Neuropharmacology - Dopamine and Serotonin Lecture Notes PDF

Lecture #20: Neuropharmacology – Dopamine & Serotonin Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx) ...

Lecture #20: Neuropharmacology – Dopamine & Serotonin Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx)  L20: Learning Objectives 1. How is dopamine synthesized and it’s signal terminated? 2. Compare and contrast the dopamine receptors 3. Identify the clinical symptoms of Parkinson’s Disease and treatment courses 4. Relate the changes that occur during Parkinson’s in the basal ganglia’s feedback circuit compared to “normal” 5. Categorize the four classes of pharmacotherapies for Parkinson’s Disease 6. Relate the MOA of each drug for Parkinson’s Disease to dopamine neurotransmission 8. Describe serotonergic neurotransmission: it’s synthesis, release, regulation, receptors, agonists and antagonists 9. How do reuptake inhibitors physiologically modulate neurotransmission? 10. Know the actions, therapeutic uses of SSRIs, SNRIs, TCAs, MAOIs; compare and contrast their MOAs Unless otherwise noted, figures in today’s lecture are from: Principles of Pharmacology 3e Baca, Golan (Ch.12, 14), Lippincott Illustrated Reviews: Pharmacology 6e Yellepeddi (Ch. 8,10,12) Take Home Slide Dopamine Neuropharmacology – Snapshot Dopamine is a catecholamine NT that is the therapeutic target for a number of CNS disorders - Parkinson’s disease and schizophrenia Dopamine is also a precursor for the other catecholamine NTs - norepinephrine and epinephrine More on catecholamines during our ANS section soon!  Dopamine Neurotransmission Dopamine Synthesis Synthesized from tyrosine and transported into secretory vesicles for storage and release Two pumps are required for the transport of dopamine into synaptic vesicles Ca2+-dependent dopamine release into synaptic cleft LO1,2  Dopamine Neurotransmission LO1,2  Pathophysiology of Parkinson’s Disease (PD) Selective loss of dopaminergic neurons in the substantia nigra pars compacta 70% of the neurons destroyed at the time symptoms first appear Underlying mechanisms are not fully understood - environmental factors and genetic influences have been implicated Destruction of these neurons results: bradykinesia, rigidity, impaired postural balance, and a characteristic tremor when limbs https://mk0 la bi otech eug l4 3g7.k in sta cdn.co m/wp-co ntent/u pl oad s/201 8/10 /ax ovan t-pa rki nson s-di sea se-mo to r-symp toms.jp g are at rest LO3,4 Feedback Circuits - IRL!  PD - Pharmacologic Classes The treatment of patients is an individualized process Extent of symptoms, patient’s age, occupation, activities, and perceived disabilities No laboratory test that can confirm the diagnosis Based on history and physical examination Almost all patients eventually require treatment with medication ”Symptomatic” - treat the symptoms, but do not alter the underlying degenerative process 1. Dopamine Precursors 2. Dopamine Receptor Agonists 3. Inhibitors of Dopamine Metabolism 4. Nondopaminergic Agents LO5  1) Dopamine Precursors: Levodopa Le-vo-do-pa is a metabolic precursor of dopamine MOA: restores dopaminergic neurotransmission in the neostriatum by enhancing the synthesis of dopamine in the surviving neurons of the substantia nigra Early PD - residual dopaminergic neurons in the substantia nigra is adequate for conversion of levodopa to dopamine Relief provided is only symptomatic, and it lasts only while the drug is present in the body LO5,6 Levodopa must be administered with carbidopa  1) Dopamine Precursors: Levodopa Car-bi-do-pa - dopamine decarboxylase inhibitor Inhibits aromatic L-amino acid decarboxylase (AADC) Diminishes the metabolism AADC AADC of levodopa in the periphery = increasing the availability of levodopa to the CNS LO5,6  2) Dopamine Receptor Agonists Pra-mi-pex-ole, ro-pin-i-role, and ro-tigotine MOA: enhance dopaminergic neurotransmission by targeting the postsynaptic dopamine receptor(s) These agents have a longer duration of action than levodopa LO5,6  3) Inhibitors of Dopamine Metabolism MAO – inhibit the breakdown of dopamine by inhibiting the enzymes that degrade it MAO B Inhibitor’s – can be administered with levodopa 1. Se-leg-iline selectively inhibits MAO type B Drawback - forms a potentially toxic metabolite, amphetamine 2. Ra-sa-gi-line irreversible and selective inhibitor of brain MAO type B Five times the potency of selegiline LO5,6  Clinical Management of PD Early PD - nonpharmacologic approach to treatment that emphasizes exercise and lifestyle modification Mild PD - MAO-B inhibitors, amantadine Advanced PD - dopaminergic therapy is indicated - Levodopa Younger patients are treated first with a dopamine agonist in the hope of delaying the onset of motor fluctuations If fluctuations present often = levodopa, dopamine agonists, MAO-B inhibitors, and amantadine will be needed Critical to monitor for changes of cognitive symptoms https://mk0 la bi otech eug l4 3g7.k in sta cdn.co m/wp-co ntent/u pl oad s/201 8/10 /ax ovan t-pa rki nson s-di sea se-mo to r-symp toms.jp g LO3 and adverse effects  Serotonergic Neurotransmission Neurotransmitter serotonin (5- hydroxytryptamine; 5-HT) Target for many of the drugs used to treat psychiatric disorders – mainly depression Many of these medications also affect norepinephrine neurotransmission Both neurotransmitter pathways are believed to be central to the modulation of mood LO8  Serotonergic and Central Adrenergic Neurotransmission Two NTs have similarly wide variety of disorders that can be treated altering serotonin and/or norepinephrine Serotonergic projections to the spinal cord Modulate pain perception, visceral regulation, and motor control Serotonergic projections to the forebrain Important for modulating mood, cognition, and neuroendocrine function Noradrenergic system modulates stress responses, neuroendocrine function, pain control, and sympathetic nervous system activity https://www.g atewayp sychi atri c.com/wp-co ntent/u pl oad s/201 5/11 /Seroto ni n-Norep in eph rin e-an d-Dopa mi ne-Sym ptoms-an d-R espo nse.jpg LO8  Serotonin Synthesis Synthesized from the amino acid tryptophan by the enzyme tryptophan hydroxylase (TPH) Converts tryptophan to 5-hydroxytryptophan Aromatic L-amino acid decarboxylase then converts 5- hydroxytryptophan to serotonin Enzymes are present throughout the cytoplasm of serotonergic neurons Both in the cell body and in cell processes Serotonin is concentrated and stored within vesicles located in axons, cell bodies, and dendrites LO8  Reuptake Inhibitors Serotonergic tone is maintained at steady state by the balance between transmitter release and reuptake Inhibitors of the serotonin reuptake transporter decrease the reuptake rate A net increase in the concentration of 5-HT in the extracellular space These drugs alleviate the symptoms of a variety of common psychiatric conditions, including depression, anxiety, and obsessive-compulsive disorder LO9  Reuptake Inhibitors Four classes of reuptake inhibitors are in use: Nonselective tricyclic antidepressants (TCAs) Selective serotonin reuptake inhibitors (SSRIs) Serotonin-norepinephrine reuptake inhibitors (SNRIs) Newer norepinephrine-selective reuptake inhibitors (NRIs) LO9,10  Selective Serotonin Reuptake Inhibitors (SSRI) Group of antidepressant drugs that specifically inhibit serotonin reuptake Flu∙ox∙e∙tine Flu∙vox∙a∙mine Ser∙tra∙line SSRIs have little blocking activity at muscarinic, α- adrenergic, and histaminic H1 receptors Common side effects associated with TCAs are not commonly seen with the SSRIs SSRIs have largely replaced TCAs and monoamine oxidase inhibitors (MAOIs) as the drugs of choice in treating LO9,10 depression  SSRIs: Actions The SSRIs block the reuptake of serotonin, leading to increased concentrations of the NT in the synaptic cleft SSRIs typically take at least 2 weeks to produce significant improvement in mood Maximum benefit may require up to 12 weeks or more Patients who do not respond to one antidepressant may respond to another ~80% or more will respond to at least one antidepressant drug LO9,10  Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) Inhibit the reuptake of both serotonin and norepinephrine Ven∙la∙fax∙ine Du∙lox∙e∙tine Effective in treating depression in patients in whom SSRIs are ineffective Depression is often accompanied by chronic painful symptoms - backache and muscle aches SSRIs are relatively ineffective for these symptoms SNRIs are sometimes effective in relieving pain LO9,10  Tricyclic Antidepressants (TCAs) Mechanism of action Inhibition of neurotransmitter reuptake: TCAs are potent inhibitors of the neuronal reuptake of norepinephrine and serotonin into presynaptic nerve terminals I∙mip∙ra∙mine Clo∙mip∙ra∙mine Tri∙mip∙ra∙mine Blocking of receptors: TCAs also block serotonergic, α- adrenergic, histaminic, and muscarinic receptors It is not known if any of these actions produce the therapeutic benefit of the TCAs LO10  Tricyclic Antidepressants (TCAs) Actions Elevate mood, improve mental alertness, increase physical activity, and reduce morbid preoccupation in 50% to 70% of individuals with major depression Therapeutic uses Effective in treating moderate to severe depression Control bed-wetting in children older than 6 years of age Prevent migraine headache and treat chronic pain syndromes (neuropathic pain) in a number of conditions for which the cause of pain is unclear LO10  Tricyclic Antidepressants (TCAs) Adverse Effects TCAs have a narrow therapeutic index five- to six-fold the maximal daily dose can be lethal Drug interactions with the TCAs are wide ranging May exacerbate certain medical conditions, such as benign prostatic hyperplasia, epilepsy, and preexisting arrhythmias LO10  Monoamine Oxidase Inhibitors (MAOIs) Monoamine oxidase (MAO) is a mitochondrial enzyme found in nerve and other tissues (gut and liver) “Safety valve” to inactivate any excess NTs MAOIs may irreversibly or reversibly inactivate the enzyme Permitting NTs to escape degradation and accumulate within the presynaptic neuron and leak into the synaptic space Use of MAOIs is limited due to the complicated dietary restrictions LO10  Monoamine Oxidase Inhibitors (MAOIs) Mechanism of action Most MAOIs form stable complexes with the enzyme, causing irreversible inactivation Results in increased stores of NTS within the neuron and subsequent diffusion of excess NTs into the synaptic space Inhibit MAO in the brain (liver and gut) that catalyzes oxidative deamination of drugs and toxic substances Show a high incidence of drug–drug and drug–food interactions LO10  Monoamine Oxidase Inhibitors (MAOIs) Actions Antidepressant action of the MAOIs (like that of the SSRIs, SNRIs, and TCAs) is delayed several weeks Therapeutic uses Phen∙el∙zine Tran∙yl∙cyp∙ro∙mine I∙so∙car∙box∙a∙zid For depressed patients who are unresponsive to TCAs and SSRIs A special subcategory of depression (atypical depression) may respond preferentially to MAOIs Because of their risk for drug–drug and drug–food interactions, the MAOIs LO10 are considered last-line agents  Monoamine Oxidase Inhibitors (MAOIs) Adverse effects SSRIs should not be coadministered with MAOIs Risk of serotonin syndrome the use of MAOIs with other antidepressants is contraindicated What clinical symptoms would be present? LO10