Dopamine system: neuroanatomy Dopamine neurons have 4 major projections: 1. Nigrostriatal pathway Substantia nigra (SNc; A9)  caudate and putamen (i.e. striatum). Motor (involuntary) control Parkinson's Disease 2. Mesolimbic pathway Ventral Tegmental Area (VTA; A10) in midbrain to limbic regions associated with reward, motivation, affect and memory Include ventral striatum (nucleus accumbens), amygdala, hippocampus & medial prefrontal cortex 3. Mesocortical pathway VTA to frontal cortex, including dorsolateral prefrontal cortex (DLPFC) cognitive function, motivation & emotional response 4. Tuberoinfundibular pathway Tuberal region to median eminence (infundibular region at top of pituitary stalk) DA acts to inhibit prolactin release from pituitary 3 1 2 4 1 1

DA abnormalities in schizophrenia Excessive DA release in striatum during illness exacerbations Positively correlated with positive symptoms (1) Correlated with good treatment response to antipsychotic drugs (2) Inadequate DA in frontal cortex Associated with deficits in cognitive function e.g. working memory (3) 3 2 1 4 DA dysregulation not thought to be a primary abnormality. Secondary to a more proximal abnormality e.g. in GABA or glutamate systems. 1. Laruelle & Abi-Dargham, 1999. J Psychopharmacol 13; 358-371 2. Abi-Dargham et al, 2000. PNAS 97: 8104-09 3. Abi-Dargham et al, 2002. J Neurosci 22: 3708 -19 2 2