IntroductionIntroduction toto neuroneuropsychopharmacologypsychopharmacology..

NeurotransmitNeurotransmit tterer mechanismsmechanisms andand specificspecific neurotransmitneurotransmit tterer systemssystems..

Alexandra Šulcov á, M.D., Ph .D., Professor of Pharmacology Central European Institute of Technology (CEITEC) MU, Group : Experimental and Applied Neuropsychopharmacology CELL NERVE TERMINALS BODY

resting refractory resting

depolarization TYP ES of

axoaxonic dendrosomatic axodendritic axosomatic

dendrodendritic descending primary modulating axon terminal

secondary

receptors electrical (“gap junction”) chemical bidirectional passage of ions and small molecules through channels CHEMICAL SYNAPSES

directed synapse nondirected synapse

20 - 30 nm till 400 nm axon

transmitter II transmitter I transmitter I D B C

postsynaptic neuron A C A postsynaptic B (presynaptic) Potential targets for transmitter C homoreceptor released from nerve terminal D ` inhibition of neurotransmitter synthesis

proteinkinasea ATP cAMP

adenylylcyclase R

ion conductance R Na + phosphorylation adenylylcyclase of membrane cAMP proteinkinase proteins K+

ATP inorganic phosphates membrane depo- or hyperpolarization GABA Cl

membrane hyperpolarization if CL channels are opened Cl

inhibiting influence of GABA `

postsynaptic potential

exciting (EPSP) or inhibiting (IPSP) COTRANSMISSION stimulation frequency

                             

                              CoCo--transmissiontransmission ❧ 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

Exogenic influences affecting just one transmitter cannot simulate the physiological synaptic effects syntéza synthesis inactivation

skladování storage impulse conduction transmitter pharmacological release response signal CNS SPECIFIC 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 reuptake 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 TO BE ABLE TO CONSIDER DRUG INTERACTIONS 3. applied locally is capableWITH of EACH mimicking NEUROTRANSMITTER the effects of nerve stimulation 4. effects of the putative neurotransmitterwe study and of nerve stimulation can be modified, enhanced,synthesis, or attenuatedstorage, in the samerelease, mannerbreakdown, by appropriateregulation, drugs specific receptors (and their subtypes) 5. on nerve stimulation is released selectively in dependence on intracellular calcium ion concentrationfor 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 reuptake neurotransmitters released by nerve cells into blood circulation

NEUROHORMONES

e.g.: oxytocine vasopressin , gonadotropin , corticotropin . . . NEUROMODUL ATORS (e.g. opioids, anandamide, NO ... )

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 AcetylcholineAcetylcholine synthesis choline → cholinacetyltransferase ( acetyl koenzym A ) ⇒⇒ Ach →→ acetylcholinesterase ⇒⇒ choline + acetate storage in synaptic vesicles breakdown ( very fast ) specific cholinesterase – in neurones and neuroeffector junction pseudocholinesterase( butyrylcholinesterase ) – throughout the body, including body fluids

reuptake choline Cholinergic synapse - acetylcholinacetylcholin (Ach)

te ta e c Ac CoA a + + e choline n li o Ach h c

h c A R AcetylcholinAcetylcholin continuation

receptors M15 ( muscarinic ) stimulation has slower and more sustained action, Gprotein coupled N ( nicotinic ) stimulation has rapid and short action, part of receptor mediated Cl channels , often occurring as (increase of neurotransmitter release)

Ach ↑↑↑↑ IQ ( learning, memory, attention, emotions, nociception, sleep . . . )

Ach ↓↓↓↓ demention, delirium CatecholaminesCatecholamines dopaminedopamine (( basalbasal ganglia,ganglia, limbiclimbic systemsystem ...... )) noradrenalinenoradrenaline (( hypothalamus,hypothalamus, cortex,cortex, cerebellumcerebellum )) adrenalineadrenaline synthesis tyrosine → tyrosine hydroxylase ⇒⇒DOPA →→ decarboxylase ⇒⇒ →→ hydroxylasea ⇒ noradrenaline →→ Nmethyltransferase ⇒⇒ adrenaline storage in vesicles ( with ATP 4 : 1 ) free in cytoplasmic fluid breakdowb reuptake !! diffusion

intracellularly MAO A (A a Na ) + MAO B ( DA ) extracellularly MAO B + COMT Adrenergic synapse - noradrenalinenoradrenaline (NA) (norepinephine)

tyrosine tyrosine

L-DOPA NA DA DA

NA NA

R CatecholaminesCatecholamines continuation receptors

DA r. partly sensitive to A a Na, too →→ D1 , 5 coupled to adenylylcyclase ↑ cAMP – excitation ↓ D2, 3, 4 coupled to phosphodiesterase (cAMP degradation) cAMP inhibition

adrenergic r. (in the CNS in ; on vessels ) αα αα 1 -- stimulation of phosphatidylinositol metabolism αα ↓↓↓↓ 2 cAMP ↑↑↑↑ K+ channel regulated by G-protein ↓↓↓↓ Ca 2+ channel ↑↑↑↑ -- ββ1, 2, 3 - cAMP KatecholaminyKatecholaminy continuation

Na (A) ↑↑↑↑ unrest

Na (A) ↓↓↓↓ sedation, depression

DA ↑↑↑↑ aggressivity

DA ↓↓↓↓ apathy SerotoninSerotonin (( 55 HTHT )) synthesis tryptophan →→ hydroxylase ⇒⇒5hydroxytryptophan →→ decarboxylase ⇒⇒5hydroxytryptamine ( 5HT ) storage in vesicles ( with ATP ) in presynaptic terminals in a mobile extravesicular cytoplasmic pool breakdown reuptake!!

MAO A ( cytoplasmic ) ↓↓↓↓ receptors 5HT 1 A, B, C, D -- cAMP 5HT 2A, B, C stimulation of phosphoinositol metabolism ↑↑↑↑ 5HT 4 cAMP 5HT 5A, B = metabotropic receptors 5HT 6, 7 5HT 3 - stimulation of ion channels ( = ionotropic receptor) SerotoninSerotonin (( 55 HTHT )) continuation

5HT ↑↑↑↑ anxiety, aggressivity

5HT ↓↓↓↓ sedation, depression GABAGABA (( gamagama aminobutyricaminobutyric acidacid )) synthesis →→ →→ →→ decarboxylase ⇒⇒ GABA storage in neurones, in glial cells beakdown reuptake GABAtransaminase (in neurones, in glial cells]

receptors GABA A , GABA C part of Cl channel structure, (postsynaptic) GABA ↑↑↑↑ ( sleep ) ↓↓↓↓ GABA B cAMP ↑↑↑↑ K+ kanálu GABA ↓↓↓↓ ↓↓↓↓ Ca 2+ kanálu, ( anxiety ) (presynaptic) GABAergic synapse gamagama--aminobutyricaminobutyric acidacid (GABA) glutamine glutamine

glutamate

GABA A B A G R ExcitatoryExcitatory aminoamino acidsacids glutamate,glutamate, aspartateaspartate receptors

ionotropic:

NMDA r ( NR 13) ( NmethylDaspartate, glutamate) AMPA r. (GluR 14 ) – ( alfaamino3hydroxy5 methyl4 isoxazolepropionic acid )

kainateergic r. (GluR 57, KA 1, K 2) metabotropic, Gprotein coupled: mGluR 18 inhibition of glutamate release from presynaptic terminal or Increase of phosphatidylinositol turnover memory functions, learning processes OtherOther neurotransmitters,neurotransmitters, coco transmitters,transmitters, neurohormonesneurohormones endogenic opioids ( enkefaline, endorphine, dynorphine ) ↑↑↑↑ euforia ↓↓↓↓ anhedonia cholecystokinine ( CCK ) ↑↑↑↑ satiety, panic disorder ↓↓↓↓ hunger angiotensine gastrine neurokinines neuropeptide Y neurotensin substance P bradykinine somatostatin ...... tyrosine tyrosine

tyrosinhydroxylase DOPA

DA

MAO HVA

DA COMT HVA E fals neurotransmitter D precursors synthesis precursor B inhibition ( antidepressants - IMAO )

MAO C transmitter depletion F – interference with A blockade vesicle discharge ( antidepressants) CH agonists/antagonists

G agonists H antagonists SitesSites ofof drugdrug actionaction atat thethe synapsesynapse DIRECT G, H, CH INDIRECT A, B, C, D, E, F RECEPTORRECEPTOR denervation supersensitivity SENSITIVITYSENSITIVITY and chronic influence of antagonists

receptor system “upregulation”

chronic influence of agonists

receptor system “downregulation” (+) central analeptics quantitavely (-) general anaesthetics analgesics DRUGS sedatives AFFECTING hypnotics CNS FUNCTIONS (+) qualitatively psychotropics (-) PSYCHOTROPICS treatment of psychic disorders

== inducinginducing behaviouralbehavioural changeschanges Psychotropics PSYCHOANALEPTICS

changes PSYCHOLEPTICS of psychic activities

PSYCHODYSLEPTICS neurotransmitters

inhibitory a excitatory

depression, anxiety, imbalanced func tions = sleeping disorders, PATHOLOGICAL epilepsy, CONDITION parkinsonism . . . . ““ NeurotransmitterNeurotransmitter diseasesdiseases ““

↑↑↑↑ activity ↓↓↓↓ activity of the neurotransmitter of the neurotransmitter system 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