Examining the Effects of Dopamine System Stimulation During Cortical Axon Guidance

VANDERBILT REVIEWS | NEUROSCIENCE VOLUME 1 | MAY 2009 | 17 ©2009 Vanderbilt Brain Institute. All rights reserved. Dopaminergic neurons originate mainly from two midbrain regions, the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc). SNc neurons project to the dorsal caudate nuclei of the striatum, forming the nigrostriatal pathway. The striatum participates in extrapyramidal motor circuits involving the thalamus and motor cortex. Altered dopaminergic tone from the SNc to the striatum can result in hypoor hyper-kinetic movement disorders such as Parkinson’s Disease (PD) and Huntington’s Disease. VTA neurons send dopaminergic projections to the prefrontal cortex (PFC), forming the mesocortical pathway, and to the nucleus accumbens (NAcc), amygdala, and hippocampus to form the mesolimbic pathway. The mesolimbic system mediates pleasure seeking, reward, and addictive behavior. Decreases in PFC gray matter and reduced PFC activation during cognitive tasks have been seen consistently in schizophrenic patients, making mesocortical dopamine (DA) signaling an area of interest in the field of psychiatry. Schizophrenia is a devastating and debilitating mental disorder that affects approximately 1% of the world population. The disease is characterized by positive symptoms (hallucinations, psychosis, delusions), negative symptoms (withdrawal, avolition, anhedonia), and cognitive deficits. Weinberger has postulated that schizophrenic patients suffer from an imbalance of DA innervation—an overactive mesolimbic system causes the positive symptoms while an underactive mesocortical system causes negative and cognitive symptoms. Postmortem analysis of schizophrenic brains reveals a decrease in tyrosine hydroxylase (TH)+ and dopamine transporter (DAT)+ axons innervating the PFC. The PFC mediates executive function, decision-making, working memory tasks, and critical thinking skills. Individuals with schizophrenia perform poorly on tests that evaluate these skills. DA receptors have long been the target for pharmacological treatment of psychotic disorders. All antipsychotic drugs (APDs) antagonize the D2 DA receptor, essentially decreasing dopaminergic signaling in patients. APDs relieve positive symptoms of the disease but do little to improve cognitive deficits and negative symptoms Overexpression of striatal D2 receptors in animal models results in decreased DA turnover in the PFC and impaired performance on PFC-mediated working memory tasks. The imbalance of DA circuitry in schizophrenia may underlie PFC dysfunction and involve mechanisms that are not alleviated with current pharmacological therapies. Early life insults, especially those involving the DA system, may profoundly contribute to the pathophysiology of schizophrenia and alter nervous system development Examining the Effects of Dopamine System Stimulation During Cortical Axon Guidance