to neuropsychopharmacology. Neurotransmitter mechanisms and pecific neurotransmitter systems, Alexandra Šulcové, M.D., Ph.D., Professor of Pharmacology Central European Institute of Technology (CEITEC) MU, Group; ^Jíparjj/JsniíjJ und AppJjsd Alsuropäyühophamj^eoJocjy DENDRITES CELL BODY • I I I I I M AXON NERVE TERMINALS resting refractory -* t > resting depolarization bipolar neuron dendrites cf «* axon terminals: axon collateral branc TYPES of SYNAPSES unipolar neuron dendrites cell bod multipolar neuron cell body dendr- dendrosomatic axon electrical ("gap junction") bidirectional passage of ions and small molecules through channels CHEMICAL SYNAPSES postsynaptic neuron A - postsynaptic receptor B - autoreceptor (presynaptic! C ■ D - heteroreceptor Potential targets for transmitter released from nerve terminal pre4J synaptic^ membrane^ post-, synaptic) membrane axon © release of* action potential synaptic cleft ion conductance Na+ phosphorylation adenylylcyclaseN^cAMp_^proteinkinase„ ^membrane ATP inorganic phosphates membrane depo- or hyperjtolarization membrane hyperpolarization if CL channels are opened v Y ; inhibiting influence Of GABA synapt membrane action potential 5i-if"ji release of* post-, synaptic) membrane synaptic ii cleft postsynaptic potential exciting (EPSP) or $r inhibiting (IPSP) stimulation frequency—|_|_|_|_|. CO-TRANSMISSION co-transmitters stored in the same vesicles; convey different messages to different receptors at the same time co-transmitters stored in the differential vesicles; released preferentially in response to different frequency nerve impulses V-Y-' Exogenic influences affecting just one transmitter cannot simulate the physiological synaptic effects CNS SPECIFIC NEUROTRANSMITTERS 1. physiologically active substance; can be identified in appropriate regions together with enzymes needed for its synthesis and breakdown 2. can be identified in the perfusate of a region when stimulated but not when it is inactive 3. applied locally is capable of mimicking the effects of nerve stimulation 4. effects of the putative neurotransmitter and of nerve stimulation can be modified, enhanced, or attenuated in the same manner by appropriate drugs 5. on nerve stimulation is released selectively in dependence on intracellular calcium ion concentration 6. it is possible to increase/decrease its effects by administration of agonists/antagonists of relevant specific receptors 7. after release is rapidly inactivated by specific enzymes or re-uptake CNS SPECIFIC NEUROTRANSMITTERS 1. physiologically active substance; can be identified in appropriate regions together with enzymes needed for its synthesis and breakdown 2. can be identified in the perfusate of a region when stimulated but not when it is TO BE ABLE TO CONSIOER ORUG INTERACTIONS WITH EACH NEUROTRANSMITTER we study synthesis, storage, release, breakdown, regulation, specific receptors (and their subtypes) for each neurotransmitter 6. it is possible to increase/decrease its effects by administration of agonists/antagonists of relevant specific receptors 7. after release is rapidly inactivated by specific enzymes or re-uptake neurotransmitters released by nerve cells into blood circulation .Dendrites Afferent stimulus NEUROHORMONES e.g.: Oxytocine vasopressin, gonadotropin, corticotropin NEUROMODULATORS (e.g. opioids, anandamide, NO ...) v__J -Y- biologically active in small amounts, released on synapses, however, also by e.g. glial cells, have impact on receptor activity either directly or through interaction with neurotransmitter j^yj^JjjjjuJjjJü I synthesis choline-> cholinacetyltransferase (acetyl ko-enzym A) => Ach -> acetylcholinesterase => choline+acetate storane in synaptic vesicles breakdown [veryfast) specific Cholinesterase - in neurones and neuroeffector junction pseutiocholinesteraset hutyrylcholinesterase 1 - throughout the body, including body fluids re-uptake choline Cholinergic synapse - j AcetylCfcOlin continuation receptors M15 [ muscarinic) - stimulation has slower and more sustained action, 6-protein coupled N I nicotinic) - stimulation has rapid and short action, part of receptor mediated CI- channels, often occurring as heteroreceptors [increase of neurotransmitter releasel Ach t IQ (learning, memory, attention, emotions, nociception, sleep...) Achl demention, delirium JJlliiJiJJJiJJUJJj]jJbJ3 dopamine (basal ganglia, limbic system... 1 i u ij; i' ij - : 11111 h (bypetbalamus,cortex, cerebellum) synthesis tyrosine ->tyrosine hydroxylase => DOPA -> decarboxylase =v dopamine 4 hydroxylasea => noradrenaline N-methyltransferase => adrenaline storage - in vesicles (with ATP - 4:1) - free in cytoplasmic fluid breakdown - re-uptake!! - diffusion - intracellulars -MA0A(AaNa) + MA0B IDA) extracellularly - MA0B+COMT Adrenergic synapse - noradrenaline (NA) (norepinephrine) tyrosin Jj'JIiJJjjwJiJJJJJJJi^ receptors DA r. - partly sensitive to A a Na, too D15 - coupled to adenylylcyclase '2,3, a i t cAMP - excitation - coupled to phosphodiesterase (cAMP degradation! - IcAMP - inhibition adrenergic r. (in the CNS in neurons; on vessels 1 ax - stimulation of phosphatidylinositol metabolism a} - 4 cAMP t K+ channel y regulated by G-protein X Ca2+ channel ■B,,, TcAMP , Katecholamiiw continuation NaUUt unrest Na UU i sedation, depression t aggressivity i apathy : ' ■ • ' erotonii [ 5-HT I synthesis tryptophan -» hydroxylase => 5-hydroxytryptophan decarboxylase => 5-hydroxytryptamine 15-HT1 storage - in vesicles I with ATP) in presynaptic terminals - in a mobile extravesicular cytoplasmic pool breakdown - re-uptake!! - MAOfl [ cytoplasmic 1 receptors 5-HTUM „ -1 cAMP 5-HT ^ B e - stimulation of phosphoinositol metabolism 5-HT,-t CAMP 5-HT 5-HT 5H.I 6,7 = metabotropic receptors 5-HT3 - stimulation of ion channels ( = ionotropic receptor) I Serotoiln 15-HT) continuation 5-HT t anxiety, aggressivity 5-HT I sedation, depression r ijjauja i jjijjjjjj-ujjjjjjjjjjmnv ujjjjj j synthesis glutamic acid decarboxylase => GABA storane in neurones, in glial cells heakdown - re-uptake - GABA-transaminase [in neurones, in glial cells] receptors GJ iBAji GABAq- part of CI- channel structure, [postsynaptic) GJ IBAB - i CAMP t K+ kanálu i Ca2+ kanálu, [presynaptic) t [ sleep) i [ anxiety) iijj]-juim ujjjjjju u jjIjjs - Jjjjjjujjjui^ Uijjjujrlirlu receptors ionotropic: - NMDA r [ NR13) - (N-methyl-D-aspartate, glutamatel - AMPA r. (GluR141 - (alf a-amino-3-hydroxy-5- methyl-4- isoxazolepropionic acid) - kainate-ergic r. (GluR5.7, KA,, K2) metabotropic, G-protein coupled: UlGIUR^g inhibition of glutamate release from presynaptic terminal or Increase of phosphatidylinositol turnover memory functions, learning processes UiiJitf jjij jjjtjj mijjijHMiR, co-transmij urn, hb u j* jj jjjjjr jjj u jj uis endogenic opioids (enkefaline, endorphine, dynorphine) t euforia i anhedonia cholecystokinine (CCK) t satiety, panic disorder i hunger angiotensine gastrine neurokinines neuropeptide Y neurotensin substance P bradykinine somatostatin E - fals neurotransmitter precursor 1-reuptake blockadi (antidepressants) JJ - precursors jj - inhibition ( antidepressants - IMAO ) transmitter depletion - agonists/antagonists Jj - agonists H - antagonists ffliiJS JJJ JJJJJiJ JJJJlJUJJ UJiJJJJ SWA US3 JJliJitfJ" - 6.H.CH ^ INIIIECT- A.I,C,I,E.F SENSITIVITY denervation supersensitivity and chronic influence of antagonists receptor system 'lip-regulation" chronic influence of agonists receptor system "down-regulation 99 DRUGS AFFECTING CNS FUNCTIONS quantitavely (+) central analeptics (■) general anaesthetics analgesics sedatives hypnotics qualitatively (+) (-) psychotropics PSYCHOTROPICS treatment of psychic disorders Psychotrop I changes of psych activities PSYCHOANALEPTICS PSYCHOLEPTICS PSYCHODYSLEPTICS inhibitory a excitatory depression, anxiety, ^ sleeping disorders, epilepsy, parkinsonism .... Newttransmituir diseases" t activity of the neurotransmitter system I activity of the neurotransmitter system Differential neuronal pathways use the same neurotransmitter it is difficult to target exogenous modulation on just one of them origin of adverse effects of drug acting in the CNS