Dopamine pathways & antipsychotics Flavio Guzmán, MD Pharmacology Instructor Health Sciences Faculty University of Mendoza Argentina Psychiatry Resident Mental Health Teaching Hospital “Dr. Carlos Pereyra “ Mendoza In this video I will introduce dopamine pathways and their physiology relevant to antipsychotics pharmacology.

Learning objective Understand basic concepts of dopaminergic pathways and their relevance to antipsychotic effects. The learning objective of this presentation is to 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) Let’s start by outlining the dopaminergic pathways. This image shows an integration of the four dopamine pathways I’ll be talking about. It’s essential that we learn about dopamine projections before studying how antipsychotics modify dopaminergic neurotransmission. By blocking these pathways antipsychotics can produce both therapeutic and adverse effects. The four pathways relevant to the pharmacology of antipsychotics in the treatment of schizophrenia are: The mesolimbic pathway (positive symptoms) The mesocortical pathway (negative symptoms) The nigrostriatal pathway (extrapyramidal symptoms and tardive dyskinesia) The 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 As I just said, the mesolimbic pathway is relevant to positive symptoms of schizophrenia. This pathway is made up of projections from the ventral tegmental area that innervate many forebrain areas, the most important is the nucleus accumbens. Research suggests this system plays a key and complex role in motivation, emotions, reward and positive symptoms of schizophrenia. D2 antagonists reduce positive symptoms of schizophrenia. All antipsychotic drugs have the ability to reduce dopaminergic neurotransmission.

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 A number of investigators propose that negative and cognitive symptoms of schizophrenia are associated with hypofunction of the mesocortical pathway. This tract is made up of dopaminergic neurons that project from the ventral tegmental area to the prefrontal cortex. The mesocortical pathway is thought to be relevant to the physiology of: Cognition and executive function (dorsolateral prefrontal cortex) Emotions and affect (ventromedial prefrontal cortex) As I just mentioned, hypofunction of the mesocortical pathway might be related to cognitive and negative symptoms of schizophrenia.

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 The nigrostriatal dopamine pathway is related to neurological effects caused by D2 antagonists. The nigrostriatal system contains about 80% of the brain’s dopamine. This tract projects from cell bodies in the pars compacta of the substantia nigra to terminals that innervate the striatum (caudate and putamen). This pathway is involved in motor planning, dopaminergic neurons stimulate purposeful movement. D2 antagonism induces extrapyramidal symptoms. This is the case of first generation antipsychotics, high-potency D2 antagonists such as haloperidol frecuently cause pseudoparkinsonism.

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 Dopaminergic projections in the tuberoinfundibular pathway influence prolactin release. Regarding anatomical considerations, this tract consists of dopaminergic projections from the hypothalamus (more specifically the arcuate and periventricular nuclei) to the infundibular region, also in the hypothalamus (or median eminence). Dopamine is released into the portal circulation connecting the median eminence with the anterior pituitary gland. This is very important, the role of dopamine release in the tuberoinfundibular pathway is to tonically inhibit prolactin release. The main implication of this is that blockade of D2 receptors by drugs such as antipsychotics increases prolactin levels. The clinical consequences of hyperprolactinemia are discussed in other videos.

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. 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.