NEUROPEPTIDES aspect from Psychiatry .pptx

Neuropeptides

1. NEUROPEPTIDES Presenter: Dr.Chandrabala p nair Chair: dr.rajani raju

2. Neuropeptide is a chain of two or more amino acids linked by peptide bonds. Direct or neuromodulatory effects: Ranging from modulating neurotransmitter release & neuronal firing patterns to the regulation of emotionality & complex behaviors.

3. BIOSYNTHESIS Transcription of an mRNA from a specific gene Translation of a polypeptide preprohormone encoded by that mRNA. Posttranslational processing involving proteolytic cleavage of the preprohormone to yield the active neuropeptide.

4. DISTRIBUTION AND REGULATION Neuropeptides are often colocalized and released with other neuropeptide or nonpeptide neurotransmitters. The colocalization of neuropeptides within classical neurotransmitter circuits suggests an interaction b/w these systems.

5. Many neuropeptides are cotransmitted with nonpeptide neurotransmitters & serve to modulate neurotransmission of both pre- & post-synaptic cells. These interactions suggests the involvement of neuropeptides in the underlying pathophysiology of psychiatric disorders.

6. NEUROPEPTIDE SIGNALING Neuropeptides act as neurotransmitters, neuromodulators, or neurohormones . Neuropeptide NT’s released from axonal terminals into a synapse- Binding to neuropeptide receptors - either depolarizing or hyperpolarizing the cell. Rest of them alter response off the cell, to other neurotransmitters through modulation of 2ndmessenger pathways.

7. Release also occurs throughout the axon / even from dendrites. In the end, Released by exocytosis of granules in response to electrical / hormonal stimulation of neurons. Stimulation of neurons increases intracellular ca2+ conc. --- fusion of peptidergic granules to the plasma membrane --- expulsion of the peptide into extracellular space.

8. Most neuropeptide receptors are G‑protein‑coupled, seven‑transmembrane domain receptors. Most common signaling pathways involve activated G‑protein modulating the activity of either adenylate cyclase or phospholipase C.

9. PEPTIDASES Released peptides are degraded into smaller fragments Enzymes – found bound to post- or presynaptic neural membranes or in the cytoplasm & ECF. Distributed widely in peripheral organs, serum, as well as in the CNS. As a result neuropeptides generally have half-lives on the order of minutes once released.

10. SPECIFIC NEUROPEPTIDES AS PROTOTYPES OF NEUROPEPTIDE BIOLOGY Thyrotropin-Releasing Hormone Corticotropin -Releasing Factor and Urocortins Oxytocin and Vasopressin Neurotensin Other Neuropeptides:CCK , substance P(SP), and NPY

11. Thyrotropin-Releasing Hormone TRH immunoreactive neurons located in olfactory bulbs, entorhinal cortices, hippocampus, extended amygdala, hypothalamus, & midbrain structures. Early studies established the hypothalamic and extra-hypothalamic distribution of TRH. The gene for TRH in humans resides on chromosome 3q13.3-q21.

12. Hypothalamic TRH neurons – project to median eminence – release TRH into hypothalamo-hypophyseal portal system—transported to the adenohypophysis --- release of TSH into circulation. TSH subsequently stimulate the release of the thyroid hormones.

13. Clinical studies, suggests existence of an increased rate of hypothyroidism among patients with refractory depression. Clinical use of a standardized TRH stimulation test measures - ve feedback responses, revealed blunting of the TSH response in approx. 25% of euthyroid patients with major depression.

14. Corticotropin -Releasing Factor and Urocortins CRF is the primary hypothalamic ACTH secretagogue Also functions as an extrahypothalamic neurotransmitter / neuromodulator , along with the urocortins , globally coordinate responses to stressors. The PVN of the hypothalamus is the major site of CRF-containing cell bodies that influence anterior pituitary ACTH.

15. Neurons originate in the parvocellular region of the PVN --- send axon terminals to median eminence --- CRF released into hypothalamic- hypophyseal portal system in response to stressful stimuli. A small group of PVN neurons also project to the brainstem and spinal cord -- they regulate autonomic aspects of stress response.

16. CRF gene expression and content in the PVN *negatively influenced by glucocorticoids (cortisol) and *positively regulated by a wide variety of stressors. The gene for CRF in humans is located on chr. 8q13 CRF is also found in the raphe nuclei and the locus coeruleus (LC), circuits long postulated to play a role in the pathophysiology of depression and anxiety.

17. Oxytocin and Vasopressin The human OT and AVP genes are situated tandemly in a head-to-tail fashion on chromosome 20p13 s OT and vasopressin mRNAs: heavily concentrated in the magnocellular neurons of PVN and the supraoptic nuclei of hypothalamus, send axonal projections to neurohypophysis .

18. In addition, magno - and parvocellular hypothalamic and extrahypothalamic neurons produce OT and AVP, and send projections to the forebrain and brainstem. AVP is released into bloodstream from neurohypophysis following a variety of stimuli incl. plasma osmolality, hypovolemia, HTN, &hypoglycemia.

19. OT released from pituitary -- functions assoc. with female reproduction -- regulating uterine contractions during parturition & milk ejection reflex during lactation. AVP(ADH), regulates H2O retention in kidney & vasoconstriction through interactions with V2 and V1a receptor subtypes.

20. Actions of OT are mediated via a single receptor subtype (OTR), which is distributed in the periphery and within the limbic CNS. In contrast to the OTR, there are three AVP receptor subtypes, V1a, V1b, and V2 receptors, each of which is G-protein–coupled

21. These peptides are now known to regulate a number of processes, ranging from anxiety, learning, & memory to complex social behaviors. OT has been reported to facilitate female sexual behavior, increase social interest, & facilitate onset of maternal behavior. OT plays a similar role in regulating human social cognition.

22. Central OT produces clear anxiolytic effects in animal models. Central AVP appears to exert anxiogenic effects. Polymorphisms of the OTR: recently shown to mediate vulnerability to depression and anxiety. OT dysfunction has also been implicated in ASDs. Dysregulation of AVP and/or its receptor may represent a risk factor that contributes to the social cognition deficits in autism

23. Neurotensin Investigated in terms of assoc. with mesolimbic dopamine system ,& has gained interest in research on the pathophysiology of schizophrenia. 1st, the NT system is positioned anatomically to modulate the neural circuits implicated in schizophrenia. 2nd, peripheral administration of antipsychotic drugs has been shown to consistently modulate NT systems.

24. 3rd, there is evidence that central NT systems are altered in schizophrenic patients. Within the midbrain, NT-producing neurons are found in the VTA and SN. These NT-dopamine cells project to the prefrontal cortex, striatum, amygdala, and lateral septum

25. Both antipsychotic drugs and NT neurotransmission enhance sensorimotor gating. Increasing evidence suggests that deficits in sensorimotor gating are a cardinal feature of schizophrenia. Both dopamine agonists and NT antagonists disrupt performance on tasks designed to gauge sensorimotor gating.

26. CCK Receptor found in areas of brain assoc. with emotion, motivation & sensory processing (e.g., cortex, striatum, hypothalamus, hippocampus, and amygdala). CCK decreases dopamine release Patients with panic disorder exhibit increased sensitivity to the CCK fragment. Pentagastrin , a synthetic CCK agonist, dose-dependently produced increased BP, PR, HPA activation, & physical symptoms of panic.

27. Substance P Substance P is localized in the amygdala, hypothalamus, periaqueductal gray, LC, and parabrachial nucleus. Substance P serves as a pain neurotransmitter More recent data suggest a role for substance P in major depression and PTSD.

28. NPY NPY is a 36 amino acid peptide found in the hypothalamus, brain stem,spinal cord, and several limbic structures Involved in the regulation of appetite, reward, anxiety, and energy balance NPY is thought to facilitate the containment of negative effects following exposure to stress

29. Neuropeptides in Psychiatry DEPRESSION: substance P, CRF, TRH,vasopressin,neuropeptide Y, and galanin . SCHIZOPHRENIA:CCK, Neurotensin AUTISM: Oxytocin, Vasopressin DEMENTIA:CRF PERSONALITY DISORDERS:oxytocin , opioids,and vasopressin

30. The Role of Neuropeptides in Suicidal Behavior Most studies have documented an association between suicidality and some neuropeptides such as: CRF, VGF, cholecystokinin, substance P, and neuropeptide Y (NPY), which have been demonstrated to act as key neuromodulators of emotional processing

31. References: Sadock , B. J., Sadock , V. A., Ruiz, P., & Kaplan, H. I. (2017). Kaplan and Sadock’s comprehensive textbook of psychiatry (10 th ed.). Wolters Kluwer. Review article,Neuropeptides in Psychiatry,Vatsal Suchak, Shashwath Sathyanath , Anil Kakunje Department of Psychiatry, Yenepoya Medical College, Mangalore, Karnataka, India Gianluca Serafini , Maurizio Pompili , Daniel Lindqvist , Yogesh Dwivedi , Paolo Girardi , “The Role of Neuropeptides in Suicidal Behavior: A Systematic Review”, BioMed Research International, vol. 2013, Article ID 687575, 22 pages, 2013. https://doi.org/10.1155/2013/687575