Fundamentally, there is a widely perceived discrepancy between the acute dopamine receptor-blocking activity of neuroleptics and their delayed therapeutic effects; this has been approached by considering secondary effects consequent to primary dopamine receptor blockade Pickar, 1988 , or by questioning the substance of the perceived discrepancy Keck et al. The revised dopamine hypothesis states that dopamine abnormalities in the mesolimbic and prefrontal brain regions exist in schizophrenia. Specifically, the right hemisphere atrophies more, while both sides show a marked decrease in frontal and posterior volume. Most of the evidence points to a presynaptic dopamine dysregulation: more synthesis, and more release, while postsynaptic dysregulation remains unclear. Evidence for excess dopamine transmission derives from pre- and postsynaptic studies.
Another study conducted by Fan et al. This hypothesis was formed upon the discovery of dopamine as a neurotransmitter in the brain by Arvid Carlsson —. This retrograde signaling to the temporal lobes that results in the parietal lobes not recognizing it as internal results in the auditory hallucinations typical of chronic schizophrenia. These are just a few of a multitude of studies that provide evidence for the dopamine hypothesis: Coccaro et al. Patients and methods A cross-sectional study was performed at five hospitals and one mental clinic and included 212 patients, 144 family members, and 347 medical staff other than psychiatrists. To have little or no motor symptoms from an antipsychotic, it is clear that D2 receptor binding in the striatum must be less than that caused by conventional antipsychotics.
The suggests a different explanation: the Glutamate Hypothesis. This hypothesis should allow us to better understand the dopaminergic dysfunction in the context of the complex pathophysiological process leading to schizophrenia. A similarly small study found low thalamic binding; however, this was later confirmed in a larger sample of drug-naive patients ;. Alternatively, the increased D 2 receptor number may reflect presynaptic factors such as increased endogenous dopamine levels 16. A theory that explains the pathogenesis of schizophrenia and other psychotic states as due to excesses in dopamine activity in various brain areas.
Cognitive discrepancies and working memory deficits in the prefrontal cortex are associated with an increase in dopamine and D 1 -receptors in the prefrontal cortex in schizophrenia patients ,. There is some evidence from healthy volunteers that acute antipsychotic treatment does increase presynaptic dopamine synthesis capacity, and while successful subacute treatment can reduce this, it is nevertheless elevated in patients who have received antipsychotic treatment for many years. This variation may be explained by different properties of the radiotracers: the effect of dopamine depletion on binding by the tracer used in the first 2 studies may obscure D1 receptor density elevation that is detectable by the tracer used in the last study. Dopamine plays a key role in guiding attention, so explains attention problems and thought disturbances in sufferers of schizophrenia. Two studies performed with low doses of relatively selective D2 receptor antagonists haloperidol and raclopride suggest that a minimum of 50 percent occupancy is required to observe a rapid clinical response ;.
What Would Lead to a Rejection of the Hypothesis? In addition to funneling through dopamine dysregulation, the multiple environmental and genetic risk factors influence diagnosis by affecting other aspects of brain function that underlie negative and cognitive symptoms. While the evidence for this in humans was indirect, animal studies provided direct evidence of a link between hypo- and hyperdopaminergia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence, findings on environmental risk factors, research into the extended phenotype, and animal studies. Instead, psychologists favour studying a combination of the contribution of both nature and nurture to schizophrenia, as the gene environment interaction explanation does. In humans, T4 concentration is associated with tyrosine conversion to dopa a precursor to dopamine ; deficiencies of T4 concentrations are linked with various neurological impairments.
If a person reduces their risk factors, they can influence whether they develop schizophrenia or not. Some studies have also shown that, after taking amphetamine, patients diagnosed with schizophrenia show greater levels of dopamine release particularly in the than non-psychotic individuals. These agents effectively improve positive symptoms e. The hypothesis was originally based on the observation that known psycho-stimulants, such as amphetamine, induce stereotypic motor behaviors. If neurotransmitters cause schizophrenia, then reducing this activity may cure the symptoms. It is also speculated that some human groups ventured to the more habitable African southern coast leading to dietary changes i.
Arguably, the strongest support for the dopamine hypothesis was provided in the 1970th by Solomon Snyder and Philip Seeman who found that the efficacy of antipsychotic medication correlated directly with its occupancy of dopamine receptors. Further studies in patients are required to clarify this, particularly because both tracers may also bind to serotonin receptors. The notions discussed in this chapter concern variants of this long-standing dopamine hypothesis of antipsychotic drug action, in terms of differing roles for distinct receptor subtypes in regulating dopamine-mediated function. More recent work, however, has shown that atypical antipsychotic drugs such as and bind and unbind rapidly and repeatedly to the dopamine D 2 receptor. Problems with dopamine function in the mesocortical pathway may be responsible for the negative symptoms.
These answers will come from more selective tracers and more direct ways of measuring cortical dopaminergic transmission, including agonists for the D1 receptor and tracers sensitive to acute fluctuations of dopamine tone in the cortex. At the other extreme, rapidly tapering or abruptly stopping their dopaminergic medicines may cast Parkinson disease patients into a state of withdrawal — with cravings, anxiety, and drug-seeking behavior — akin to when amphetamine abusers are deprived of their stimulants. Interactions between gene variants, including those influencing dopaminergic function, and environmental risk factors are another possible route to dopaminergic dysfunction. For example, poor people are much more at risk from schizophrenia. Furthermore, it is unknown whether antipsychotic efficacy is linked to reductions in dopamine synthesis capacity. When levels of glutamate are low dopamine is overactive and results in the expression schizophrenic symptoms.
Methods: Dopamine synthesis capacity indexed as influx rate constant and clinical symptoms measured using Positive and Negative Syndrome Scale were measured before and after at least 5 weeks of antipsychotic treatment in people with first-episode psychosis. This question is much harder to address because schizophrenia is considered a neuro-developmental disease, consequently patients are diagnosed long after the disease has started its course. Overall, these findings indicate that dopaminergic abnormalities are not just seen in people who are frankly psychotic but are also seen in people with risk factors for psychosis, who often have symptoms, albeit at a less severe level. In a major meta-analysis Weinberger and Laruelle, 2001 , 17 imaging studies comparing D2 receptor parameters in patients with schizophrenia were analyzed including a total of 245 patients and 231 control subjects ; ; ; ; ; ; ; ; ; ; ;. Both the classic and -current antipsychotic drugs act primarily by increasing high-affinity D 2 -receptor expression —.
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. Further supportive research comes from the role of anti-psychotic drugs in animal studies who suggest that these drugs can induce positive symptoms very similar to acute schizophrenia in healthy individuals and can exacerbate symptoms in people who are already vunerable. Because schizophrenia is highly heritable, and because the exact neurobiological correlates of genetic risk are largely unknown, we will focus on studies examining dopaminergic abnormalities in individuals at genetic risk. Increased density of D2 receptors dopamine receptors increase hyperactivity of the mesolimbic pathway which contributes to the positive symptoms in schizophrenia. This focus on drugs suffers from the treatment aetiology fallacy: the cure is not necessarily the cause. Social isolation rearing in rats, which is a valid neurodevelopmental model of schizophrenia, reduces dopamine levels in the frontal cortex. Second, the propensity to present a psychotic reaction to a psychostimulant challenge is predictive of relapse upon antipsychotic discontinuation.