Understanding Schizophrenia: The Dopamine Hypothesis And Its Application In First And Second Generation Neuroleptics

The Dopamine Hypothesis of Schizophrenia

Discuss about the Role Of Dopamine In Schizophrenia.

Schizophrenia can be defined as the long term mental disorder that involves the breakdown in the relation between the thoughts, emotions, and behavior of an individual that results into a faulty perception, inappropriate actions and feelings, withdrawal from the reality and personal relationships that leads onto fantasy and delusions leading to a state of mental; fragmentation in the individual. The pathology of the diseases is intricately associated with the inhibitory transmitter called the dopamine. There is a abundantly utilized hypothesis called the dopamine hypothesis of Schizophrenia that serves as the model for understanding and evaluating the symptoms of the diseases with accordance to the disturbed and hyperactive dopaminergic signal transduction procedure (Howes, McCutcheon & Stone, 2015). This model has been constructed on the basis of the evidence that the most of the antipsychotic medication has a significant dopamine receptor antagonistic effect.

Although, researchers are of the opinion, that the theory does not give the idea that the schizophrenic effect is not completely facilitated by the dopamine overabundance. Rather the theory states the fact that the over-activation of the D2 receptor leads directly to the global chemical synaptic dys-regulation in the individual which is a characteristic part of the pathology observed in the patients suffering with this particular disorder. According to the Brisch et al. (2014), the revised dopamine hypothesis states the fact that dopamine abnormalities has been observed to be occurring in the mesolimbic and prefrontal brain regions of a patient suffering with schiozophrenia. This paper will attempt to discuss the pathology of schizophrenia symptoms favoring the dopamine hypothesis with respect to the effects of the first generation neuro-leptics and the effects of the second generation neuroleptics in the procedure.

Dopamine can be defined as the neurotransmitter that belongs to the catecholamine family and is produced in the substantia nigra and the ventral tegmental regions of the brain. It has to be mentioned that the dopaminergic projections are divided into three different systems, nigrostriatal, mesolimbic, and mesocortical systems. Researchers are of the opinion that the impairments in the dopamine is facilitated by the dopamine dysfunctions that occurs in the substantia nigra, ventral tegmental region, striatum, prefrontal cortex, and hippocampus. There have been many schools of thoughts arguing the efficiency of the hypothesis however the recent studies have been successful in exploring and evaluating the pathology of the schizophrenia symptoms. According to the Madras (2013), the dopamine hypothesis of the schizophrenia has postulated the fact that the hyperactivity of the dopamine D2 receptor neurotransmission is reported in the subcortical and limbic brain regions of the schizophrenics and it facilitates the positive symptoms of schizophrenia.

Supporting Evidence for the Dopamine Hypothesis

Supporting this idea, the Lau et al. (2013) have stated the fact that the negative cognitive functions of this disease can be attributed to the hypofunctionality of the Dopamine D1 receptor neurotransmission that occurs in the prefrontal cortex. Another study has stated the fact that increase in the density of the dopamine receptor D2 has been found vene in the post mortem brain tissue of schizophrenia patients. Considering the neurotransmitter function irregularity that leads to the symptom development of the disease schizophrenia, it has been proved that the poorer performance in the cognitive tasks involves the corticostriatal pathways (Moghaddam & Javitt, 2012). Now these corticostriatal pathways have been found to be directly correlated with upregulation of the D2 receptors present in the caudate nucleus of the schizophrenia patient, further confirming the profound role played by the dopamine in the pathology of the disease. Hence it can deduced from the above evidences that the development of the disease is intricately associated with the excessive stimulation of the dopamine D2 receptors in the associated striatum that is accompanied by the lack of stimulation in the dopamine 1 receptors in the prefrontal cortex. Along with that, the entre phenomenon is facilitated by the modifications in the prefrontal neuronal connectivity that involves the glutamate transmission at N-methyl aspartate receptors (NMDA) (Grace, 2016).

Deficits in the release of extrastriatal dopamine from the prefrontal cortical regions were established by a brain imaging study that aimed to evaluate the release of amphetamine-induced dopamine in the dorsolateral PFC among drug-naïve and drug-free schizophrenic patients. PET imaging with carbon 11–labeled FLB457, prior to an after administration of 0.5mg/kg amphetamine suggested that significant differences in its effect on ?BP_ND. It was found to be higher among drug-naïve patients, in comparison to their drug-free counterparts. Significant relationship was also observed between BOLD activation and DLPFC ?BP_ND in the dorsolateral PFC among schizophrenic and healthy control individuals. Thus, the findings were able to confirm the fact that patients suffering from schizophrenia demonstrated blunted release of dopamine, as induced by amphetamine, in the DLPFC (Slifstein et al., 2015).

Significant alterations in the brain structure upon administration of first line of treatment were demonstrated by another study that evaluated the brain sizes of schizophrenic patients before and after the exposure to antipsychotics. Significant reductions in whole brain volumes were observed among the schizophrenic patients at baseline, marked by an enlarged ventricle, when compared to controls. Progressive decrease was also found in the volume of gray matter among the patients, in addition to an enlargement in their lateral ventricles. This decrease in gray matter volume was inversely associated with the cumulative antipsychotic treatment exposure, thereby providing evidence for the neuroanatomical alterations in schizophrenia (Fusar-Poli et al., 2013).

Neuroanatomical Alterations in Schizophrenia

Neuroleptics can be defined as the drug that causes a syndrome known as the neurolepsis which is the amalgamation of three main features, psychomotor slowing, emotional slowing and affective indifference. These are also known as the antipsychotics and the first and second generation antipsychotics are mostly the dopamine antagonists. Now it has to be mentioned in this context that the dopamine hypothesis has been introduced in the 1990s and ever since, the treatment trajectory for the schizophrenics have focused on altering or reverting the effect of dopamine pathway on the cognitive functionality of the patients (Howes et al., 2017).

Considering the exact mechanism of action for the first generation neuroleptics, it has tp be mentioned in this context that the first generation neuroleptics are the D2 antagonist. Although, they include all of the antipsychotics in the following groups: phenothiazines, butyrophenones, thioxanthenes, dibenzoxazepines, dihydroindoles, and diphenylbutylpiperidines. According to the Laruelle (2014), the dopamine theory of schizophrenia states that the positive symptoms of the schizophrenia is a direct result of an overactivity in the mesolimbic dopamine pathway. In support the authors have stated the fact that the D2 antagonists such as the L-DOPA and amphetamines increases the dopaminergic availability which in turn triggers psychotomimetic effects in the schizophrenia patients. On a more elaborative note, it has to be mentioned that there are 4 dopamine pathways that are associated with the first generation antipsychotics. The first pathways are the mesocortical pathway, mesolimbic pathway, Nigrostriatal pathway and the Tuberoinfundibular pathway. However, it has to be mentioned tahta there are significant side effects associated with the use of first generation antipsychotics to treat the schizophrenia in the patients. And hence, the use of the first generation antipsychotics has declined over the years with the introduction of the second generation neuroleptics (Dold et al., 2015).

On a more elaborative note, it has to be mentioned that the second generation neuroleptics have been identified as the atypical neuroleptics and it has been introduced in the treatment pathway for schizophrenia is based on the dopamine hypothesis as well. According to the dopamine hypothesis of schizophrenia, the negative symptoms that develop in the disease is due to the reduced ability of the dopamine receptor binding. The second generation neuroleptics target the manifestation of the negative symptoms, and it has been reported by many studies that the effect of the second generation antipsychotic medication are even more potent than the action of the first generation neuroleptics (Nielsen et al., 2015). Elaborating more, it has to be mentioned that the first generation antipsychotics, such as the haloperidol, is only optimally effective in the high doses. on the other hand, the effects of the second generation neuroleptiocs such as the olanzapine, amilsulpride, and risperidone had been found to be far more effective in even low doses.

First Generation Neuroleptics

Hence, it can be very easily stated that the risk of side effects, which is evident for the first generation neuroleptics as they are needed in high doses, is very minimal for the second generation neuroleptics as they are effective in even low doses in facilitating higher dopamine availability for the binding process. as described by the Leucht et al. (2012), the risk for extrapyramidal side effects and tardive dyskinesia is much lower in the second generation neuroleptics when compared to the first generation neuroleptics. Considering the mechanism of action of the drugs, the strong interrelation with the dopamine pathway cannot be neglected. on the basis of the postulates of the theory, both the first and second generation neuroleptics target the psot synaptic blockade of the brain dopamine D2 receptors. However, the exceptional cases of the aripiprazole and brexpiprazole serve as D2 receptor partial agonists whereas the cariprazine is a D3-preferring D3/D2 receptor partial agonists. As discussed by the Hartling et al. (2012), the main difference between the first and second generation medication is the fact that with usage of the second generation neuroleptics, the serotonin 5HT2 receptor binding results in exceeding the affinity for the dopamine D2 receptors. And as the 5HT2 activity has been noted to be the main contributor to the overall risk of extrapyramidal side effects or the EPS. Along with that it has to be mentioned in this context that the occurrence of loose D2 receptor binding is also reduced along with rapid dissociation rates in case of the second generation neuroleptics.

On a concluding note, it has to be mentioned that the role of the dopamine in progression of schizophrenia and the development of the symptoms is essential. It has to be mentioned in this context that the dopamine hypothesis has been introduced in the 1990s and ever since the role of dopaminergic effect has been discovered in facilitating schizophrenia symptoms, the pharmacological therapy has focused mostly on altering or reverting the dopaminergic effect in the schizophrenia patients and neuroleptics have been the most significant intervention in this regard. The essay has been successful in including the evidence in the relevant and authentic studies in support of the dopamine hypothesis, the progression of the disease, and lastly the fundamental role played by the neurotransmitter in pathogenesis of the disease. with respect to experimental evidence, two brain imaging studies with relevant results were used in order to establish the supportive argument for dopamine hypothesis. 

Second Generation Neuroleptics

With respect of the treatment with first and second generation neuroleptics, the drugs have been noted to target the D2 receptors in order to enhance the dopamine receptor binding affinity and the action of the medication of both the first generation and the second generation have been proved to be extremely beneficial for the schizophrenia patients, effectively reducing the manifestation of the symptoms. Hence, it can be deduced from the evidence that the dopamine pathway has a fundamental role in the diseases development for schizophrenia patients and that is reason why the pharmacological treatment pathway for the disease includes the dopamine receptor agonists.

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