PHARMACOLOGYPHARMACOLOGICAL MANIPULATION OF NEUROTRANSMITTERS

Learning Objectives- Pathways involved in synthesis and metabolism of neurotransmitters- Describe their principle pathways in the CNS- Roles in CNS function (normal and abnormal)- A few examples of drugs affecting neurotransmitters systems in the CNS

Criteria for Neurotransmitters- Transmitters are made/stored in vesicles- Transmitter released upon nerve stimulation- Action is terminated in some way- Exogenous application mimics effects of nerve stimulation

Neurotransmitters - Diverse Range of ChemicalsAmino Acids (Glutamate, GABA)Classical Neurotransmitters (Serotonin, Dopamine, Noradrenaline, Adrenaline, Acetylcholine)Neuropeptides (Opioids, tachykinins, neuropeptide Y)Diffusible Mediators (Nitric Oxide)

Amino Acid Neurotransmitter- essential for CNS function (excitation vs inhibition)- ionotropic receptors mediate rapid neurotransmission (effects determined by ions, selective

compounds)

Glutamate and GABAA. RestingB. Excited (Glutamate Release)C. Inhibited (GABA)

L-Glutamate (Glu)Major excitatory transmitter in mammalian CNSGlu is vital for normal brain function. It is involved in development, learning and memory, cognition, pain and nociception.Excessive activation of Glu receptors is neurotoxic.

Ionotropic Glu Receptors (IGluRs)

AMPA and kainate receptors mediate fast excitatory transmission.NMDA receptors mediate slower responses- voltage dependent- effects mediated by Ca2+ entry- Synaptic platicity- Glycine is a co-agonist- Voltage dependent Mg2+ channel block

Big Problems with blockade of iGlu receptorsThe normla excitatory function is vital.The competitive antagonists block Glu signalling at all synapses/regionsCompetitive antagonists most effective at low Glu concentrationHigh affinity (slow off-rate = lasting effects) —> coma (MK801)Moderate affinity —> hallucinations (PCP) or drowsiness (ketamine)

Metabotropic Glu Receptors

Glutamateric NeuronNo extracellular enzymes to metabolise Glu, therefore must be revoked to prevent excitotoxicityThere are 5 subtypes of Glu transporter- EAAT1,2 - glial- EAAT3-5 - neuronal

Therapeutic Relevance of Glu Receptors and TransportersiGluR blockage potentially beneficial in excitotoxicity BUT they have serious side-effects- Seizures- PCP-like effects- Memantine - used for Alzhemiers DiseasemGluR modulation promising- subtype selectivity difficultEAAT modulation promising- Blockade - subtype selectivity difficult- Modulation - ?

Gamma-Aminobutyric Acid (GABA)Major inhibitory neurotransmitter in the mammalian CNSThey are present in all areas of the CNS ~60-80% of neurons may have GABA receptorsGabaergic neurons widespread in brainRoles in - respiration- cardiovasucalr- visculera function- learning and memory- seizures- schizophrenai- anxiety disordersHyperpolarize nuerons by triggering an increase in anion conductance

GABAergic NeuronGlutamin acid Decarboxylase (GAD) converts glutamate to GABAGABAa - ionotropic GABAb - metabotropic

Common Therapeutic Drugs that affect GABA system in CNSBenzodiazepines - positive allosteric modulators of GABAA receptor. Used as sedative, hypnotic and to prevent seizures. (Diazepam)

Acetylcholine (ACh)Interneurons and projection neutronsBasal forebrain nuclei project to forebrain structuresSeptohippocampal ProjectionShort interneurons in the striatum

Choline + Acetyl coenzyme A —> Choline acetyl transferase (ChAT) —> Acetylcholine + Coenzyme A —> Acetylcholinesterase (AChE) —> Choline + Acetate

CNS Roles for ACh- Memory- Attention- Movement- Addiction- MoodAlzheimers Patients - loss of memory related to degeneration of cholinergic neutronsScopolamine (muscarinic antagonists) - induce memory deficit, reversed using donepezil (AChE inhibitor)

ACh receptorsMuscarininc and Nicotinic Receptors

CNS Effects of Nicotine- Generally via smoking tobacco- Involved in pleasure, reward and addiction- Stimulates release of dopamine in nucleus accumbent (pleasure centre)- Regular nicotine exposure - changes in receptor numbers and sensitivity

Common therapeutic Drugs that affect ACh system in CNS- Donepezil - AChE inhibitor - effective in Alzhemiers Disease by slowing down cognitivee

decline- Nicotine (Gum,Patches) - smoking cessation

Dopamine (DA)- Mesolimbic / Mesocortical Pathways - ventral tegmental area - project to limbic (amygadala,

nucleus accumbent ) and cortical frontal structures- Nigrostriatal pathway - substantia nigra - project to striatum- Tuberoinfundibular Pathway - arcuate nucleus (hypothalamus) - projections to pituitary- Others in retina, olfactory system

Tyrosine —> Tyrosine Hydroxylase —> Dihydroxyphenylalainine (Dopa) —> Dopa Decarboxylase —> Dopamine

CNS Roles for Dopamine- Movement (Parkinsons - dopamine deficiency)- Memory - Mood- Reward (Consumption of reward can be reduced with DA antagonist)- Addiction- Vomiting

Common Therapeutic Drugs that affect DA (Dopamine Adrenergic) system in CNS- Schizophrenia - D2 antagonists - haloperidol- Parkinsons Disease - L-dopa (increasing DA), carbidopa (AADC inhibitor), entacapone

(COMT inhibitor), selegeline (MAOB inhibitor)

Noradrenaline (NA)- Select brainstem nuclei- Mainly locus coereleus (LC)- Terminals Widespread (Cortex, Hippocampus)- Used by sympathetic neurons of ANS- Alpha, Beta Adrenergic Receptors

CNS Roles for NA- Sleep- Attention- Arousal- Learning, Memory- Mood- Blood Pressure RegulationNA is metabolised by Catechol-O-methyl transferase (COMT) and Monoamine Oxidase (MAO) enzymesNA acts on alpha and beta adrenergic receptors - G protein coupled receptors

NA Transporter (NET)Re-uptake of NA from synaptic cleftSimilar structures to SERT, DATHigh levels of protein expression throughout brain (projections, nerve terminals)

Drugs which affect NET- Antidepressants inhibit NET- Cocaine - ionhibit NET - increase release of NA- Amphetamines 0 are taken up by transporters (NET) and then VMAT, leading to leakage of

transmitter out vesicles

Common Therapeutic Drugs that affect NA in CNS- Antidepressants (TCA, MAO Inhibitors, SNRI)- Stimulants (Methylhenidate, Amphetamines)

Serotonin - 5 Hydroxytryptamine (5HT)

CNS Roles for 5HT- Hallucinations- Behaviour- Sleep (lesion of raphe nucleus reduce sleep)- Mood, Emotion- Memory- Autonomic Control- MigraineMany receptor sybtypes (14 so far). All except 5HT3 - GPCR

5HT Tranpsort SERTRe-uptake of 5HT from synaptic cleftHigh levels of protein expression throughout brain (projection, nerve termiansl)Drugs which inhibit transport - can promote / prolonged signalling

Drugs Affecting SERT- MDMA - substrate for SERT- Antidepressants - inhibitors of SERT ( SSRI , TCA)- Cocaine - inhbiite SERT

Common Therapeutic Drugs- Smatripatin- Clozapine- Fluoxetine

Neuropeptides as neurotransmittersLarge molecules - chains of amino acids - actions mediated by GPCR

Synthesis Release and Terminatino of Action of Neuropeptides- Precursors of neuropeides are synthesised in the cell body, packaged into Vesicles and

transport ed to presynaptic terminal by fast axonal transpors, along microtubulers.- The prescursor sare modified to become neuropeptides before reaching the terminal- Following exocytosis, the membranes o the large dense-crd vesicles are returned to the

cellbody for recyling. Inactivation also occurs via diffusion or enzymatic activity.

Nitric Oxide- Retrograde messengers as neurotransmitter- Non-vesicular mechanisms- NO synthesis is induced at postsynaptic sites in neurons, after activation of the NMDA

receptors, which uses calcium influx and activation of nNOS.- The gases diffuse through neuronal membranes of presysntapci terminals to influence

subsequent transmitter release.

Summary- Glutamate, GABA (fast synaptic transmittion) - some modulatory (using metabotropic)- ACh - some fast (nicotininc_ some modulatory (muscariininc)- DA, NA, 5HT modulation- Neuropeptides modulation- Nitric Oxide modulation- Many others such as purines, histamine, endocannabinoids