May 2016 1 Circuits regulating pleasure and

May 2016 | 1 Circuits regulating pleasure and happiness Biomarkers in psychiatry: identification and future directions › Prof. dr. Anton J. M. Loonen Pharmacotherapy and Pharmaceutical Care

May 2016 | 2 Circuits regulating pleasure and happiness › Two essential forces necessary for survival of the individual and species • Motivation to obtain food, water, warmth, comfort (reward driven) • Motivation to escape from threat, heat, cold (missery driven) › Very ancient mechanisms regulating behaviour Social Pharmacy Pharmaco-epidemiology Pharmacotherapy

May 2016 | 3 Brain of the lamprey Social Pharmacy Pharmaco-epidemiology Pharmacotherapy

May 2016 | 4 Position of the lamprey’s habenula-projecting globus pallidus Social Pharmacy Pharmaco-epidemiology Pharmacotherapy

May 2016 | 5 Function of lamprey’s GPh (reward-driven behaviour) › › Rhinocortex striatum Striatum motor centres GPh habenula SNc/VTA striatum › Succesful continue › Unsuccessful discontinue Social Pharmacy Pharmaco-epidemiology Pharmacotherapy

May 2016 | 8 Circuits regulating pleasure or happiness › Extrapyramidal basal ganglia • Caudate nucleus • Putamen • Nucleus accumbens - core › Limbic basal ganglia • • Nucleus accumbens – shell Bed nucleus stria terminalis Extended amygdala Centromedial amygdala Social Pharmacy Pharmaco-epidemiology Pharmacotherapy

May 2016 | 9 The extrapyramidal system › Cognitive CSTC circuit • Cortex – caudate – thalamus – cortex › Motor CSTC circuit • Cortex – putamen – thalamus – cortex › Motivational CSTC circuit • Cortex – accumbens – thalamus – cortex Social Pharmacy Pharmaco-epidemiology Pharmacotherapy

May 2016 | 10 The limbic system › Amygdala initiates › Hypothalamus controls • Autonomic component • Endocrine component • Thalamic component • Perception (insula) • Frontal cortex • Motor response • Cognitive response • Drive Social Pharmacy Pharmaco-epidemiology Pharmacotherapy

May 2016 | 11 Relevant re-entry circuits (regulating motivation) Social Pharmacy Pharmaco-epidemiology Pharmacotherapy

May 2016 | 12 Overview of regulating system Social Pharmacy Pharmaco-epidemiology Pharmacotherapy

May 2016 | 13 Five theories of the mechanism of depression – Course 2013 Depression may originate from two different brain structures: › Brainstem/hypothalamus/prefrontal cortex • Depression as a ‘lust’ disorder • Hypoactivity of the extrapyramidal CSTC circuit • Anhedonia and loss of energy › Hippocampus/amygdala • Depression as a ‘concern’ disorder • Hyperactivity of the limbic CGTC circuit • Dysphoria and hopelessness Social Pharmacy Pharmaco-epidemiology Pharmacotherapy

May 2016 | 14 The kindling hypothesis of mood disorders Social Pharmacy Pharmaco-epidemiology Pharmacotherapy

May 2016 | 15 The neuro-immune hypothesis of mood disorders Social Pharmacy Pharmaco-epidemiology Pharmacotherapy

May 2016 | 16 Putative mechanism in depressive disorder › Continuous stressful circumstances chronic activation stress response › Chronic activation stress response neuroplastic changes (neurotrophins/cytokines/cortisol) • Excess activation leads to activation of medial habenula-interpeduncular nucleus axis (MHb-IPN axis) • Disinhibition of hippocampal influence leads to activation of MHb-IPN axis • IPN activation leads to disproportional misery-fleeing behaviour • Excess activation of MHb leads to activation of lateral habenula-rostromedial tegmental nucleus axis (LHb-RMTg axis) • Excess activation of LHb-RMTg axis leads to decreased reward-seeking behaviour Social Pharmacy Pharmaco-epidemiology Pharmacotherapy

May 2016 | 17 Be cautious when studying depression › Depression is too common to be an illness › Life expectancy at birth should be less than 25 years › Early immune activation may have been a beneficial mechanism for survival (low hygiene, infections after injuries) › Depression results from exaggerated/continued misery-fleeing mechanisms › Depression may be a selection mechanism by eliminating the least capable individuals from reproduction (and possible life) Social Pharmacy Pharmaco-epidemiology Pharmacotherapy

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