Lesson 10 - CNS Neurotransmission PDF

Lesson 10 CNS Neurotransmission 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 Summary Types of Neurotransmission: 1. Monoamines system: – Noradrenergic system – Dopaminergic system – Serotonergic system...

Lesson 10 CNS Neurotransmission 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 Summary Types of Neurotransmission: 1. Monoamines system: – Noradrenergic system – Dopaminergic system – Serotonergic system – Cholinergic system 2. Aminoacid transmitter: – Excitatory – Inhibitory 3. Other transmitters and modulators. 4. Neuropeptide system 2  What is a neurotransmitter? These are chemical molecules released from nerve terminals, which are recognised by specific receptors located on the membranes of postsynaptic cells. As a consequence of this binding, an excitatory or inhibitory response is triggered.  Monoamines System: Important neurotrasmitters in CNS. They are divided into 2 groups: 1) Catecholamines: that derivates from the aa tyrosine and contains a catechol group (adrenaline, noradrenaline and dopamine) 2) Indolamines: neurotransmitters containing an indole group from the aa tryptophan (Serotonine and Melatonine) Serotonine Melatonine 4  1. MONOAMINES SYSTEM: NORADRENALINE IN THE CNS The actions of noradrenaline are mediated through α1, α2, β1 and β2 receptors. Noradrenergic transmission is believed to be important in: – controlling wakefulness and alertness – blood pressure regulation – control of mood Drugs that act partly or mainly on noradrenergic transmission: – antidepressants, cocaine and amphetamine. – Some antihypertensive drugs (e.g. clonidine, methyldopa) 5  1. MONOAMINES SYSTEM: DOPAMINE IN THE CNS What is Dopamine? It is a catecholamine that is essential for: Mood regulation: is involved in the sensation of pleasure and reward, influencing emotions and behavior. Movement control: It plays a crucial role in motor coordination; its deficiency is associated with disorders like Parkinson's disease. Cognitive function: It impacts attention, memory, and decision- making abilities. Motivation regulation: It helps motivate behavior toward goals and rewards. 6  1. MONOAMINES SYSTEM: DOPAMINE IN THE CNS There are five dopamine receptor subtypes. D1 and D5 receptors are linked to stimulation of adenylyl cyclase. – Schizophrenia symptoms : Related with D1and D2 receptors. – Parkinson’s disease is associated with a deficiency of nigrostriatal dopaminergic neurons (D2) – prolactin release is inhibited and growth hormone release stimulated by Dopamine. 7 1. MONOAMINES SYSTEM: SEROTONINE IN THE CNS What is Serotonine o 5-Hydroxytryptamine (5-HT)? This neurotrasmitter is important because regulates: Mood regulation: It contributes to feelings of well-being and happiness; it is often called "the happiness hormone.» Sleep and wake cycle: It influences sleep quality and regulates circadian rhythms. Appetite and digestion: It regulates appetite and intestinal function; a large portion of serotonin is produced in the gut. Cognitive function: It plays a role in learning and memory. serotonin -> melatonin after decarboxylation 9 1. MONOAMINES SYSTEM: SEROTONINE IN THE CNS 5-Hydroxytryptamine in the CNS Drugs acting selectively on 5-HT receptors or transporters include: buspirone, 5-HT1A receptor agonist – for anxiety ‘triptans’ (e.g. sumatriptan), 5-HT1D : – to treat migraine 5-HT2 antagonists (e.g. pizotifen) used – for migraine prophylaxis selective serotonin uptake inhibitors (e.g. fluoxetine) used – to treat depression ondansetron, a 5-HT3 antagonist, used – to treat chemotherapy-induced emesis vomitting MDMA (ecstasy), produce its mood-altering effects 10  5-Hydroxytryptamine in the CNS – Functions associated with 5-HT pathways include: various behavioural responses (e.g. hallucinatory behaviour) feeding behaviour control of mood and emotion control of sleep/wakefulness control of sensory pathways, including nociception control of body temperature vomiting. 11 12 1. MONOAMINES SYSTEM: ACETILCHOLINE IN THE CNS Certain neurodegenerative diseases are associated with abnormalities in cholinergic pathways. Both nicotinic and muscarinic ACh receptors occur in the CNS. 14 INDEX 1. Monoamines system: – Noradrenergic system – Dopaminergic system – Serotonergic system – Cholinergic system 2. Aminoacid transmitter: – Excitatory – Inhibitory 3. Other transmitters and modulators. 4. Neuropeptide system 15 2. Excitatory Aminoacid transmitter: GLUTAMATE L-Glutamate is the principal excitatory aminoacid transmitter (EAA) in the CNS. 16  2. Excitatory Aminoacid transmitter: GLUTAMATE There is a great interconnection between the pathways for the synthesis of EAAs and inhibitory amino acids (GABA and glycine). Disturbance of any one step will affect both excitatory and inhibitory mediators. GABA and glycine = inhibitory Glutamate = excitatory 17 2. Excitatory Aminoacid transmitter: GLUTAMATE Glutamate is stored in synaptic vesicles 18  2. Excitatory Aminoacid transmitter: GLUTAMATE Released glutamate is taken up into nerve terminals. 19  2. Excitatory Aminoacid transmitter: GLUTAMATE Glutamate taken up by astrocytes is converted to glutamine 20  2. Excitatory Aminoacid transmitter: GLUTAMATE Produced from glucose (α-ketoglutarate transamination) or by glutamine hydrolysis, it is the main excitatory neurotransmitter of the CNS After release, it is recaptured by specific transporters present in glia and neurons. Excess glutamate (example in ischemia) causes excitotoxic effects that can lead to cell death. Glutamate and related excitatory amino acids activate both ionotropic (ligand-gated cation channels) and metabotropic (G protein-coupled) receptors. 21  2. Excitatory Aminoacid transmitter: GLUTAMATE Glutamate receptors: Ionotropics: based on the different affinity for glutamate they are divided into: NMDA: high affinity, high permeability to Ca2+. Closed to the resting potential by the ion Mg2+.Activate for voltage-dependent removal of the Mg2+ blockade. They mediate slow synaptic responses. non-NMDA: permeable to Na+ and K+, low permeability to Ca2+ include: AMPA: mediate rapid synaptic transmissions Kainato: mediate slow synaptic transmissions Metabotropics: eight types divided into three groups: I (mGluR1, R5) phospholipase C activation II (mGluR2, R3) and III (mGluR4, R6, R7, R8) Inhibition of adenylate cyclase. 22  2. Excitatory Aminoacid transmitter: GLUTAMATE NMDA (N-Methyl-D-Aspartate) and mGlu (Metabotropic Glutamate) receptors play a particular role in long-term adaptive and pathological changes in the brain. Potential drug targets. 23  2. Excitatory Aminoacid transmitter: GLUTAMATE Only two NMDA receptor antagonists are in clinical use: – ketamine (anaesthesia, analgesia and depression) – memantine (Alzheimer’s disease). 24 2. Excitatory Aminoacid transmitter: GLUTAMATE Metabotropic glutamate receptor antagonists Antagonists or negative allosteric modulators – 1 mGlu receptors : fragile X syndrome, various pain states, Parkinson’s disease neuroprotection, epilepsy and drug abuse. – 2 mGlu receptors: as cognition enhancers 25 INDEX 1. Monoamines system: – Noradrenergic system – Dopaminergic system – Serotonergic system – Cholinergic system 2. Aminoacid transmitter: – Excitatory – Inhibitory 3. Other transmitters and modulators. 4. Neuropeptide system 26 2. INHIBITORY TRANSMITTER γ-Aminobutyric Acid (GABA) GABA is the main inhibitory transmitter in the brain. – its function is ubiquitous in the brain. – antagonists: bicuculline 27  2. INHIBITORY TRANSMITTER γ-Aminobutyric Acid (GABA) GABA acts on two distinct types of receptor: – GABAA receptors are ligand-gated ion channels gamma alpha beta alcohol = alosteric site – GABAB receptors are G protein-coupled. 28  2. INHIBITORY TRANSMITTER γ-Aminobutyric Acid (GABA) GABAA Receptors are the target for several important centrally acting drugs: benzodiazepines, alcohol ,barbiturates, neurosteroids (include metabolites of progesterone and androgens) and many general anaesthetics. 29 2. INHIBITORY TRANSMITTER γ-Aminobutyric Acid (GABA) GABAB Receptors GABAB Receptors Selective Agonists: – Baclofen to treat spasticity and motor disorders – Maybe: drug dependence 30 2. INHIBITORY TRANSMITTER γ-Hydroxybutyrate γ-Hydroxybutyrate (sodium oxybate or GHB) occurs naturally in the brain as a side product of GABA synthesis. as a sleepl inducing drug – to treat narcolepsy and alcoholism. It is also used as an intoxicant and ’’rape drug’’. activates ‘reward pathways’ in the brain, and its use is now illegal in most countries low doses = euphoria, well-being high doses = depression of CNS and loss of consciousness 31  2. INHIBITORY TRANSMITTER. Glycine Glycine is an important inhibitory neurotransmitter in the spinal cord and brain stem. – Strychnine (glycine antagonist), a convulsant poison, blocks the response to glycine. – Tetanus toxin, acts selectively to prevent glycine release causing excessive reflex hyperexcitability and violent muscle spasms. GlyT2 inhibitors may have potential as analgesics. 32 INDEX 1. Monoamines system: – Noradrenergic system – Dopaminergic system – Serotonergic system – Cholinergic system 2. Aminoacid transmitter: – Excitatory – Inhibitory 3. Other transmitters and modulators. 4. Neuropeptide system 33 3. OTHER TRANSMITTERS AND MODULATORS PURINES ADENOSINE exerts mainly inhibitory effect on adenosine receptors A1 and A2, with sedative, anticonvulsant and neuroprotective effect, and acting as a safety mechanism. antagonist Metilxanthines (e.g. caffeine) are agonist on A1 receptors and increase wakefulness. 34 3. OTHER TRANSMITTERS AND MODULATORS HISTAMINE The functions of histamine are not well understood Histaminergic neurons are active during waking hours, and histamine receptor (H1) antagonists are strongly sedative. H1 receptor antagonist are antiemetic drugs antivomitting MELATONIN Acts on melatonin receptors M1 M2 in the CNS Agonist of M receptors induce sleep and have antidepressant properties 35 3. OTHER TRANSMITTERS AND MODULATORS NITRIC OXIDE NO affects neuronal function by increasing cGMP formation, producing both inhibitory and excitatory effects on neurons 36 INDEX 1. Monoamines system: – Noradrenergic system – Dopaminergic system – Serotonergic system – Cholinergic system 2. Aminoacid transmitter: – Excitatory – Inhibitory 3. Other transmitters and modulators. 4. Neuropeptide system 37  4. NEUROPEPTIDES IN CNS Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. MAIN NEUROPEPTIDES IN CNS: – Opioid peptides – Pituitary peptides – Hypothalamic peptides – Gastro-intestinal peptides – Others: Angiotensin II Bradykinin Peptide related to calcitonin gen Atrial natriuretic factor (ANF) 38 Questions?????