The Dopamine Hypothesis Part 2 The function of neurotransmitters as an explanation of schizophrenia

Version 2: Davis (1991) Davis’ work addressed problems presented by a wave of conflicting data from… postmortem studies metabolite studies brain imaging data animal studies. It became obvious that not all people with schizophrenia have an excess of dopamine

Research into typical anti-psychotics as many as 40% of people with schizophrenia do not experience relief from dopamine antagonists such as chlorpromazine (D2 receptor blockers) many people with schizophrenia who do experience some relief still experience negative symptoms The dopamine hypothesis was in trouble!

Atypical antipsychotics: CLOZAPINE new drugs were being found to be particularly helpful to those people who did got get any relief from typical antipsychotics (dopamine blockers). These people seemed to respond well to drugs like CLOZAPINE which block both dopamine and serotonin receptors.

Clozapine continued effective in reducing both positive and negative symptoms possible that negative symptoms are linked to an excess of serotonin. Also, it had been found that serotonin regulates dopamine in areas such as meso-limbic pathway and this demonstrates the importance of considering how neurotransmitters influence and effect each other.

Hypodopaminergia PET scanning had revealed that many schizophrenics have low blood flow in the frontal lobes, known as hypofrontality they also had low levels of metabolites for dopamine in their cerebro-spinal fluid, suggesting low levels of dopamine (hypodopaminergia) in the frontal regions.

Davis hypothesized that schizophrenia was caused by… hypodopaminergia in the frontal lobes hyperdopaminergia in the striatum

he also suggested that.. negative symptoms result from hypodopaminergia in the frontal lobes and meso-cortical pathways positive symptoms result from hyperdopaminergia in the striatum and mesolimbic pathway.

Version 3: Howes and Kapur (2009) The common pathway to psychosis - “dopamine dysregulation” in the striatum discusses a wide range of genetic and environmental factors that may lead to excess dopamine in this region focus on presynaptic dopamine levels as responsible for schizophrenic symptoms as opposed to irregularities of D2 receptors as previous versions had highlighted. softer view than previous version an explanation of “psychosis proneness” not an explanation of schizophrenia socio-cultural factors are critical in determining the actual diagnosis.

“Aberrant salience” dopamine dysregulation may alter the way a person appraises external stimuli abnormal firing of dopamine neurons and the abnormal release of dopamine leads the individual to erroneously perceive links between innocuous (unlinked) stimuli. Psychotic symptoms, especially delusions and hallucinations, emerge over time as the individual attempts to explain to him or herself the experience of “aberrant salience”. Psychosis is, therefore, aberrant salience driven by dopamine and filtered through the individual's existing cognitive and sociocultural schemas—thus allowing the same chemical (dopamine) to have different clinical manifestations in different cultures and different individuals.

Negative symptoms and noise in the system negative symptoms can also be explained this way dopamine dysregulation may increase the “noise in the system” and therefore, “drowning out”, dopaminergic signals linked to stimuli indicating reward. net result would be reduced motivational drive that would lead over time to negative symptoms, such as social withdrawal, and neglect of interests.

Howes and Kapur concluded… as the dopamine hypothesis evolves further, the scientific challenge will be not just to find predisposing genes but to articulate how genes and environment interact to lead to dopamine dysfunction.