1. Dr. M.G.SRINIVAS ROLE OF MONOAMINE NEUROTRANSMITTERS IN PSYCHIATRY
2. CONTENTS DISCOVERY OF 1ST NEUROTRANSMITTER DEFINITION OF NEUROTRANSMITTER CRITERIA FOR NEUROTRANSMITTER 7 PROCESSESS IN NEUROTRANSMITTER ACTION FATE OF NEUROTRANSMITTERS CLASSIFICATION OF NEUROTRANSMITTERS BIOGENIC AMINES DOPAMINE SEROTONIN EPINEPHRINE & NOREPINEHRINE HISTAMINE ACETYLCHOLINE
3. DISCOVERY OF 1st NEUROTRANSMITTER Acetylcholine - The first neurotransmitter identified, in 1926, by Otto Loewi. He demonstrated that Acetylcholine carried a chemical signal from vagus nerve to the heart that slowed the cardiac rhythm. Got NOBEL in physiology & medicine in the year 1936
4. NEUROTRANSMITTERS DEFINITION Neurotransmitters are chemical signals released from presynaptic nerve terminals into the synaptic cleft. The subsequent binding of neurotransmitters to specific receptors on postsynaptic neurons (or other classes of target cells) transiently changes the electrical properties of the target cells, leading to an enormous variety of postsynaptic effects.
5. CRITERIA FOR NEUROTRANSMITTERS 1. Molecule is synthesized in neuron 2. Molecule is present in presynaptic neuron & is released on depolarisation in physiologically significant amount 3. When administered exogenously as a drug, the exogenous molecule mimics the effect of endogenous neurotransmitter 4. A mechanism in neurons or synaptic cleft acts to remove or deactivate the neurotransmitter
6. MAJOR STEPS IN NEUROTRANSMITTER PROCESSING are: 1. SYNTHESIS 2. STORAGE 3. RELEASE 4. RECEPTION 5. INACTIVATION
7. FATE OF NEUROTRANSMITTERS 1. It is consumed ( broken down or used up) at postsynaptic membrane leading to action potential generation. 2. Degraded by enzymes present in synaptic cleft. 3. Reuptake mechanism( reutilization), this is the most common fate.
10. All monoaminergic systems share common anatomical features. Each has a cluster of cell bodies in a few restricted sub cortical or brainstem regions, which then send long and extensively branched axonal processes into multiple cortical and limbic target regions. The precise evolutionary reasons for this organization are unclear, although it could in principle allow monoaminergic systems to coordinately control spatially distant brain
12. DOPAMINE HISTORY The function of DA as neurotrasmitter was discovered in1958 by arvid carlsson & nils ake hillarp. ARVID CARLSSON got NOBEL for physiology or medicine in 2000 for showing that DA is not Just a precursor of NE & E but a Neurotransmitter as well.
13. DOPAMINE DEGRADATION
14. DOPAMINE PATHWAYS 5 dopamine pathways in the brain: 1. The MESOLIMBIC DA pathway, 2. The MESOCORTICAL DA pathway, 3. The NIGROSTRIATAL DA pathway, 4. The TUBEROINFUNDIBULAR DA pathway, 5. The THALAMIC DA pathway DA pathways in the brain can explain the symptoms of schizophrenia as well as the therapeutic effects
15. (1) THE MESOLIMBIC DOPAMINE PATHWAY projects from the midbrain ventral tegmental area to the nucleus accumbens, a part of the limbic system
16. MESOLIMBIC PATHWAY role in -emotional behaviour -pleasure -motivation -reward
17. HYPERACTIVITY OF MESOLIMBIC PATHWAY -positive psychotic symptoms accompanying mania, depression, dementia. INCLUDES: -delusion -hallucination -aggression -hostility -euphoria in drug abusers
18. HYPO ACTIVITY OF MESOLIMBIC PATHWAY lack of general motivation & interest, anhedonia negative symptoms, drug abuse.
19. (2) MESOCORTICAL DOPAMINE PATHWAY projects from midbrain ventral tegmental area & sends its axons to areas of the prefrontal cortex Dorsolateral prefrontal cortex, DLPFC Ventromedial prefrontal cortex, VMPFC
20. MESOCORTICAL pathway dorsolateral prefrontal cortex role -Regulates cognition & -Executive functions Hypofunction: -Cognitive deterioration -Negative symptoms in schzophrenia
23. Chronic D2 blockade leads to neuroleptic induced Tardive dyskinesia
24. (4) TUBEROINFUNDIBULAR DA PATHWAY
25. TUBEROINFUNDIBULAR DA PATHWAY Activity - decrease in prolactin release Postpartum- increase in prolactin Antipsychotics - increase in prolactin -galactorrhoea -amenorrhoea -sexual dysfunction
26. (5) THALAMIC DA PATHWAY arises from multiple sites, -periaqueductal gray, -ventral mesencephalon, -hypothalamic nuclei, & -lateral parabrachial nucleus, projects to the thalamus. Function is not currently well known. In primates it involves in sleep & arousal mechanisms No evidence of its involvement in
27. DOPAMINE RECEPTORS. 5 Types D1, D2, D3, D4, D5. 2 Groups D1 Like D2 Like D1, D5 D2, D3,D4 Cyclic AMP Cyclic AMP D2- Striatum
28. -D2 receptor was initially distinguished from the D1 receptor on the basis of its high affinity for butyrophenones Moreover D2 receptor stimulation was observed to inhibit rather than stimulate adenylate cyclase activity. Unlike D1-like receptors, D2 receptor may have either a postsynaptic function or an auto receptor function
29. D2 auto receptors may be found on dopaminergic terminals or on the cell bodies and dendrites of dopaminergic neurons, where they mediate the inhibition of evoked dopamine release and the inhibition of dopaminergic neuronal firing. Furthermore, the over expression of striatal D2 receptors during brain development can cause long-lasting defects in prefrontal dopaminergic transmission and working memory in mice, a finding relevant to neurodevelopmental hypotheses of schizophrenia.
30. D2 receptors are also expressed in the anterior pituitary and mediate the -dopaminergic inhibition of prolactin and -a-melanocyte-stimulating hormone release. Molecular cloning has revealed long and short forms of the D2 receptor Auto receptor functions are mediated by the short form of this receptor
31. Catalepsy induced by neuroleptics such as haloperidol appears to be largely mediated by the long form of the D2 receptor Post mortem analyses of schizophrenic brains reveals elevations in D2 receptor density. Furthermore, radioligand binding studies have revealed -a correlation between the clinical efficacy of antipsychotic drugs and their antagonist affinities for this receptor subtype.
32. This finding has contributed significantly to the dopamine hypothesis of schizophrenia. The extrapyramidal side effects of antipsychotic drugs have been attributed to blockade of striatal D2 receptors.
33. D3, D4 receptors D3 receptor expression is highest in the nucleus accumbens. The highest levels of D4 receptors are expressed in -frontal cortex, -midbrain, -amygdala, -hippocampus, and medulla D4 receptors are abundant in the heart and kidney.
34. The D3 receptor may play a role in the control of locomotion. Elevated D4 receptor levels have been found in post-mortem schizophrenic brains. Moreover, the atypical antipsychotic drug clozapine has a high affinity for the D4 receptor.
36. IMPORTANT PERSONALITIES IN DISCOVERY OF SEROTONIN A.BETTY TWAROG B.ARDA GREEN C.MAURICE RAPPORT D. IRVINE PAGE
37. Dr. VITTORIO ERSPAMER (1909 1999)
38. SEROTONIN 2% in CNS 98% in PERIPHERY 5HT Cannot cross B.B.B. 80% in G.I. Tract(motility & contractility) 15-18% in Mast cells & platelets(aggreg. & clotting) -
39. Serotonin Synthesis & degradation
40. SEROTONIN PATHWAYS Clustered in midline raphe nuclei of brainstem 1)ROSTRAL NUCLEI- sends ascending axonal projections throughout the brain 2)CAUDAL NUCLEI sends projections to medulla, cerebellum & spinal cord Innervation of dorsal horns implicated in suppression of noceceptive pathways, relate to
41. Rostral System: The Rostral midbrain cluster of cells (raphe nuclei) are distributed throughout the midbrain, it provides over 80% of the 5-HT innervation of the forebrain. Sends projections to Prefrontal cortex, -basal forebrain, - striatum, -nucleus accumbens, -thalamus, -hypothalamus, -amygdala, -hippocampus
42. A cluster of cells located medially and another located dorsally MEDIAN RAPHE NUCLEUS: sends projections predominantly to Limbic system including hippocampus. DORSAL RAPHE NUCLEUS: sends predominantly to striatum & thalamus. Projections from these nuclei course through the MEDIAN FOREBRAIN BUNDLE before diverging to many regions. Innervation of forebrain structures by serotonergic processes is complementary to that
43. OTHER SYSTEMS: In addition to the above two pathways, another 5-HT pathway projects partially from one of the Rostral nuclei and partially from two caudal nuclei to innervate the cerebellar cortex and deep cerebellar nuclei. There is also a widespread 5-HT projection to structures within the brainstem, including the locus coeruleus, several cranial nuclei, inferior olivary nucleus, and nucleus solitarius.
44. SEROTONIN RECEPTORS 7 types of serotonin receptors are now recognized: 5-HT1 through 5-HT7, with numerous subtypes, totaling 14 distinct receptors The 5-HT1- is the largest serotonin receptor subfamily, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, & 5-HT1F The most intensively studied of these has been