Catecholamines: Dopamine and Norepinephrine - BIO344 Part 3 PDF

CATECHOLAMINES DOPAMINE AND NOREPINEPHRINE BIO344 Part 3 Matthew Churchward Slides are © 2022-2025 Matthew Churchward Figures are from Meyer’s Psychopharmacology 3e – 4e © 2018-2023 Sinauer/Oxfo...

CATECHOLAMINES DOPAMINE AND NOREPINEPHRINE BIO344 Part 3 Matthew Churchward Slides are © 2022-2025 Matthew Churchward Figures are from Meyer’s Psychopharmacology 3e – 4e © 2018-2023 Sinauer/Oxford unless otherwise attributed Course content, digital or otherwise, created and/or used within the context of the course is to be used solely for personal study, and is not to be used or distributed for any other purpose without prior written consent from the content author(s). Learning objectives Distinguish monoamine neurotransmitters of the catecholamine and indolamine families Describe and identify neurotransmitters of the catecholamine (dopamine and norepinephrine) family Identify features of dopaminergic and noradrenergic neurons including the mechanism of synthesis, storage, release, breakdown, and reuptake Describe the receptors responsible for transmission at dopaminergic and noradrenergic synapses Identify the systems (central and peripheral) using dopaminergic and noradrenergic neurotransmission Describe the application of pharmacological agents to dopaminergic and noradrenergic neurotransmission and the resulting effects on the brain and body 2  OH HO NH2 HO NH2 HO HO Dopamine Norepinephrine Catecholamines NH2 OH H HO N HO Melatonin HO N H Epinephrine Serotonin Monoamines (biogenic amines) are a group of neurotransmitters / hormones that share a 3 common single amine functional group.  Catecholamine neurotransmitters have common structure (with individual variations) 4 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford  OH O H Epinephrine HO N OH Phenylethanolamine-N- NH2 HO methyltransferase (PNMT) HO L-tyrosine (dietary) OH Tyrosine synthesis HO NH2 hydroxylase Norepinephrine (TH) HO O HO Dopamine- -hydroxylase OH (DBH) NH2 HO L-dihydroxyphenylalanine (L-DOPA) DOPA decarboxylase Dopamine 5  Vesicular transport VMAT is the transporter that loads monoamines into synaptic vesicles Reserpine inhibits VMAT and depletes DA and NE as cytosolic catecholamines are rapidly degraded Reserpine treatment causes sedation in animals and induces depression in humans 6 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford  Dopamine transporter Cocaine and amphetamine affect DAT function Cocaine & amphetamines inhibits DAT preventing dopamine reuptake Increases dopamine in the synapse Prolongs dopamine signalling Hyperactivity of dopaminergic circuits 7 © 2014 Lundbeck Institute https://www.cnsforum.com/educationalresources/imagebank/substance_abuse/drug_amphet_low  Catecholamine Metabolism Intracellular pathway Extracellular pathway O O H3 C H HO 8 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford Vanillin  Dopaminergic synapse Presynaptic cell rich in anabolic enzymes (TH, DOPA decarboxylase) VMAT expressed on vesicles for loading dopamine Dopamine receptors in postsynaptic membrane Autoreceptors in presynaptic membrane for feedback inhibition Dopamine transporter (DAT) responsible for reuptake 9 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford  Dopamine receptors D1 family [D1, D5] – G- protein coupled receptors signalling through Gs to cAMP (Excitatory) D2 family [D2, D3, D4] – G- protein coupled receptors signalling through Gi to cAMP (Inhibitory) 10 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford glutamatergic terminal Dopaminergic terminals Unlike classical synapses, dopamine can often synapse dopaminergic terminal onto the neck of dendritic spines This allows dopamine to modulate the activity of the synapse Dopamine can gate the signals at dendritic spines – increasing or decreasing signal transmission 11  Dopaminergic pathways Dopamine accounts for 90% of catecholamine neurotransmission in the CNS 1. Nigrostriatal system projects from substantia nigra and ventral tegmental area to striatum (caudate and putamen) 2. Tuberoinfundibular system projects from the hypothalamus to the medial eminence to stimulate the pituitary prolactin secretion 3. Mesolimbic/mesocortical system Projects from the ventral tegmental area to the limbic system, nucleus accumbens, mesial frontal, anterior cingulate, and entorhinal cortex 12 © 2014 Lundbeck Institute http://www.cnsforum.com/upload/imagebank/large/Neuro_path_DA_SCH.png  Dopaminergic lesions 6-hydroxydopamine (6-OHDA) is a selective neurotoxin. BBB impermeable, taken up by catecholaminergic neurons (after injection using a stereotactic apparatus). Bilateral nigrostriatal lesion – sensory neglect, motivational deficits, motor impairment. Unilateral lesion of nigrostriatal pathway results in postural asymmetry and turning. 13 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford  Nigrostriatal system Projects to the striatum Involved in motor control D1 and D2 family receptors Degradation in Parkinson’s leads to motor symptoms Treatment includes L-DOPA, precursor to dopamine MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin that degrades dopaminergic neurons in the Substantia nigra and produces Parkinson’s symptoms Resistant to L-DOPA treatment 14 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford Nigrostriatal dopaminergic pathways Degeneration of dopaminergic neurons in the nigrostriatal system central to the pathophysiology of Parkinson’s disease tremors, rigidity, forward-flexed posture and shuffling steps, bradykinesia (slowed movement) Targets enriched with D1 and D2 receptors in the basal ganglia 15 https://commons.wikimedia.org/w/index.php?curid=12218566  Degradation of neurons in the substantia nigra in Parkinson’s disease © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford 16  Nigrostriatal dopamine Genetic modification of dopamine function induces locomotor effects DAT knockout causes hyperactivity Decreased re-uptake prolongs DA signalling at the synapse 17 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford  Cocaine (inhibiting DAT activity) has comparable effects on locomotion to DAT knockout. 18 D1 receptor knockout ablates cocaine’s hyperlocomotion. © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford  Mesolimbic dopaminergic pathways Mesolimbic projections Targets enriched in D1, D2 family receptors Limbic connections are proposed to mediate memory, learning, and affect The nucleus accumbens is proposed to act to modify salience of information flow, implicated in Mesolimbocortical projections motivation & addictions (motivational salience), and psychosis (sensory salience) 19 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford Schizophrenia and Psychotic disorders Exist along a spectrum of severity with combinations of symptoms: Delusions + Hallucinations Disorganized speech Grossly disorganized or catatonic 2010 Joe McLaren https://www.flickr.com/photos/joemclaren/4407916183/ motor behaviour Avolition Psychosis proposed to result from – Social deficits Flattened affect altered dopaminergic signalling Hyperactivity in mesolimbic system leads Cognitive deficits to positive symptoms 20  Nucleus accumbens in SCZ – VTA Mesolimbic dopamine is Mesolimbic DA pathway proposed to mediate salience Cocaine Dopamine Motivational salience – Amphetamines addictions Sensory salience – sensory Ketamine gating PCP Nucleus Excess dopamine activity Accumbens leads the patient to perceive Information flow voices, sounds, and imagery sensory, as inappropriately salient behavioural, metabolic, etc False significance assigned to Hippocampus internal and external stimuli Amygdala are interpreted as delusions Cortex (mPFC) and hallucinations 21 Antipsychotics & adverse effects Therapeutic effects Adverse side effects Typical antipsychotics inhibit D1 and D2 Extrapyramidal side effects (nigrostriatal): family dopamine receptors Akinesia – inability to initiate movement Chlorpromazine (first discovered neuroleptic) Akathisia – inability to remain motionless Haloperidol (still widely used front-line Acute dystonic reaction – sustained muscle antipsychotic) contraction, twisting and repetitive Antipsychotic efficacy is correlated with D2 movements binding potential Pseudoparkinsonism – fixed (non-progressive) Parkinsonism without degeneration of Dopaminergic stimulants (esp. dopaminergic neurons amphetamine) can induce psychosis at Tuberofundibular: sufficient dose Hyperprolactinaemia can result from antipsychotic treatment Amenorrhea ( ), infertility( / ), sexual dysfunction ( / ), hypogonadism ( ), spontaneous lactation ( / ) 22  Mesolimbic dopamine and addictions 23 DA neuron GABA neuron Lüscher C J. Neurosci. 2013;33:17641-17646 Dopamine and addictions Addictive behaviour is linked to impulsive traits in humans High correlation to impulsive disorders (e.g. ADHD, antisocial personality disorder) Impulse control is a manifestation of inhibitory control (component of executive function) Involves structures such as anterior cingulate, dorsolateral prefrontal cortex, lateral orbital prefrontal cortex, and motor/premotor cortex Inhibitory control can be considered a gating event 24  Operant task for impulsivity testing in rats. Nose poke results in food reward with a predictable delay between subsequent trials. Premature responding resets the timer (slightly punitive) and is recorded as impulsive behaviour. Nature Medicine 13, 413 - 414 (2007) 25 doi:10.1038/nm0407-413 Dopamine and impulsivity › Impulsive rats ( ) show increased premature responses and have increased self-administration of cocaine than low impulsive rats ( ) 26 Science 2007 315; 1267-1270 DOI: 10.1126/science.1137073  PET imaging of a dopamine receptor D2/3 antagonist showed high impulsive rats have reduced binding potential in the ventral striatum. Reduced D2/3 binding potential correlates with high impulsivity and addictive behaviour (cocaine self- administration). 27 Science 2007 315; 1267-1270 DOI: 10.1126/science.1137073 Key points: Dopamine Dopamine L-DOPA Dopamine precursor and PD treatment Synthesized from tyrosine Signals only to metabotropic receptors Reserpine Plays a role in gating synaptic activity VMAT inhibitor Cocaine Nigrostriatal system DAT inhibitor DA projections from the substantia nigra to striatum Movement control (motivation) Amphetamine DAT inhibitor Degraded in PD Stimulates dopamine efflux through DAT Extrapyramidal side effects of antipsychotics Implicated in impulsive behaviour 6-OHDA Selective neurotoxin vs catecholaminergic neurons Mesolimbic / mesocortical system MPTP VTA to cortex and limbic structures (esp NAc) Potent dopaminergic neurotoxin Reward and sensory salience, motivation (food, social, etc) Haloperidol Dysfunction implicated in reward, addictions, psychosis in SCZ Typical antipsychotic, D1 and D2 receptor antagonist Norepinephrine (NE) AKA Noradrenaline (UK) Neurons secreting norepinephrine are noradrenergic or Adrenergic 29  OH O H Epinephrine HO N OH Phenylethanolamine-N- HO NH2 methyltransferase (PNMT) HO L-tyrosine (dietary) OH Tyrosine synthesis HO NH2 hydroxylase Norepinephrine (TH) HO O HO Dopamine- -hydroxylase OH (DBH) NH2 HO L-dihydroxyphenylalanine (L-DOPA) DOPA decarboxylase Dopamine 30 Catecholamine breakdown occurs by MAO or COMT. Major metabolic end-products are vanillylmandelic acid (VMA) and 3-methoxy-4-hydroxy phenylglycol (MHPG). Levels of MHPG in the CSF or VMA in urine can be used to assess catabolism 31 of catecholamines. https://commons.wikimedia.org/w/index.php?curid=10867780  Noradrenergic synapse NE is synthesized in vesicles from dopamine via dopamine- - hydroxylase (D H). After release, NE is recylced into the cell by the NE transporter (NET). NE is catabolised by MAO and COMT or is recycled into vesicles through the vesicular monoamine transporter (VMAT). 32 ©2014 Lundbeck https://www.cnsforum.com/educationalresources/imagebank/antidepressants/drug_nari_norm Adrenergic receptors Norepinephrine and epinephrine bind and activate adrenergic receptors Metabotropic receptors – G-protein coupled Responsible for both CNS effects (neurotransmitters) and peripheral effects (autonomic / hormones) Function as post-synaptic receptors and as presynaptic autoreceptors 33  Fight or flight response Conservation and relaxation Agonists of adrenergic systems are sympathomimetic Antagonists of adrenergic systems are sympatholytic 34 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford -adrenergic receptors -adrenergic receptors 1 – coupled to Gq 1 – coupled to Gs 2 – coupled to Gi 2 – mostly coupled to Gs Phenylephrine 1/2) 3 – coupled to Gs Vasoconstriction Isoprenaline 1/2/3) Agonists at 2 receptors can lower blood pressure – Vasodilation CNS acting Agonists at -adrenergic receptors relax bronchial 2 receptors in the brainstem (vasomotor centre) are muscles autoreceptors Albuterol is a specific -adrenoceptor agonist used to Clonidine prescribed to treat hypertension treat asthma Side effects include sedation, drowsiness Delivered via inhalation (direct effects at site of Also effective treatment for ADHD by increasing NE tone absorption, avoids effects on heart) in the PFC at postsynaptic 2A receptors Antagonists at 1 receptors affect heart rate and contractile force Metoprolol is a selective 1 receptor antagonist ( -blocker) used to treat arrhythmia and angina pectoris 35  Noradrenergic projections emanate from the locus coeruleus (brainstem/pons) to many areas of the brain Small region (3000 neurons), big impact on behaviour 36 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford  Norepinephrine – arousal, eating, and depression Noradrenergic projections innervate regions involved in arousal, attention, and vigilance Medial septum Norepinephrine affects eating behaviours Paraventricular nucleus (hypothalamus) Noradrenergic pathways innervate areas involved in depression Limbic cortex, amygdala, hippocampus 37 © 2104 Lundbeck https://www.cnsforum.com/educationalresources/imagebank/neurochemical_pathways/neuro_path_n_dpn  Vigilance LC activity recorded in awake, free moving animals. Low firing rates: Sleep Grooming Eating Novel sensory stimuli resulted in short burst activity in LC. LC adrenergic neurons part of the reticular activating system Fire when awake or slow wave sleep Inactive in REM sleep Slow breakdown of NE might account for latency during changes of consciousness 38 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford  Selective agonists for and adrenoreceptors increase awake time when microinjected into the medial septum. Cumulative effects suggest both receptor systems are involved in normal functioning. 39 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford Specific roles of NE in depression Adrenergic system is implicated in depression Antidepressants 1) Often target norepinephrine reuptake or breakdown Monoamine neurotransmitters are a common target for antidepressants MAOI antidepressants reduce the breakdown of all monoamine NTs (dopamine, norepinephrine, serotonin) 41 THE MONOAMINE HYPOTHESIS Depression is a result of a functional deficit of the neurotransmitters norepinephrine and serotonin (5-HT) at specific synapses in the CNS 42 The Monoamine Hypothesis First antidepressant was a monoamine oxidase inhibitor (MAOI), iproniazad, an anti-tuberculosis drug (1952) MAOI cause elevation of monoamines by inhibiting their catabolism Elevated monoamines leads to increases in monaminergic neurotransmission (dopamine, norepinephrine, serotonin[ 5-HT]) Phenylzine was the most common MAOI in use clinically Discontinued due to the cheese effect 43 Tricyclic antidepressants (TCA) Developed in the 1950’s from chlorpromazine analogues Imipramine (Tofranil) is an inhibitor of both norepinephrine transporters (NET) and 5-HT transporters (SERT) Impaired reuptake leads to elevated synaptic NE/5-HT Sustained NE/5-HT levels lead to prolonged and increased post-synaptic activity Side effects on muscarinic receptors (anti-cholinergic) Parasympatholytic – dry mouth, constipation, urinary retention Poor safety margin – induces mania at higher doses 44 Targeted drug design SSRI SNRI Selective serotonin reuptake inhibitors Serotonin-norepinephrine reuptake Second generation antidepressants – inhibitors targeted drug design Second generation antidepressant – Fluoxetine (Prozac, 1987) most widely replaces TCA prescribed First SNRI was venlafaxine (Effexor, 1994) Selective inhibitors for SERT Inhibits both SERT and NET 5-HT accumulates in the synapse, Fewer side effects than TCAs, improved enhancing post-synaptic activity safety margin 45 Challenges to the Monoamine hypothesis Pharmacologic effects are very rapid (hours-days) but therapeutic effects are slow (weeks-months) Monoamines normalize rapidly, but mood normalizes slowly Demonstrated efficacy of drugs that do not affect NA/5-HT reuptake Tianeptine, a selective serotonin reuptake enhancer is equally effective as SSRIs in clinical trials Cocaine (potent NA reuptake inhibitor) does not have antidepressant effects Inconsistent findings in antidepressant effects of amino acid precursors to NA/5- HT (e.g. tyrosine and tryptophan) 46 Selective NE reuptake inhibitors Norepinephrine reuptake inhibitors represent the third class of 2nd generation antidepressants brought to market First was reboxetine (Edronax/Prolift) in 1997 Selectivity of ~20x for NET (NE transporter) over SERT (5-HT reuptake transporter) [Not brought to market in USA or Canada] 2009 meta-analysis questioned the efficacy of reboxetine 47 Drugs are reported in alphabetical order. Results are the ORs in the column-defining treatment compared with the ORs in the row-defining treatment. For efficacy, ORs higher than 1 favour the column-defining treatment (ie, the first in alphabetical order). For acceptability, ORs lower than 1 favour the first drug in 48 alphabetical order. The Lancet, Volume 373, Issue 9665, 2009, 746 - 758 http://dx.doi.org/10.1016/S0140-6736(09)60046-5 Ranking for efficacy (solid line) and acceptability (dotted line) Ranking indicates the probability to 49 be the best treatment, the second best, the third best, and so on, among the 12 antidepressants. The Lancet, Volume 373, Issue 9665, 2009, 746 - 758 http://dx.doi.org/10.1016/S0140-6736(09)60046-5 Systematic review In a more thorough systematic review that included unpublished research data from Pfizer 74 % of patient data from the original Pfizer trials was previously unpublished Reboxetine found to be indistinguishable from placebo Significantly more adverse consequences Study author’s conclusion: “Reboxetine is, overall, an ineffective and potentially harmful antidepressant. Published evidence is affected by publication bias, underlining the urgent need for mandatory publication of trial data.” 50 Attention disorders NE reuptake inhibitors are psychostimulants Absence of activity at the dopamine transporter prevents addictive effects of psychomotor stimulants (e.g. cocaine) Noradrenergic drugs have been demonstrated effective in treating attention deficit hyperactivity disorder (ADHD) Clonidine – 2A agonist increases NE tone in the PFC Reboxetine – NET inhibitor Thought to act to increase / prolong NE signalling to cortex, affecting attention 51 Key points: Norepinephrine Reserpine – VMAT inhibitor Same synthetic pathway from tyrosine as dopamine Directly from dopamine by DBH Cocaine & amphetamine – NET inhibitors NE is immediate precursor to EPI phenylephrine – 1 adrenoceptor agonist Breakdown by MAO and COMT to vanillylmandelic acid isoprenaline – adrenoceptor agonist (VMA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) albuterol – receptor agonist used to treat asthma clonidine – receptor agonist used to treat hypertension, ADHD, Adrenergic receptors are metabotropic and function as 2 withdrawal post-synaptic and autoreceptors metoprolol – receptor antagonist ( -blocker) used to treat – mostly Gi, vasoconstrictors cardiac arrhythmia and angina – mostly Gs, vasodilators iproniazad & phenylzine – MAO inhibitor antidepressants Extensive NE projections from locus coeruleus (irreversible) Medial septum – vigilance imipramine – tricyclic antidepressant inhibitor of NET and SERT Limbic/Cortex – depression/mood venlafaxine – SNRI antidepressant inhibitor of NET and SERT Hypothalamus – eating behaviours reboxetine – selective NET inhibitor, poor antidepressant, used to treat ADHD 52