, Laboratory of drugs synthesis and investigation, Vilnius University, Vilnius, Lithuania. or electronic contact via:
Prof. Osvaldas Ruksenas.
Tel: +370 2 332 239. Fax: +370 2 235 049.
E-mail: osvaldas.ruksenas@gf.vu.lt

This is the compulsory course (32 hours of lectures and 48 hours of practicals) for the first year M.Sc. in Neurobiology students at Dept. Biochemistry- Biophysics, Vilnius University, Vilnius, Lithuania.

The first part of the course issues the general problems of the neuropharmacology: the neurotransmitters, neuromodulators, and neurohormones, their essence, function and some methods for their localization in central nervous system. Discussed in short the morphological properties of the cells in CNS, polymorphism, the structure of the receptors, their types and subtypes, the methods of identification of receptors, the mechanisms of modulation of receptors, which are related to second messenger systems.

In the second part of the course are discussed neurotransmitters: the aminoacids (GABA, glycine, glutamate etc.), acetylcholine, norepinephrine and epinephrine, dopamine, serotonin, histamine, their metabolism. Discussed the types and subtypes of neurotransmitter receptors, agonists and antagonists. The last part of the course issues the neuroactive peptides (vasopressin, oxitocin, vasoactive intestine peptide, pancreatic polypeptide – related peptides, opioid peptides, somatostatin, and others), physiological role and relations with other neurotransmitters. Cellular mechanisms in learning and memory are discussed at the end of course .

THE EXTENDE PROGRAM OF NEUROPHARMACOLOGY

1. The subject of neuropharmacology and its relationship with other sciences. Psychotropic drugs and their influence on the CNS. Neurotransmitters, neuromodulators, neurohormones, and specificity of their activity. The methods of investigation in neuropharmacology: morphological (radioimmunological, immunocytochemical, biochemical), identification of ion channels, neurocartography (localization of transmitters and neuroactive peptides in the CNS), the methods of microinjections into localized sites of the CNS.

2. Cellular basis of neuropharmacology. Main features of the nerve cells. Neurones, its structure and shape (unipolar, bipolar, and multipolar neurones). Synapse, synaptic vesicles and other structures of neurons. Two types of neuroglia: fibrous astrocytes and oligodendrites. Microglia and its functions. Brain permeability barriers - its anatomical and physiological properties.

3. Transmitters. The interaction of transmitters with membranes. Systems of second messengers. Action potential.

4. Receptors - description and identification. The ligand and its use for identification of receptors. Electrophysiological methods for identification of different receptors. The main properties of receptors (saturability, specificity, reversibility, restoration of functions). Fast receptors, currently referred to as receptor ionophores or ionotropic receptors, are directly linked to an ion channel and mediate millisecond responses when activated by transmitter. G -–protein – coupled receptors mediate slower responses (seconds to minutes). The modulation of synaptic transmission (a chain in the transport or reuptake of transmitters, affecting ion conductance). Autoreceptors. Postsynaptic modulation (a long – term change in the number of receptors, a change in the affinity of ligand for receptor, an effect on ionic conductance).

5. Second messengers (protein phosphorylation, phosphoinositide hydrolysis, arachidonic acid metabolites, nitric oxide, carbon monoxide).

6. Amino acids transmitters.

6.1. GABA (gamma – aminobutyric acid), its importance and metabolism. The agonists of GABA (baclofen) and antagonists (bicucullin). The endogenous modulators of GABA (DBI, DOC). GABA receptors (GABA_A, GABA_B), their localization in the CNS.

6.2. Glycine, the receptors of glycine and localization in the CNS. Glycine transporters. Glycine and NMDA receptors.

6.3. Glutamic acid (glutamate). Glutamate – related acids (ibotenic acid and kainic acid). Glutamate receptors.

6.4. Excitatory amino acid receptors. NMDA, kainic, AMPA, AP₄ and ACPD (metabotropic) receptors. NMDA receptors and their role in LTD and LTP. Non – NMDA receptors (AMPA and kainic), their agonists and antagonists. Metabotropic glutamate receptors (mGLuR₁ – mGLuR₇ ), and three subtypes. Domoic acid.

7. Acetylcholine - metabolism and physiological role. Choline acetyltransferase (CAT), acetylcholinesterase, and butirylcholinesterase. Cholinergic pathways and receptors in the brain and peripheral nervous system (M and N). Choline agonists and antagonists. The role of acetylcholine in the pathology of some diseases (miastenia gravis).

8. Norepinephrine and epinephrine. Catecholamines. Biosynthesis of epinephrine. DOPA and other enzymes, participating in the process of biosynthesis of catecholamines. Adrenergic receptors, their agonists and antagonists. The pathways of the catecholaminergic neurones.

9. Dopamine and dopaminergic system in the brain, its differences from noradrenergic system. Ultrashort, intermediate – length and long-length dopaminergic systems in the brain. Biosynthesis and metabolism of dopamine. Dopamine transport. Dopamine autoreceptors. Postsynaptic D₁ and D₂ receptors. Pharmacology of dopaminergic systems. Dopamine inhibitors – antipsychotic drugs: phenothiazines, thioxantines, butyrophenones. Anxiolytics, antidepressants, CNS stimulants and their influence on the dopaminergic system. Parkinson’s disease.

10. Serotonin (5 – hydroxytryptamin, 5–HT). Biosynthesis and distribution of serotonin in organism, its metabolism. Pineal body and melatonin. Serotonergic systems in the brain. Cellular effects of the 5–HT. The receptors of 5–HT (5–HT_4, 5-HT₆, 5-HT₇). 5-HT transport. Influence of the 5-HT on behaviour. The interaction of 5-HT receptors with adenylatcyclase and phospholypase C. Serotonin and some disorders of the CNS (schizophrenia, migrena, disorders of sleep). Agonists and antagonists of serotonin.

11. Histamine - distribution and physiological role. Biosynthesis of histamine. Histaminergic regions in the CNS (hypothalamus, formatio reticularis, telencephalon). Relationship of histaminergic neurones with systems of other neurotransmitters. Receptors of histamine (H₁, H₂, H₃), their agonists and antagonists (metilhistamine, impromidine, and mepiramine, terphenadine, rinitidine), clinical importance.

12. Neuroactive peptides. Peptide – secreting systems and difference from systems of other neurones. The role of a mRNA in biosynthesis of peptides. The main ways for investigation of the peptides.

12.1. Vasopressin and oxitocyn. The difference of their structure and localization. Physiological importance of oxytocin and vasopressin.

12.2. The tachykinin peptides (subst. P, kassikinin, neurokinin A, neurokinin B, endoisin). Receptors of tachykinin peptides (NK₁, NK₂, NK₃).

12.3. Vasoactive intestinal polypeptides (VIP), their localization. Distribution of VIP – reactive neurones in the CNS and properties. Growth hormone releasing hormone (GHRH), PHI-27, PHM-27, PACAP and secretin.

12.4. Pancreatic polypeptides – related peptides. Localization of PYY and NPY, and their influence on the blood vessels. The receptors Y₁ and Y₂.

12.5. Opioid peptides. Three groups of opioid peptides. Met⁵ and Leu ⁵ enkephalines and endorphines. The chemical and cellular relation between opioid peptides. Promelanocortin (POMC) peptides. The cellular effects of opioid peptides. Influence of the opioid peptides on behaviour.

12.6. Somatostatin (somatotropin release – inhibiting factor), its physiological role. Distribution of somatostatin – reactive cells. Receptors of the somatostatin (SST₁, SST₂, SST₃).

12.7. Cholecystokinin (CCK) and its polymorphism. Receptors of CCK (CCK_A, CCK_B).

12.8. Neurotensin, its distribution in the CNS and physiological role.

12.9. Calcitonin gene – related peptide (CGRP), its receptors and physiological importance.

12.10. Corticotropin – releasing factor (CRF), its localization in the CNS and its physiological role. Antagonist of CRF (CRF_9-41).

13. Cellular mechanisms in learning and memory. The methods used in the investigation of learning process. Cellular models used in the invertebrate nervous system. The monoamine hypothesis of learning and memory in mammalians (the rabbit nictitating membrane reflex). The long - term and short – term memory. Role of hippocampus in the processes of memory and learning. Protein S-100 and its importance in the processes of learning and memory. The influence of environment for growing of brain.

Literature:

1. Martinez-Rodriguez M. (1994). Molecular and cellular aspects of neurotransmission and neuromodulation. International reviews of Cytology, 149,217-292.

2. Caulfield M.P. (1993). Muscarinic receptors – characterization, coupling and function. Pharmacology and Therapeutics, 58,319-379.

3. Stone T.W. (1994). CNS neurotransmitters and neuromodulators. Vol. 1:Acetylcholine., Boca Raton, CRC Press.

4. Ashton H. (1993). Brain systems, disorders and psychotropic drugs. Oxford University Press.

5. Stone T.W. Neuropharmacology., 1995, Spectrum, Oxford.

6. The biochemical basis of neuropharmacology (Cooper J.R., Bloom F.E. and Roth R.H., eds.), Oxford University Press.

7. Xuxo F. Neurochimija. Osnovy I principy.(In Russian) Mir, Moskva, 1990.

8. Way W.L., Fields H.L., and Way E.L. (1998). Basic and clinical pharmacology (Katzung B.G., ed.), pp.496-515, Appleton and Lange, Stansford.

9. Belmonte C. and Cervero F. eds. (1996). Neurobiology of nociceptors, pp.440-451, Oxford University Press.

10. Carvey P.M. (1998). Drug action in the central nervous system