There Findings have supported the latest hypothesis in

There is avast amount of evidence to support the dopamine hypothesis III in explainingschizophrenia.

However, evidence is inconsistent to the extent it plays a rolein the onset of schizophrenia, and how all the individual aspects of thehypothesis may link to its development. One of the main symptoms that has been focused on is psychosis, whichdopamine has consistently been linked to, thus makingit easier to account for the positive symptoms (McKenna, 2013), than it does for negative andcognitive symptoms (Kapur, 2003). Vivo imaging studies has alloweddopaminergic functioning to be assessed in the pre synaptic, leading away fromthe idea that the disorder is due to elevations in D2 receptors (Kambeitz et al., 2013).

Findings have supported the latest hypothesis in that dopaminedysregulation occurs further upstream in the presynaptic system, which explainswhy when apatient 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 schizophreniathat dopamine must not be disregarded in order to understand psychosis.However, it fails to acknowledge what may be driving these alterations indopamine, therefore indicating that other neurotransmitters such as glutamate dysfunctionmust be taken into account to explain these changes.

  To fully comprehend the latest dopaminehypothesis, it must be acknowledged that it has come a long way since it wasfirst introduced as the dopaminereceptor hypothesis from the discovery of antipsychotic drugs, linking todopamine receptors The focus of this finding was to block excess dopaminereceptors to stop psychosis from occurring. This was far too simple to fullyexplain the onset of schizophrenia, with no other possible factors taken intoconsideration. Dopamine hypothesis II 1991 Davis et al incorporated regionalspecificity, and found that the effects of abnormalities in dopamine functionvary depending on brain region.

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However, most the studies conducted were onanimals, and there was limited framework in the hypothesis.  Although this may be the case, these findingshelped guide a framework to develop throughout the years into the dopaminehypothesis III.  The dopaminehypothesis III takes into account an array of factors that all contribute tothe onset of schizophrenia. These include ‘hits’ resulting in dopaminedysregulation, presynaptic dopamine dysregulation, psychosis as a result ofincreased dopamine instead of schizophrenia, the account sociocultural factors,and how increased dopamine causes aberrant salience. By doing so it is able toexplain both positive and negative symptoms  Howes andKapur (2009) found that there was an abnormally large amount of D2/D3 receptorsin individuals with schizophrenia (10%-20% increase) in comparison to a healthycontrol group. However, it must be taken into account that an increase indopamine sensitivity may be due to larger amount of receptors making it easierto transmit, causing these abnormalities.

Animal models have been of particularinterest in relation to the onset of schizophrenia. Studies show that there arehigh-affinity states of D2 in these animal models, giving implication intotreating psychosis with antipsychotics that target these areas (Seeman, 2006). Seeman(2006) found that giving amphetamine leads to hypersensitivity and elevated D2receptors in the striatum.

 Amphetaminehas also been found to cause psychosis even in healthy individuals. This givesgreat support to increased levels of dopamine and the extent to which is canexplain schizophrenia. Amphetamine induced psychosis has been linked to thedevelopment of schizophrenia. Medhus et al (2015) found that 33% of 12 patientswent onto develop schizophrenia after being administrated amphetamine. Althougha relatively low percentage, it gives insight into how dysregulation ofdopamine through drugs such as amphetamine can eventually cause healthy patientsto fully develop schizophrenic symptoms. However, one limitation of this studyis the small sample size, however this should encourage future research to be carriedout into the transition from using stimulant drugs such as amphetamine, and theonset of psychiatric disorders.  However,such studies do not account for the development of negative symptoms, thussuggesting that there is more to the disorder than dopamine dysregulation.   Research hasbeen highly concentrated on psychosis and positive symptoms, whereby clinicalresearch searches to alleviate those by not for the negative symptoms orcognitive deficits.

The dopamine hypothesis III is able to account for this by acknowledgingD1 dysfunction (Howes and Kapur, 2009). Dopamine depletion has been studiedusing PET in the prefrontal cortex, whereby changes in the D1 in d1PFCnhasshown to cause negative symptoms and cognitive deficits. This suggests that thed1PFC has an impact on the symptoms seen in schizophrenia patients due to theinsufficient signalling between the D1 receptors (Goldman-Rakic et al., 2004).  Such research supplies the knowledge thattreatment must also be targeted at D1 receptors in order to downplay cognitivedeficits in order to restore cognitive functioning in schizophrenic patients asthey do not currently exist (Tamminga, 2006).  Such findings give high support for hedopamine hypothesis III in explaining schizophrenia as it takes into accountboth aspects of negative and positive symptoms. Although this may the case,much is biased towards the psychosis aspect due to drug treatments, such asantipsychotics.

 The psychoticsymptoms of is seen as a state of aberrant salience when too much dopamine isproduced. The hypothesis is able to explain how elevated dopamine able tounderpin the physiology of schizophrenia through aberrant salience, which is dueto a dysfunctional reward system whereby irrelevant stimuli becomes of interestto the schizophrenic individual due to a hyper-dopaminergic state (Kapur,2003). These pathways are related to predict reward, and through this leads tothe emergence of delusions and hallucinations.

Although this is the case, it isup to the individual to make sense of these experiences which leads them tohave delusions and hallucinations.  Therefore,it can be difficult to gain explicit evidence, as highly based on selfexperiences and how the individuals perceive these experiences.  Roiser et al(2009) used the Salience Attribution Test in order to evaluate aberrantsalience 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 toprobes on the screen. Patients on medication for their positive symptoms tookless time to respond than those not. These results give a good understanding onthe effectiveness of antipsychotics drugs in regulating the positive symptoms (Roiser et al., 2008).

Another interesting finding that occurred was the aberrant salience was linkedto negative symptoms. As the individuals were interested in the irrelevantstimuli, this could account for withdrawal and lack of social interest.However, these were not explicitly measured from the experiment, so must betaken with caution, although give future implications into how aberrantsalience and deregulated dopamine may lead to negative symptoms too. Anotherlimitation of this study is that the schizophrenic patients were all onmedication, making it had to make bold judgements on the extent to which they areexperiencing aberrant salience.

However, a study supporting this with the useof non-medicated patients using fMRI scans to scan neurological networks withinthe brain found that in the ventral-striatal caused responses to irrelevantstimuli, leading to high risk psychosis, and dopamine synthesis negativelycorrelated with hippocampal responses to irrelevant stimuli. This indicatesthat the dopamine hypothesis that aberrant salience is a main cause ofpsychosis, due to alterations in the dopaminergic system is supported (Roiseret al., 2012). Research supports the dopamine hypothesis III in suggesting thatincreased striatal dopamine causes aberrant salience to induce psychosis. Italso supports the fact that individuals may become less interested in relevantstimuli over time, leading to negative symptoms, which Rosier et al (2008)found in their SAT andantipsychoticsare able to lessen these symptoms by blocking D2 receptors to reduce aberrantsalience.  However, itmust be taken into consideration that a large amount of research is targetedtowards psychosis and aberrant salience. As mentioned above, negative symptomshave now been correlated with the tendency to be stimulated by irrelevantstimuli, thus suggesting that further research should be conducted into theseareas to fully understand the reward system pathway is these other symptoms. Itis crucial to take into account other neurotransmitters and dopamine to furtherexpand on current treatments, and understand the underlying pathophysiology ofschizophrenia.

 GENETICS –  There aremultiple routes that may cause dopamine dysregulation. Evidence for hyperdopaminergic in the striatum is pre synaptic function. Specific gene groups andpresynaptic function have been related to neurotransmitters glutamate and D2 receptors (Mirnics et al., 2001). Studiessuggest that there is no one gene that encodes for schizophrenia, although itmay be caused by forms of DNA sequence variations called single nucleotide polymorphisms (SNPs). Though this is true, a largemajority of research is inconsistent, making it difficult to pinpoint exactgenes that encode genetic susceptibility in schizophrenia (Allen et al, 2008). Over8000 SNPs have been found in conjunction with schizophrenia, giving explanationto over 50% individuals having a genetic predisposition (Harrison, 2015).

MultipleSNPs have been associated with four dopaminergic genes; SLC6A3, DRD3, COMT andSLC18A2. These genes encode a dopamine transporter, controlling the intensityand duration of dopamine by modulating re-uptake into the presynaptic nerves.These dopamine transporter genes may individually and jointly put an individualat risk for developing schizophrenia. The DRD3 gene is of particular interestas it encodes for the D3 dopamine receptor, and is highly associated withincreased receptor binding, leading to greater reuptake of dopamine (Database, 2017). Thus, supportingthe dopamine hypothesis III, by taking in account genetics that have an impacton dopamine, by increasing re-uptake in receptors, leading to psychosis.

 Although this may be the case, other studieshave reached different conclusions on the extent to which genes may have animpact on developing schizophrenia. Harrison (2015) states that genes may onlyhave a small effect on schizophrenia and their impact on the dopaminergicsystem with very low odd ratios between 1.10-1.

20. This may suggest that genesonly operate on a vulnerability level, making an individual more susceptible tobecoming schizophrenic rather than being the sole cause.  However,an important implication that has risen from genetic research is that there ismajor genetic pleiotropy between specific SNP genes in schizophrenia, and otherpsychiatric disorders (Lee et al., 2013). Leeet al (2013) found high genetic correlation (0.

68) in common SNPs inschizophrenia and bipolar disorder. This suggests that there are common geneticvariations linked to dopamine in psychiatric disorders, which should encouragefuture research to look into pathophysiology’s for related disorders.  Furthermore, HITS are able to capturemultiple factors that interplay in the onset of psychosis. Genes and stressorshave been interlinked and connected to dopamine functioning. Behaviouralsensitization refers to an individual’s stress and trauma they’ve experiencedwhich causes dysregulation in the hypothalamus pituitary adrenal axis, leadingto stress induced dopamine increase.

Thus, giving the impression thatenvironmental factors are able to regulate dopamine sensitivity, and the onsetof psychosis. Supportingevidence comes from Winkel, Stefanis and Myin-Germeys (2008) using vivo imaging data findingdopamine release in group high negative schizoptypy. This may be due todifferent genes playing a role in risk factor ofdeveloping schizophrenia symptoms. Supporting Evidence using PET scans suggeststhat stress induced synaptic dopamine release is significantly correlated withnegative schizotypy in healthy individualsat risk of developing psychosis (Soliman et al., 2007). Studies such as this help us intervene before the onset ofschizophrenia occurs.   Glutamate- Although this may be the case,specific genes have been identified to affect glutamate neurotransmission. Anissue with the dopamine hypothesis is that it only links one neurotransmitterwith schizophrenia, and does not recognize others.

As antipsychotic drugs onlytend to block D2 receptors to decrease positive symptoms, and the fact that atleast 30% do not respond implies that other mechanisms have a role in thepositive and negative symptoms. In order to study the implications of glutamateon schizophrenia, HMRS and PET imaging are used. Glutamate receptors NMDARsblock neurotransmission at the site causing schizophrenic symptoms toarise.  Dopamine regulation is sensitivetowards glutamine, indicating that changes in glutamate levels mediatesdopamine activity. By doing so it puts a wider understanding of how dopamine isregulated in the pre frontal cortex and hippocampus, when other factors are notpresent.

Studies using ketamine have been of particular interest, as the drugis able to block the NMDAR receptor causing dysregulation of glutamate leadingto an increased sensitivity of dopamine. Poels et al (2013) found that inhealthy controls when given ketamine found that there was an NMDA blockade onstriatal dopamine release leading to similar cognitive impairments, negativeand positive symptoms likewise to those seen in schizophrenia (Coyle, 2006).  Although this may be the case, it is hard todirectly link this to schizophrenia as the studies consisted of healthycontrols, with no thought of future development of schizophrenia. However, bydoing so, it helps understand how these two neurotransmitters may interplay todevelop the symptoms of schizophrenia. Studies have also found that giving lowdoses of ketamine over a period of time exaggerates dopamine release by actingon the NMDA receptors supporting the glutamate theory.

Such research is furthersupported by the amphetamine challenge whereby it causes a disruption ofglutamate, in turn disrupting the dopamine release.  While plausible, there are limitations whenstudying 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 betweenintra or extracellular compartments, limiting the extent to which these studiescan be validated.  Radiotracers are far ablerto give insight into specific areas, inferring that future research shouldfocus on these techniques.

  Conclusion – Although the dopamine hypothesis III seemsplausible, there is not enough strong evidence to suggest a big enough role innegative symptoms. As the hypothesis has been revived throughout the years,this is most likely going to happen in the future, contributing as moreevidence is added. However, by accepting the dopamine hypothesis as the biggestcontributor to the onset of schizophrenia, it is easy to rationalize the use ofdrugs to treat the positive symptoms (Read, Mosher and Bentall, 2005). It ishard to imagine schizophrenia being explained without the dopamine hypothesisdue to its response to antipsychotics in dampening its effects, giving greataccountability to the neurochemical imbalance in the brain. Moreover, a largepercentage of people are said to be treatment-resistant, with 30% ofindividuals with schizophrenia failing to respond to dopaminergicantipsychotics (Lally et al., 2016).

This leaves a number of individuals stillsuffering with positive symptoms, and majority still unable to reach fullbenefits due to the persistent negative and cognitive symptoms. However, bytaking into account different aspects of the dopamine hypothesis III and otherneurotransmitters, it enables us to target different stages of the illness, byusing a selection of treatments. Dopamine can be described at the driving forceof schizophrenia, and by acknowledging the dopamine hypothesis III by takinginto account a wider context of how it may interact with other factors toproduce schizophrenic symptoms.  Sex differences need to be taken intoconsideration when evaluating the dopamine hypothesis due to their biologicaldifferences. Woman are more likely to present positive symptoms such aspsychosis, and men present more negative symptoms. This must be considered whenchoosing the best treatment, and main cause for the onset of theirschizophrenia, suggesting it is not as straight forward as one size fits all (Feigenson,Kusnecov and Silverstein, 2014).