There Findings have supported the latest hypothesis in

There is a
vast amount of evidence to support the dopamine hypothesis III in explaining
schizophrenia. However, evidence is inconsistent to the extent it plays a role
in the onset of schizophrenia, and how all the individual aspects of the
hypothesis may link to its development. 
One of the main symptoms that has been focused on is psychosis, which
dopamine has consistently been linked to, thus making
it easier to account for the positive symptoms (McKenna, 2013), than it does for negative and
cognitive symptoms (Kapur, 2003). Vivo imaging studies has allowed
dopaminergic functioning to be assessed in the pre synaptic, leading away from
the idea that the disorder is due to elevations in D2 receptors (Kambeitz et al., 2013). Findings have supported the latest hypothesis in that dopamine
dysregulation occurs further upstream in the presynaptic system, which explains
why when a
patient stops taking antipsychotics the symptoms come back almost instantaneously,
thus indicating that there are many factors that need to be held accountable. However,
research on antipsychotics have been at the forefront of treating schizophrenia
that dopamine must not be disregarded in order to understand psychosis.

However, it fails to acknowledge what may be driving these alterations in
dopamine, therefore indicating that other neurotransmitters such as glutamate dysfunction
must be taken into account to explain these changes.  

 

To fully comprehend the latest dopamine
hypothesis, it must be acknowledged that it has come a long way since it was
first introduced as the dopamine
receptor hypothesis from the discovery of antipsychotic drugs, linking to
dopamine receptors The focus of this finding was to block excess dopamine
receptors to stop psychosis from occurring. This was far too simple to fully
explain the onset of schizophrenia, with no other possible factors taken into
consideration. Dopamine hypothesis II 1991 Davis et al incorporated regional
specificity, and found that the effects of abnormalities in dopamine function
vary depending on brain region. However, most the studies conducted were on
animals, and there was limited framework in the hypothesis.  Although this may be the case, these findings
helped guide a framework to develop throughout the years into the dopamine
hypothesis III.

 

The dopamine
hypothesis III takes into account an array of factors that all contribute to
the onset of schizophrenia. These include ‘hits’ resulting in dopamine
dysregulation, presynaptic dopamine dysregulation, psychosis as a result of
increased dopamine instead of schizophrenia, the account sociocultural factors,
and how increased dopamine causes aberrant salience. By doing so it is able to
explain both positive and negative symptoms 

 

Howes and
Kapur (2009) found that there was an abnormally large amount of D2/D3 receptors
in individuals with schizophrenia (10%-20% increase) in comparison to a healthy
control group. However, it must be taken into account that an increase in
dopamine sensitivity may be due to larger amount of receptors making it easier
to transmit, causing these abnormalities. Animal models have been of particular
interest in relation to the onset of schizophrenia. Studies show that there are
high-affinity states of D2 in these animal models, giving implication into
treating psychosis with antipsychotics that target these areas (Seeman, 2006). Seeman
(2006) found that giving amphetamine leads to hypersensitivity and elevated D2
receptors in the striatum.  Amphetamine
has also been found to cause psychosis even in healthy individuals. This gives
great support to increased levels of dopamine and the extent to which is can
explain schizophrenia. Amphetamine induced psychosis has been linked to the
development of schizophrenia. Medhus et al (2015) found that 33% of 12 patients
went onto develop schizophrenia after being administrated amphetamine. Although
a relatively low percentage, it gives insight into how dysregulation of
dopamine through drugs such as amphetamine can eventually cause healthy patients
to fully develop schizophrenic symptoms. However, one limitation of this study
is the small sample size, however this should encourage future research to be carried
out into the transition from using stimulant drugs such as amphetamine, and the
onset of psychiatric disorders.  However,
such studies do not account for the development of negative symptoms, thus
suggesting that there is more to the disorder than dopamine dysregulation. 

 

Research has
been highly concentrated on psychosis and positive symptoms, whereby clinical
research searches to alleviate those by not for the negative symptoms or
cognitive deficits. The dopamine hypothesis III is able to account for this by acknowledging
D1 dysfunction (Howes and Kapur, 2009). Dopamine depletion has been studied
using PET in the prefrontal cortex, whereby changes in the D1 in d1PFCnhas
shown to cause negative symptoms and cognitive deficits. This suggests that the
d1PFC has an impact on the symptoms seen in schizophrenia patients due to the
insufficient signalling between the D1 receptors (Goldman-Rakic et al., 2004).  Such research supplies the knowledge that
treatment must also be targeted at D1 receptors in order to downplay cognitive
deficits in order to restore cognitive functioning in schizophrenic patients as
they do not currently exist (Tamminga, 2006).  Such findings give high support for he
dopamine hypothesis III in explaining schizophrenia as it takes into account
both aspects of negative and positive symptoms. Although this may the case,
much is biased towards the psychosis aspect due to drug treatments, such as
antipsychotics.

 

The psychotic
symptoms of is seen as a state of aberrant salience when too much dopamine is
produced. The hypothesis is able to explain how elevated dopamine able to
underpin the physiology of schizophrenia through aberrant salience, which is due
to a dysfunctional reward system whereby irrelevant stimuli becomes of interest
to the schizophrenic individual due to a hyper-dopaminergic state (Kapur,
2003). These pathways are related to predict reward, and through this leads to
the emergence of delusions and hallucinations. Although this is the case, it is
up to the individual to make sense of these experiences which leads them to
have delusions and hallucinations.  Therefore,
it can be difficult to gain explicit evidence, as highly based on self
experiences and how the individuals perceive these experiences.  Roiser et al
(2009) used the Salience Attribution Test in order to evaluate aberrant
salience in both medicated and unmediated schizophrenics and a control group.

In order to do this the participants had to respond as fast at they could to
probes on the screen. Patients on medication for their positive symptoms took
less time to respond than those not. These results give a good understanding on
the effectiveness of antipsychotics drugs in regulating the positive symptoms (Roiser et al., 2008).

Another interesting finding that occurred was the aberrant salience was linked
to negative symptoms. As the individuals were interested in the irrelevant
stimuli, this could account for withdrawal and lack of social interest.

However, these were not explicitly measured from the experiment, so must be
taken with caution, although give future implications into how aberrant
salience and deregulated dopamine may lead to negative symptoms too. Another
limitation of this study is that the schizophrenic patients were all on
medication, making it had to make bold judgements on the extent to which they are
experiencing aberrant salience. However, a study supporting this with the use
of non-medicated patients using fMRI scans to scan neurological networks within
the brain found that in the ventral-striatal caused responses to irrelevant
stimuli, leading to high risk psychosis, and dopamine synthesis negatively
correlated with hippocampal responses to irrelevant stimuli. This indicates
that the dopamine hypothesis that aberrant salience is a main cause of
psychosis, due to alterations in the dopaminergic system is supported (Roiser
et al., 2012). Research supports the dopamine hypothesis III in suggesting that
increased striatal dopamine causes aberrant salience to induce psychosis. It
also supports the fact that individuals may become less interested in relevant
stimuli over time, leading to negative symptoms, which Rosier et al (2008)
found in their SAT andantipsychotics
are able to lessen these symptoms by blocking D2 receptors to reduce aberrant
salience.  However, it
must be taken into consideration that a large amount of research is targeted
towards psychosis and aberrant salience. As mentioned above, negative symptoms
have now been correlated with the tendency to be stimulated by irrelevant
stimuli, thus suggesting that further research should be conducted into these
areas to fully understand the reward system pathway is these other symptoms. It
is crucial to take into account other neurotransmitters and dopamine to further
expand on current treatments, and understand the underlying pathophysiology of
schizophrenia.  GENETICS –  There are
multiple routes that may cause dopamine dysregulation. Evidence for hyper
dopaminergic in the striatum is pre synaptic function. Specific gene groups and
presynaptic function have been related to neurotransmitters glutamate and D2 receptors (Mirnics et al., 2001). Studies
suggest that there is no one gene that encodes for schizophrenia, although it
may be caused by forms of DNA sequence variations called single nucleotide polymorphisms (SNPs). Though this is true, a large
majority of research is inconsistent, making it difficult to pinpoint exact
genes that encode genetic susceptibility in schizophrenia (Allen et al, 2008). Over
8000 SNPs have been found in conjunction with schizophrenia, giving explanation
to over 50% individuals having a genetic predisposition (Harrison, 2015). Multiple
SNPs have been associated with four dopaminergic genes; SLC6A3, DRD3, COMT and
SLC18A2. These genes encode a dopamine transporter, controlling the intensity
and duration of dopamine by modulating re-uptake into the presynaptic nerves.

These dopamine transporter genes may individually and jointly put an individual
at risk for developing schizophrenia. The DRD3 gene is of particular interest
as it encodes for the D3 dopamine receptor, and is highly associated with
increased receptor binding, leading to greater reuptake of dopamine (Database, 2017). Thus, supporting
the dopamine hypothesis III, by taking in account genetics that have an impact
on dopamine, by increasing re-uptake in receptors, leading to psychosis.  Although this may be the case, other studies
have reached different conclusions on the extent to which genes may have an
impact on developing schizophrenia. Harrison (2015) states that genes may only
have a small effect on schizophrenia and their impact on the dopaminergic
system with very low odd ratios between 1.10-1.20. This may suggest that genes
only operate on a vulnerability level, making an individual more susceptible to
becoming schizophrenic rather than being the sole cause.  However,
an important implication that has risen from genetic research is that there is
major genetic pleiotropy between specific SNP genes in schizophrenia, and other
psychiatric disorders (Lee et al., 2013). Lee
et al (2013) found high genetic correlation (0.68) in common SNPs in
schizophrenia and bipolar disorder. This suggests that there are common genetic
variations linked to dopamine in psychiatric disorders, which should encourage
future research to look into pathophysiology’s for related disorders.  Furthermore, HITS are able to capture
multiple factors that interplay in the onset of psychosis. Genes and stressors
have been interlinked and connected to dopamine functioning. Behavioural
sensitization refers to an individual’s stress and trauma they’ve experienced
which causes dysregulation in the hypothalamus pituitary adrenal axis, leading
to stress induced dopamine increase. Thus, giving the impression that
environmental factors are able to regulate dopamine sensitivity, and the onset
of psychosis. Supporting
evidence comes from Winkel, Stefanis and Myin-Germeys (2008) using vivo imaging data finding
dopamine release in group high negative schizoptypy. This may be due to
different genes playing a role in risk factor of
developing schizophrenia symptoms. Supporting Evidence using PET scans suggests
that stress induced synaptic dopamine release is significantly correlated with
negative schizotypy in healthy individuals
at risk of developing psychosis (Soliman et al., 2007). Studies such as this help us intervene before the onset of
schizophrenia occurs.   Glutamate- Although this may be the case,
specific genes have been identified to affect glutamate neurotransmission. An
issue with the dopamine hypothesis is that it only links one neurotransmitter
with schizophrenia, and does not recognize others. As antipsychotic drugs only
tend to block D2 receptors to decrease positive symptoms, and the fact that at
least 30% do not respond implies that other mechanisms have a role in the
positive and negative symptoms. In order to study the implications of glutamate
on schizophrenia, HMRS and PET imaging are used. Glutamate receptors NMDARs
block neurotransmission at the site causing schizophrenic symptoms to
arise.  Dopamine regulation is sensitive
towards glutamine, indicating that changes in glutamate levels mediates
dopamine activity. By doing so it puts a wider understanding of how dopamine is
regulated in the pre frontal cortex and hippocampus, when other factors are not
present. Studies using ketamine have been of particular interest, as the drug
is able to block the NMDAR receptor causing dysregulation of glutamate leading
to an increased sensitivity of dopamine. Poels et al (2013) found that in
healthy controls when given ketamine found that there was an NMDA blockade on
striatal dopamine release leading to similar cognitive impairments, negative
and positive symptoms likewise to those seen in schizophrenia (Coyle, 2006).  Although this may be the case, it is hard to
directly link this to schizophrenia as the studies consisted of healthy
controls, with no thought of future development of schizophrenia. However, by
doing so, it helps understand how these two neurotransmitters may interplay to
develop the symptoms of schizophrenia. Studies have also found that giving low
doses of ketamine over a period of time exaggerates dopamine release by acting
on the NMDA receptors supporting the glutamate theory. Such research is further
supported by the amphetamine challenge whereby it causes a disruption of
glutamate, in turn disrupting the dopamine release.  While plausible, there are limitations when
studying glutamate is that the main way of studying them is through H-MRS.

Although they can give a wide picture, they are not able to distinguish between
intra or extracellular compartments, limiting the extent to which these studies
can be validated.  Radiotracers are far abler
to give insight into specific areas, inferring that future research should
focus on these techniques.   Conclusion – Although the dopamine hypothesis III seems
plausible, there is not enough strong evidence to suggest a big enough role in
negative symptoms. As the hypothesis has been revived throughout the years,
this is most likely going to happen in the future, contributing as more
evidence is added. However, by accepting the dopamine hypothesis as the biggest
contributor to the onset of schizophrenia, it is easy to rationalize the use of
drugs to treat the positive symptoms (Read, Mosher and Bentall, 2005). It is
hard to imagine schizophrenia being explained without the dopamine hypothesis
due to its response to antipsychotics in dampening its effects, giving great
accountability to the neurochemical imbalance in the brain. Moreover, a large
percentage of people are said to be treatment-resistant, with 30% of
individuals with schizophrenia failing to respond to dopaminergic
antipsychotics (Lally et al., 2016). This leaves a number of individuals still
suffering with positive symptoms, and majority still unable to reach full
benefits due to the persistent negative and cognitive symptoms. However, by
taking into account different aspects of the dopamine hypothesis III and other
neurotransmitters, it enables us to target different stages of the illness, by
using a selection of treatments. Dopamine can be described at the driving force
of schizophrenia, and by acknowledging the dopamine hypothesis III by taking
into account a wider context of how it may interact with other factors to
produce schizophrenic symptoms.  Sex differences need to be taken into
consideration when evaluating the dopamine hypothesis due to their biological
differences. Woman are more likely to present positive symptoms such as
psychosis, and men present more negative symptoms. This must be considered when
choosing the best treatment, and main cause for the onset of their
schizophrenia, suggesting it is not as straight forward as one size fits all (Feigenson,
Kusnecov and Silverstein, 2014).