Centrality of N-Methyl D Aspartate receptors in ameliorating the cognitive symptoms of Schizophrenia

Faculty of Pharmaceutical sciences Usmanu Danfodiyo University Sokoto Lecture Series

1. CENTRALlTY OF N-METHYL D-ASPARTATE RECEPTOR IN AMELIORATING COGNITIVE SYMPTOMS OF SCHIZOPHRENIA Faculty of Pharmaceutical Sciences Seminar Series BY DR . Y . I. ALKALI Department of Pharmacology and Toxicology, Usmanu Danfodiyo University Sokoto 11 th September, 2024 1

2. Outlines Introduction The Dopamine Theory of Schizophrenia The Serotonin Theory of Schizophrenia The Cholinergic Theory of Schizophrenia The Glutamate Theory of Schizophrenia The NMDA receptor The NMDA and its Modulation by other neurotransmitters NMDA receptor and Neuroplasticity (LTP and LTD) Regio -specific targets within the CNS Conclusion 2

3. Introduction A normal working brain reserved the ability to think, imagine, memorize, remember And integrates information in order to perform a specified tasks (Ward et al ., 2020). Pathological conditions of the brain are eminent threat to human society (Range et al., 2016). 3

4. Introduction …………………. Schizophrenia is a chronic debilitating disorder that affect mood, with estimated burden of 1% of global population ( Seeman , 2022). The African countries prevalence of schizophrenia is on the increased from 1.1% to 4.4% (Claire et al., 2022). In Nigeria about 0.45% of the population are affected by schizophrenia (WHO, 2022) 4

5. The Dopamine Theory of Schizophrenia The dopaminergic hypothesis of schizophrenia was proposed for the first time in the 1960s when chlorpromazine was introduced (Lau, 2018) T he discovery that amphetamine produces psychosis was another proof for a role of excessive dopamine in schizophrenia Prolonged dopamine D2 receptor blockade leads to downregulation of D1 receptors in the prefrontal cortex and, consequently, results in significant deterioration of working memory ( Luedtke , 2018) 5

6. The Serotonin Theory of Schizophrenia This hypothesis was reported from the mechanism of action of the hallucinogenic drug lysergic acid diethylamide on 5HT- receptors It was suggested that the overload of serotonin from the dorsal raphe nucleus (DRN) resulting from stress can disturb the activity of cortical neurons in schizophrenia E xtensive stress-derived serotonergic overload in the cerebral cortex in schizophrenia, ( ACC) and dorsolateral frontal lobe (DLFL), may be a key reason of this disorder ( Jone et al ., 2021) 6

7. The Cholinergic Theory of Schizophrenia Cholinergic neurotransmission is impaired in patients with schizophrenia and in animal models of schizophrenia (Egger, 2020) Importantly , muscarinic receptor antagonists deteriorate cognitive and negative symptoms in schizophrenia patients Xanomeline , a muscarinic receptor agonist, ameliorates some symptoms in schizophrenia patients (Meltzer, 2019). 7

8. The Glutamate Theory of Schizophrenia Disturbances in the glutamatergic neurotransmission may influence synaptic plasticity and cortical micro-circuitry, especially NMDA receptor functioning ( Egerton , 2021) NMDA-receptor hypofunction state can lead to morphological and structural brain changes which can result in the development of psychosis ( Seeman , 2020) NMDA-receptor antagonists , e.g., phencyclidine and ketamine, can mimic psychosis with similar symptoms as in schizophrenia (Jones et al ., 2018) 8

9. THE NMDA RECEPTOR N-methyl-D-aspartate receptors are ionotropic receptors mediating glutamatergic neurotransmission and play a role in several basic functions in the central nervous system From regulating neurodevelopment and synaptic plasticity, learning and memory formation, cognitive processes, breathing, and excitotoxicity NMDA receptors have been established to play a role in the pathophysiology of several neuropsychiatric disorders ( Fon and Porkess , 2019) 9

10. The NMDA and its Modulation by other neurotransmitters Activation of D1 and D2 receptors modulate NMDA receptor mediated LTP and LTD ( Elham et al ., 2022) nAChR stimulation facilitates glutamatergic transmission at selected CNS synapses and enhances a synapse selective form of LTP in the amygdala Pregnenolone sulfate potentiates NMDA receptors in relatively high concentrations in a voltage dependent manner NMDA receptor and Inflammatory cytokines in Kynurenine pathway 10

11. Neurodevelopmental Models Isolation rearing MAM Ibotenic acid 11

12. Y- maze The method of Monte et al., (2013). Spontaneous alternation was assessed on Y- maze 12

13. Novel Object Recognition Test (NORT) 13 Recognition memory test ( Baker, 2011; Lueptow , 2017) Day 1: Training session -5 mins Day 2: Testing - 5 mins Recognition index was evaluated Training sessions Test sessions

14. Elevated Plus maze 14

15. Regio -specific targets within the CNS Prefrontal cortex Hippocampus Mesorcortex 15

16. Conclusion There have been an increasing knowledge about the role of NMDA receptors in cognitive deficit and positive modulation of this receptor within the prefrontal cortex and hippocampus sub regions would yield a promising outcome in resolving cognitive symptoms 16

17. References Abi-Dargham , A ( 2022). Alterations of serotonin transmission in schizophrenia. Int. Rev. Neurobiol ., 78, 133–164. Aghajanian , G ( 2021). Serotonin model of schizophrenia: Emerging role of glutamate mechanisms. Brain Res. Rev., 31, 302–312. Akanmu M.A., Adeosun S.O., Ilesanmi O.R. ( 2019). Neuropharmacological effect of oleamide in male and female mice. Behavioral brain research . 182(1):88-94. Allen, J.A.; Roth, B.L ( 2022). Strategies to discover unexpected targets for drugs active at G protein-coupled receptors. Annu . Rev. Pharmacol . Toxicol . 51, 117–144. 17

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