Dopamine pathways & antipsychotics Pharmacology Instructor Health Sciences Faculty University of Mendoza Argentina Psychiatry Resident Mental Health Teaching Hospital “Dr. Carlos Pereyra “ Mendoza Argentina Flavio Guzmán, MD

Learning objective Understand basic concepts of dopaminergic pathways and their relevance to antipsychotic effects.

Dopaminergic pathways: outline The physiological processes under dopaminergic control include reward, emotion, cognition, memory, and motor activity. Dysregulation of the dopaminergic system is critical in a number of disease states, including Parkinson disease, Tourette's syndrome, bipolar depression, schizophrenia, attention- deficit hyperactivity disorder, and addiction/substance abuse. - Mesolimbic pathway (positive symptoms) - Mesocortical pathway (negative symptoms) - Nigrostriatal pathway (EPS and TD) -Tuberoinfundibular pathway (hyperprolactinemia)

Mesolimbic pathway & positive symptoms of schizophrenia Projections from the ventral tegmental area (VTA) to the nucleus accumbens. Anatomy Motivation, emotions, reward, positive symptoms of schizophrenia Physiology D2 antagonists reduce positive symptoms of schizophrenia. Implications

Mesocortical pathway: negative & cognitive symptoms Projections from the ventral tegmental area (VTA) to the cortex (PFC). Anatomy Cognition and executive functions (DLPFC), emotions and affect (VMPFC). Physiology Hypofunction of the mesocortical pathway might be related to cognitive and negative symptoms in schizophrenia Implications

Nigrostriatal pathway & EPS Projections from substantia nigra (pars compacta) to striatum (caudate and putamen). Anatomy Stimulation of purposeful movement. Physiology D2 antagonism induces extrapyramidal symptoms (pseudoparkinsonism) Implications

Tuberoinfundibular pathway & prolactin release Hypothalamus (arcuate and periventricular nuclei) to infundibular region (median eminence). Anatomy Dopamine is released into the portal circulation connecting the median eminence with the anterior pituitary gland. Dopamine tonically inhibits prolactin release. Physiology D2 antagonism increases prolactin levels. Implications

Summary Hyperactivation from the VTA to limbic areas might be related to positive symptoms of schizophrenia. Hypofunction of the mesocortical pathway might in part explain cognitive and negative symptoms of schizophrenia. D2 blockade of the nigrostriatal pathway can cause EPS. D2 blockade of the tuberoinfundibular pathway increases prolactin blood levels.