Neurotransmitters


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1 : NEUROTRANSMITTERS IN PSYCHIATRY Dr. Kanwar Saurabh Singh JR - II
2 : LOEWI, 1921 Stimulated the vagus nerve of a perfused (donor) frog heart & allowed the perfusion fluid to come in contact with a second (recipient) frog heart used as a test object. The recipient frog heart was found to respond, after a short lag, in the same way as the donor heart. Vagusstoff & Acceleranstoff DISCOVERY of NTs
3 : NTs are chemicals that amplify or inhibit the depolarization signal from one neuron to that of an adjacent neuron. Typically released from a presynaptic neuron & travels across a small space, the synaptic cleft or synapse, to act upon the postsynaptic neuron. An action potential travels down a neuronal axon to the presynaptic terminal, a specialized appendage where neurotransmitters are stored in specialized vesicles. The action potential opens voltage-sensitive calcium channels in the membrane, allowing for an increase in cellular calcium that results in the vesicles releasing their contents into the synaptic cleft & acting upon receptors on the postsynaptic neuron membrane INTRODUCTION
4 : SEVEN PROCESSES in NEUROTRANSMITTER ACTION
5 : COMPONENTS of a SYNAPSE
6 : It is consumed ( broken down or used up) at postsynaptic membrane leading to action potential generation. Degraded by enzymes present in synaptic cleft. Reuptake mechanism( reutilization) ? most common fate. FATE of the NTs
7 : NT CRITERIA
8 : CLASSIFICATION
9 : BIOGENIC AMINES are of central importance to the pharmacological therapy of thought, mood, & anxiety disorders
10 : DOPAMINE CNS DOPAMINERGIC TRACTS The three major dopaminergic projections in the CNS The nigrostriatal pathway - Neurons in the substantia nigra project to the dorsal striatum (upward dashed blue arrows); this is the pathway that degenerates in Parkinson ds The meso-cortical meso-limbic pathway - Neurons in VTA project to most areas of the cerebral cortex, & to the limbic system (solid blue arrows) Neurons in the arcuate nucleus of the hypothalamus project by the tuberoinfundibular pathway in the hypothalamus, from which DA is delivered to the anterior pituitary (red arrows)
11 : DOPAMINE LIFE CYCLE …Contd Site ? Dopaminergic axon terminal Starting A.A. ? Tyrosine Rate limiting step ? Enzymatic step catalyzed by tyrosine hydroxylase DOPA is beyond the rate-limiting step ? Thus can can be administered orally to increase the rate of synthesis of dopamine Action terminated by ? Reuptake or metabolism Metabolism by ? MAO & COMT MAOB selectively metabolizes dopamine Primary metabolite ? homovanillic acid (HVA)
12 : DOPAMINE RECEPTORS …Contd Five subtypes divided into 2 groups 1st grp (D1 & D5) ? stimulate the formulation of cAMP by activating the stimulatory G protein, Gs Dopamine affinity D5 > D1 2nd grp (D2, D3, D4) ? D2 receptor inhibits the formation of cAMP by activating the inhibitory G protein, Gi, & some data indicate that the D3 & D4 receptors act similarly
13 : …Contd
14 : Blockade of dopamine receptors, esp. D2, has been a/w the efficacy of antipsychotic drugs Long-term administration of dopamine receptor antagonists results in an up-regulation in the number of dopamine receptors present ? may be involved in the development of tardive dyskinesia SDAs ? block predominantly the serotonin type 5-HT2 &, to a lesser extent, the D2 receptors a/w greatly reduced risk of development of parkinsonian S/Es & TD treat positive & negative symptoms of schizophrenia Nicotine ? stimulates the release of dopamine & glutamate reduced risk of developing Parkinson's disease, Alzheimer's disease nicotine analogue that stimulates dopamine release is under study for t/t of Parkinson's disease nicotine transdermal patch is being studied to counteract the cognitive impairment caused by treatment with haloperidol DOPAMINE & DRUGS …Contd
15 : Amphetamines & Cocaine ? …Contd Amphetamines - cause the release of dopamine Cocaine - blocks the uptake of dopamine increase the amount of dopamine present in the synapse involved in the brain's so-called reward or pleasure-seeking system this involvement may explain the high addiction potential of cocaine
16 : The Dopamine Hypothesis of Schizophrenia drugs blocking dopamine receptors ? antipsychotic activity drugs stimulating dopamine activity ? can induce psychotic symptoms in non-schiz persons when given in sufficiently high doses A recent series of studies showed that plasma concentrations of HVA, in fact, are reduced in many patients with schiz who respond to antipsychotic drugs Dopamine in the pathophysiology of mood disorders Dopamine activity may be low in depression & high in mania Amphetamines ? highly effective antidepressants Levodopa ? can cause mania & psychosis in some patients with parkinsonian side effects also supports the hypothesis DOPAMINE & PSYCHOPATHOLOGY …Contd
17 : The major conc. of noradrenergic (& adrenergic) cell bodies that project upward in the brain is in the compact locus ceruleus in the pons The axons of these neurons project through the medial forebrain bundle to the cerebral cortex, the limbic system, the thalamus, & the hypothalamus. NOREPINEPHRINE & EPINEPHRINE CNS NORADRENERGIC TRACTS
18 : Synthesized from ? Tyrosine Rate limiting enzyme ? tyrosine hydroxylase In NE releasing neurons ? enzyme dopamine ß-hydroxylase converts dopamine to NE; neurons that release dopamine lack this enzyme In Epinephrine releasing neurons ? enzyme phenylethanolamine-N-methyltransferase (PNMT) converts NE into epinephrine. Neurons that release either dopamine or norepinephrine do not have PNMT Action terminated by ? Reuptake or metabolized Metabolism by ? MAO (esp. MAOA) & COMT NE & EPINEPHRINE LIFE CYCLES …Contd
19 : 2 broad grps ? a & ß a receptors ? seem to inhibit the formation of cAMP ß receptors ? seem to stimulate the formation of cAMP ß1 & ß2 receptors ? antagonist to the effects of a - receptors ß3 receptors recently found to regulate energy metabolism expressed in adipocytes, & their activation by agonists reduces the amount of body fat are a target for the development of anti-obesity drugs NORADRENERGIC & ADRENERGIC RECEPTORS …Contd
20 : Psychiatric drugs most a/w NE ? TCAs, MAOIs &, more recently, venlafaxine, mirtazapine, bupropion, & nefazodone NE & DRUGS …Contd TCAs, venlafaxine, bupropion, & nefazodone, block the reuptake of NE (& serotonin) into the presynaptic neuron MAOIs block the catabolism of NE (& serotonin) Imm. effect ? increase the concentrations of NE (& serotonin) in the synaptic cleft Mirtazapine acts by blocking the presynaptic a2-receptors & thus removing the feedback inhibition normally exerted on the release of NE. The net effect of mirtazapine is to increase NE secretion eventually lead to a down-regulation of the number of postsynaptic ß-receptors clinical improvement
21 : Blockade of a1-receptors is a/w sedation & postural hypotension Clonidine (a-receptor agonist) ?  inhibition of noradrenergic activity through presynaptic stimulation of a2-receptors neurons. By so doing, it counteracts the anxietogenic effects that make opiate withdrawal so unbearable Methyldopa (competitive inhibitor of L-aromatic amino acid decarboxylase) ? Normally transforms methyldopa to methyldopamine - to methylnorepinephrine - displaces NE from storage vesicles ? Methylnorepinephrine acts as an a2-receptor agonist to lower blood pressure Yohimbine (a2-receptor antagonist) ? used to reverse the antisexual effects of antidepressants, especially those of the serotonergic class Propranolol (ß2 antagonist) ? results in a decrease in cAMP formation in the postsynaptic neuron used to treat social phobia, akathisia, & lithium-induced tremor …Contd
22 : The biogenic amine hypothesis of mood disorders Based on the observation that the tricyclic drugs & the MAOIs are effective in alleviating the symptoms of depression Roles of serotonin & norepinephrine are in the pathophysiology of depression is still unclear Drugs affecting both the NTs as well as individual NTs are affective In experimental animal models If noradrenergic neurons are destroyed ? drugs affecting serotonin don’t have their usual affect Vice-versa NE & PSYCHOPATHOLOGY …Contd
23 : The major site of serotonergic cell bodies ? upper pons & midbrain - specifically, the median & dorsal raphe nuclei &, to a lesser extent, the caudal locus ceruleus, the area postrema, & the interpeduncular area These neurons project to the basal ganglia, the limbic system, & the cerebral cortex SEROTONIN CNS SEROTONERGIC TRACTS
24 : Site ? Axon terminal Synthesized from ? Tryptophan Rate limiting step ? availability of tryptophan After synthesis ? packaged into vesicles Action terminated by ? reuptake by plasma membrane transporter Metabolism by ? MAO (esp. MAOA) Primary metabolite ? 5-HIAA SEROTONIN LIFE CYCLE …Contd
25 : SEROTONERGIC RECEPRTORS …Contd
26 : 5HT1A (Buspirone, Ipsapirone) ? treat anxiety, depression (partial agonist) 5HT1D (Sumatriptan) ? treat migraine (partial agonist) 5HT2A/2C (Methysergide, Trazodone, Risperidone) ? treat migraine, depression, schizophrenia (antagonist) 5HT3 (Ondansetron) ? treat chemotherapy- induced emesis (antagonist) 5HT4 (Cisapride) ? treat GI disorders (agonist) 5HT transporter SSRIs (Fluoxetine, sertraline) ? treat depression, OCD, panic disorder, social phobia, post traumatic stress disorder (inhibitor) SEROTONIN & DRUGS …Contd
27 : The permissive hypothesis Postulates that low levels of serotonin permit abnormal levels of NE to cause depression or mania With the success of SSRIs & buspirone, which are effective antianxiety agents, the theory of anxiety needed room for a role for serotonin Similarly, schiz was previously thought to result from an imbalance of dopamine, but since the therapeutic success of the SDAs, schiz is now thought to result from misregulation of both dopamine & serotonin function SEROTONIN & PSYCHOPATHOLOGY …Contd
28 : NT REGULATION of MOOD & BEHAVIOR Motivation Pleasure Reward Alertness Energy Obsession Compulsion Dopamine Norepinephrine Serotonin Mood Attention Interest Anxiety
29 : Neurons location ? hypothalamus Project to ? cerebral cortex, limbic system, & thalamus HISTAMINE
30 : A group of cholinergic neurons in the nucleus basalis of Meynert projects to the cortex & limbic system Some pts with AD or Down syndrome ? sp degeneration of the neurons in the nucleus basalis of Meynert ACETYLCHOLINE CNS CHOLINERGIC TRACTS BIOSYNTHESIS of ACh
31 : CHOLINERGIC RECEPTORS …Contd
32 : M/C use of anticholinergic drugs in psychiatry ? T/T of the motor abnormalities caused by the use of typical antipsychotics ? efficacy determined by the balance b/n ACh activity & DA activity in the basal ganglia Blockade of muscarinic receptors ? blurred vision, dry mouth, constipation, and difficulty in initiating urination Excessive blockade of CNS cholinergic receptors ? confusion & delirium Drugs increasing cholinergic activity by blocking breakdown by acetylcholinesterase ? shown to be effective in the T/T of dementia of the Alzheimer's type Recent evidence has shown that nicotine increases the strength of synaptic connections in the hippocampus, the brain region that supports short-term memory Several nicotine-like compounds that stimulate acetylcholine release are under study as cognitive enhancers for treatment of Alzheimer's disease ACh & DRUGS …Contd
33 : M/C association with ACh is dementia of the Alzheimer's type With the recent identification of the protein structures of the various muscarinic & nicotinic receptors, many researchers are working on specific muscarinic & nicotinic agonists that may have some benefit in the t/t of dementia of the Alzheimer's type. Acetylcholine may also be involved in mood & sleep disorders ACh & PSYCHOPATHOLOGY …Contd
34 : AMINO ACID NTs
35 : Inhibitory NT of CNS Found exclusively in the CNS & does not cross the BBB Highest conc. ? midbrain & diencephalon GABA Glutamic acid decarboxylase (GAD) converts glutamate to GABA
36 : 2 subtypes of GABA receptors GABAA receptor ? ionotropic (Cl- channel, postsynaptic receptor) GABAB receptor ? metabotropic (K+ channel, G protein-coupled, postsynaptic receptor & presynaptic autoreceptor) GABA RECEPTORS & IMPLICATIONS GABA is thought to suppress seizure activity, anxiety, & mania Progabide ? GABA receptor agonist Tiagabine ? inhibits the GABA transporter Vigabatrin ? inhibits GABA-T, raise the effective synaptic levels of GABA & exhibit anticonvulsant activity Topiramate ? potentiates GABA receptor activity by unclear mechanisms Gabapentin ? a GABA derivative Benzodiazepines ? increase the affinity of the A-receptor for GABA …Contd
37 : Clinical research on the GABAergic system, because it is a/w benzodiazepines, has focused on its potential role in the pathophysiology of anxiety disorders Many of the standard anticonvulsants also have their effects on the GABA system; therefore, researchers in epilepsy also are actively studying the GABA system The success of the anticonvulsants carbamazepine & valproic acid for the t/t of rapid cycling bipolar I disorder has stimulated trials of the GABAergic anticonvulsants GABA & PSYCHOPATHOLOGY …Contd
38 : Synthesized primarily from ? serine Enzymes ? serine trans-hydroxymethylase and ß-glycerate dehydrogenase, both of which are rate limiting Does double duty ? as a mandatory adjunctive NT for glutamate activity & an independent inhibitory NT at its own receptors Improvement of NMDA receptor activity by occupancy of the glycine-binding site has been hypothesized to present an adjunctive mode for the t/t of schizophrenia. Some, but not all, clinical trials of this hypothesis have shown a reduction in the negative symptoms of schizophrenia by glycine GLYCINE
39 : In the normal brain the prominent glutamatergic pathways are the cortico-cortical pathways the pathways b/n thalamus & cortex; and extrapyramidal pathway (the projections b/n cortex & striatum) Other glutamate projections exist between the cortex, substantia nigra, subthalmic nucleus and pallidum GLUTAMATE
40 : Synthesized from ? glucose & glutamine in presynaptic neuron terminals Stored in ? synaptic vesicles Glutamate release is stimulated by nicotine 5 major types of glutamate receptors The NMDA receptor is the best understood and most complex of the receptors ? may play an essential role in learning & memory, as well as psychopathology …Contd
41 : Major pathophysiological conditions currently a/w the glutamate systems ? excitotoxicity & schizophrenia Excitotoxicity relates to the hypothesis that excessive stimulation of glutamate receptors leads to prolonged & excessive intraneuronal concentrations of calcium & NO Such conditions activate many enzymes (especially proteases) that are destructive to neuronal integrity Schiz ? a reduction in NMDA receptor activity is thought to cause psychotic symptoms Attempts to reduce excitotoxicity during strokes with the NMDA receptor blocker MK-801 were terminated because of precipitation of psychosis Too much NMDA receptor activity kills neurons, and too little NMDA receptor activity induces psychosis Studies show that dopamine & glutamate have opposing effects GLUTAMATE & PSYCHOPATHOLOGY …Contd
42 : SCHIZOPHRENIA Over 2/3rd of treated pts with D2 antagonist remain substantially disabled Early PM studies indicated a reduction in the activity of GAD in the cortex in patients with schizophrenia as compared to suitable controls Immunocytochemistry & gene expression techniques ? have more precisely defined the GABAergic deficit in schizophrenia The theory that hypofunction of NMDA receptors is an etiologic factor in schizophrenia initially arose from the observation that PCP & related dissociative anesthetics that block NMDA receptors produce a syndrome that can be indistinguishable from schizophrenia NEUROPSYCHIATRIC IMPLICATIONS OF AMINO ACID TRANSMITTERS
43 : ANXIETY & DEPRESSION GABAergic dysfunction ? a/w anxiety D/Os, esp. panic d/o, & MDD Decreased levels of the GABAA receptor modulators have been found both in plasma & in CSF in MDD MRS ? significant reductions in GABA levels in the anterior cingulate & in the basal ganglia of medicated patients with panic d/o significant reductions in both GABA & glutamate/glutamine in the prefrontal cortex in MDD NMDA receptor antagonists have antidepressant effects in several animal models of depression Two placebo-controlled clinical trials have shown that a single dose of ketamine can produce a rapid, substantial, & persistent reduction in symptoms in patients with MDD …Contd
44 : AMINO ACID NTs
45 : Alkaloid morphine isolated in 1806 In the mid-1970s, peptides isolated from brain extracts were shown to interact with opioid receptors & were called opioids Act on 3 major receptors ? µ, ?, d ? believed to be involved in the regulation of stress, pain, & mood Three classes of endogenous opioids ? enkephalins, endorphins, and dynorphins, & recently, endomorphins Emerging data on endomorphins yet unlock the mystery of addiction ENDOGENOUS OPIOIDS
46 : First isolated & characterized in 1981 as the hypothalamic messenger molecule that stimulated the release of ACTH Location ? throughout the CNS Receptors ? CRF1 & CRF2 M/C hypotheses ? modulating the organism's response to internal & external stress observation that a subpopulation of depressed patients has elevated cortisol levels, sometimes evidenced by non-suppression on a DST, has led to the hypothesis that a CRF antagonist might be useful in the t/t of depression CORTICOTROPIN-RELEASING FACTOR
47 : Primary NT in most primary afferent sensory neurons & in the striato-nigral pathway most prominently a/w mediation of the perception of pain Abnormalities affecting substance P have been hypothesized for Huntington's disease, dementia of the Alzheimer's type, & mood disorders SUBSTANCE P Hypothesized to be involved in the pathophysiology of schizophrenia ? mostly because of its coexistence with dopamine in some axon terminals NEUROTENSIN a.k.a growth hormone-inhibiting factor Postmortem studies have implicated somatostatin in Huntington's disease & AD SOMATOSTATIN
48 : Hypothesized to be involved in the pathophysiology of schizophrenia Also been implicated in the pathophysiologies of eating D/Os & movement D/Os Causes anxiety & triggers panic attacks in people with panic disorder CCK antagonists are under study as possible anxiolytic agents CHOLECYSTOKININ Postulated to be involved in the regulation of mood & social behavior VASOPRESSIN & OXYTOCIN Shown to stimulate the appetite Development of neuropeptide Y receptor antagonists is an active area of interest for obesity researchers NEUROPEPTIDE Y
49 : OTHER NTs
50 : Purine adenosine & its high-energy phosphorylated form, ATP 2 Receptors P1 - high affinity for adenosine - 2 subtypes : adenosine A1 & A2 receptors (opp. actions) - P1 receptors are blocked by xanthines, such as caffeine & theophylline - During a seizure, it is released from cells & appears to act to terminate the seizure - various research efforts to study adenosine analogues for use as anticonvulsants or sedatives P2 - high affinity for ATP NUCLEOTIDES
51 : Diverse class of protein molecules that bind to the tyrosine kinase receptors A no’s of families of neurotrophic factors exist ? the neurotrophins, the glial-derived neurotrophic factor family, the insulin family, & the cytokines Neurotrophins ? brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), & neurotrophin-3 and -4 Major role for neurotrophic factors ? long-term effects such as neuronal growth, development, & survival More closely resemble the activities of classic neurotransmitters NEUROTROPHIC FACTORS
52 : aka prostanoids Are the metabolites of arachidonic acid, prostaglandins, prostacyclins, thromboxane, & leukotrienes Have not yet fulfilled all the criteria for NTs, efforts are being made to explore this possible role EICOSANOIDS Formed from ? arachidonic acid & ethanolamine Products ? N-arachidonoylethanolamine (anadamide), & 2-arachnidonylglycerol ? Ligands for the cannabinoid receptor family Cannabinoids ? active ingredients in marijuana 2 types of cannabinoid receptors ? central (CB1) & peripheral (CB2), bind tetrahydrocannabinol (THC), the active ingredient of marijuana ENDOCANNABINOIDS
53 : TARGETING DIFFERENT ASPECTS OF SYNAPTIC TRANSMISSION
54 : RECEPTOR SYSTEMS AFFECTED BY ATYPICAL ANTIPSYCHOTICS
55 : SUMMARY
56 : Comprehensive textbook of Psychiatry, Kaplan & Sadock, 9th Edition, Lippincott Williams & Wilkins Shorter oxford textbook of psychiatry, 5th edition Synopsis, Kaplan & Sadock, Tenth Edition, Lippincott Williams & Wilkins Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e > Chapter 8. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems > Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e > Chapter 14. Neurotransmission and the Central Nervous System > Various internet sites REFERENCES
57 : THANK YOU !!!

 

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