Dopamine essay

Dopamine essay

Introduction

Dopamine, which is also termed as 3, 4-Dihydroxytyramine, serves as a neurotransmitter in the brain, which refers to chemicals neurons released to transmit electrical signals from one neuron to the next chemically. Dopaminergic neurons of the brain produce it. Dopaminergic neurons that produce dopamine are located in the ventral tegmental and the substantia area of the brain, both found in the midbrain and arcuate nucleus of the hypothalamus. Hydroxyl groups are added to tyrosine, transforming it to Levo-DOPA, which is followed by the removal of carboxylic acid groups from the ethyl side chain that has links to the amine group, therefore, producing dopamine (Delcambre et al., 2016). After production, the neurotransmitters are packaged into synaptic vesicles and stored until dopamine release is induced in synaptic clefts, which cause binding to dopamine receptors. The binding of the neurotransmitters occurs in various types of dopamine receptors: D1, D2, D3, D4, and D5, which belong to the receptor family of the G-protein that can be divided into two major subclasses: D-1-like (D1 and D5) and D-2-like (D2,D3, D4). As the dopamine binds to the receptors, signaling cascades are initiated, which are responsible for the activation of functions in the associated brain areas where there is a high prevalence of the receptor types. There is usually a higher prevalence of D1-like receptors compared to D2-like receptors.

One of the greatest threats to brain functioning is dementia, which is defined as the loss of cognitive functions, including remembering, thinking, and reasoning, to such a great extent that an individual daily life is interfered with. United States census data shows that as of 2016, dementia prevalence among adults aged 65 years and older stood at 5.2 million people or 11% of the population. Total costs estimated for long-term care, healthcare, as well as a hospice for those living with dementias stood at $236 billion in 2016, and this is expected to reach even higher levels with increases in the aging population (Alzheimer’s Association, 2016). One of the Healthy People 2020 goals is to reduce costs and morbidity associated with dementia and to enhance or maintain the quality of life of patients. As a result, there is a need to improve the diagnostic accuracy of the various types of dementias that usually result from different neurodegenerative diseases like Alzheimer’s and Parkinson’s disease. Despite the establishment of pathological and clinical diagnostic criteria for dementia, close to 15% of patients continue to be misclassified (Garn et al., 2017).

It is essential to separate the various dementia types as patients may warrant different management of their psychotic symptoms, cognitive fluctuations, and parkinsonian features. One significant neurochemical difference has been identified in dopaminergic metabolism, where the detection of extensive dopaminergic degenerations has been suggested as a way of allowing distinctions among the various neurodegenerative diseases in vivo. Nobili et al. (2017) point out that the rapid death of dopaminergic neurons presents a point of view that is entirely new on dementia and Alzheimer’s disease. Experimental and clinical evidence shows nigrostriatal deficits in many frontotemporal dementia cases with losses of dopaminergic neurons, reduced binding of dopamine transporters, reduced dopamine levels as well as abnormal dopamine receptor binding. In vivo imaging shows reduced dopamine transporter levels in the putamen and caudate with the degree of such losses correlating with symptom severities.

Background of the Study

Dopamine is crucial in various brain functions, including motor control, executive function, arousal, motivation, reward, and reinforcement via the signaling cascades. The cascades are exerted through binding to receptors at projections located in the arcuate nucleus of the hypothalamus, the ventral tegmental area, and the substantia area of the human brain (Klein et al., 2019). The substantia region is characterized by nigrostriatal pathways that project dopaminergic neurons from the pars compacta or input area to the dorsal striatum, and this is essential in learning motor skills and controlling of motor functions. A hallmark of Parkinson’s disease involves dysregulations in motor control, which can result from the degeneration of dopaminergic neurons in the nigrostriatal pathway. The ventral tegmental area (VTA) is characterized by the mesolimbic pathway, which projects dopaminergic neurons from the prefrontal cortex to the nucleus accumbens of the cingulate gyrus, amygdala, olfactory bulb’s pyriform complex, and the hippocampus. Emotion processing and formation are the responsibility of the dopaminergic projections in the cingulate gyrus and amygdala.

Dopaminergic neurons present in the hippocampus are associated with working memory, learning as well as the formation of long-term memory. The olfactory bulb’s pyriform complex has the responsibility of enabling humans to have a sense of smell. Dopamine is also released in situations that are pleasurable in the mesolimbic pathway, which causes arousal while also influencing behavior or motivations (Volkow et al., 2017). As a result, individuals seek out pleasurable occupations or activities for release of dopamine, which binds to dopaminergic receptors present in the prefrontal cortex and the nucleus accumbens. An increased projection activity to the nucleus accumbens plays a significant role in reinforcement behavior as well as addictions in more extreme cases. Dopamine neurons also make up the tuberoinfundibular pathway in the arcuate nucleus of the hypothalamus, which is responsible for projecting to the pituitary gland and inhibiting secretions of the prolactin hormone. Dopamine emanating from neurons in the arcuate nucleus is released in the hypothalamohypophysial blood vessels supplying the pituitary gland with dopamine and inhibiting prolactin production. It can help in preventing hyperprolactinemia, which, when left unmanaged, can impact fertility and bone density, leading to osteoporosis as well as neurological symptoms in some cases.

The presence of various pathological changes in the dopaminergic system bears both clinical and Pathogenetic relevance in cases of Alzheimer’s disease and other dementias. Neurons that form the nigrostriatal pathway have been found to have various pathological changes including decrease in dopamine content and neuronal loss (Martorana and Koch, 2014). All these changes suggest the apparent involvement of dopamine in non-cognitive symptoms and the cognitive decline of Alzheimer’s disease. Apathy occurrence, which is an adverse prognostic sign in both Alzheimer’s disease and the elderly, is considered a consequence of dopamine transmission impairments evident during normal aging. Other studies have shown that dopamine and its derivatives are low in early onset Alzheimer’s disease and that dopamine D2 and D3 agonists like rotigotine can have rescuing effects on Alzheimer’s disease patients. They can accomplish by restoring cortical plasticity, therefore, suggesting new Alzheimer’s disease therapeutic strategies. Various investigations have also shown that through D2-like receptors, cortical excitability is increased by dopamine, and through D1-like receptors, cortical acetylcholine release is increased. Thus, the idea that dopaminergic system disruption is associated with Alzheimer’s disease and other dementia pathophysiology is supported, and this can enable novel approaches to therapeutic developments.

The rationale of the Study

Dementia is a clinical syndrome rather than a disease. It is usually referred to as an acquired condition where multiple cognitive impairments are present that are sufficient to interfere with daily living activities. It is commonly progressive but not necessarily. One of its most common deficits involves memory impairment, but other domains like language, visual perception, praxis, and mainly executive functions are often involved (Barkhof and van Buchem, 2016). Progressive difficulty with daily living activities is experienced with increasing function loss due to these cognitive problems. Dementia can develop from various diseases, many of which have relentless continuous courses with an insidious onset. They are characterized by long durations like 5 to 10 years from diagnosis as well as relatively prolonged end-stage periods where all independence and self-care are lost. Age-related incidences are the most common cause of dementia. However, the condition is not a normal part of aging. The most common cause is neurodegenerative diseases. Enormous burdens are placed by dementia on patients, families, carers and health and social care systems. The identification of the relationship between dopamine and dementias and the causes of neurodegeneration can result in the establishment of evidence-based diagnostic criteria as well as new and effective treatments.

Dementia is caused by neurodegeneration, especially from neurodegenerative diseases, which are debilitating and incurable conditions that lead to progressive death and degeneration of nerve cells and brain neurons. They include various conditions primarily affecting neurons in the human brain resulting in dementia or problems with mental functioning as well as movement problems or ataxias. Examples of neurodegenerative diseases include Alzheimer’s disease and Parkinson’s disease. Alzheimer’s disease (AD) is considered the main form of dementia, which currently affects 0.5% of the global population of 45 million people (ADI, 2016). Substantial evidence in recent discoveries from early AD mouse models as well as late-onset patients shows that dopamine neurons in the ventral tegmental area become compromised. The degeneration of dopamine neurons leads to lower dopamine outflow in the nucleus accumbens and hippocampus. These correlate with impairments in hippocampal neuronal excitability, memory, synaptic plasticity, and reward performance (Nobili et al., 2017). Pharmacological interventions have also been consistent with these observations with manipulations that aim to increase dopaminergic transmission in the cortex and hippocampus, improving cognitive impairment, synaptic functions, and memory deficits, which emphasizes the critical role of dopamine for proper brain functioning.

Parkinson’s disease (PD) is another degenerative disorder that usually affects body movements, but dementia can also occur. Many patients with PD eventually develop overt dementia, and this ranges from 10 to 30% and reaches as high as 70% in PD patients over 80 years of age (Aarsland et al. 2017). There are different causes of dementia in PD patients, and they usually include subcortical system degeneration with neuronal losses in dopaminergic systems. A significant neuropathological finding in PD involves a neuronal loss in substantia nigra par compacta with inclusions of Lewy bodies in the cytoplasm of neurons that usually provide dopaminergic innervations to the striatum. Patterns of cell loss in the midbrain, loss of dopamine in the striatum, and loss of binding to dopamine transporter sites in the striatum show consistency with severe damage to cells in nigrostriatal dopamine projection. Substantial evidence has also shown that nigral neuron degeneration in the midbrain, as well as dopamine depletion in the putamen, are underlying causes of PDs motor symptoms, especially akinesia (Kulisevsky, 2000). Reduced caudate dopaminergic output causes compromised outflows of caudate nuclei to the frontal cortex, while reduced input via the mesocortical dopamine pathway causes lesser frontal dopamine deficiency. Both offer an anatomic basis for the frontal cognitive deficits as well as the cognitive effects of dopaminergic agents in PD patients.

Various studies have sought to determine the role and influence of dopamine on mental health, bearing in mind its neurotransmitter ability. Researchers have recently found that levels of dopamine may provide clinicians with more clues of diagnosing Alzheimer’s disease and other dementias. By studying dopamine affluent areas of the brain like the ventral tegmental area, they sought to determine how Alzheimer’s can be diagnosed earlier by examining how the area interacted with other brain areas. Results showed associations linkages between functionality and size of the dopamine rich area with hippocampus size and new information learning abilities (De Marco and Venneri, 2018).  Structural and functional imaging changes in the striatum have shown that dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia are characterized by striatal dopaminergic deficits.

It has become increasingly important to make a precise diagnosis of dementia subtypes, especially to enable different clinical management approaches that will allow better patient outcomes. For neurodegenerative conditions, the call has been for making an early diagnosis with interventions being most active at prodromal stages. Therefore early detection can help in planning for the future and avoiding drug contraindications. Dementia researchers have agreed that to enable timely diagnosis, biomarkers are required as most symptoms are detectable years before dementia sets in (Thomas et al. 2019). Clinical symptoms are not sensitive or specific enough for prodromal stage diagnosis, and the most informative biomarker has been identified as assessing dopaminergic function through brain imaging. The identification of the relationship between dopamine and dementias and the causes of neurodegeneration can result in the establishment of evidence-based diagnostic criteria as well as new and effective treatments. Thus, this study aims to examine the impact of dopamine on the dementia condition, drawing inferences from previous undertaken primary research studies.

Objectives of the study

This research seeks to achieve the following objectives

1. To examine the influence of dopamine on brain functioning
2. To establish the link between dopamine and dementia
3. To compare experiences between patients with dysfunctional dopamine and those with dementia

Research questions

1. Does low dopamine levels in the human brain affect behavior in dementia patients?
2. Do high dopamine levels affect the behavior of people with dementia?

Research Sub questions

1. Is there a link between loss of dopamine-firing cells and the brain’s ability to respond to emotional and movement responses in dementia patients?
2. Is there a connection between the formation of dopamine-firing cells and the brain’s ability to respond to emotions and movement in dementia patients?

The aim of the study

This research seeks to determine whether dopamine is associated with cases of dementia by comparing the manifestations of Dopamine dysfunction to common dementia complications. The study will draw inferences from other relevant primary-focused studies relevant to the topic of study.

Chapter two: Literature Review

Historical Background

The association of Dopamine in Dementia has been researched for a long time and is still under consideration (Sweet et al., 1998; Holmes et al., 2001; Trillo et al., 2013). The dopamine system follows through various transformational steps during the physiological aging process. Generally, these studies identify that the decline in the discharge of dopamine from its terminuses, the decrease dopamine transmitter expression in specific Dementia, and the anterior cortex of humans are characteristics generally observed in the brain while it is aging.

The story of dopamine and its association with brain reactions, attitudes, and emotions dates back in 1957. In this era, the perception was dopamine was a neurotransmitter in the human brain and not just a foretaste of norepinephrine (Carlson et al., 1972; Freedman & Wo, 1974). At this time, various studies started to emerge to find more knowledge on the function of dopamine in the human brain and its direct association with brain functions. In this course, Arvid Carlson, a pharmacologist, developed a test to determine the amount of dopamine in the human brain, which he found out that the highest concentration of dopamine exists in the basal ganglia (Carlson, 1993). Carlson’s researches were among the works that led to several investigations into the story of dopamine. For instance, experiments conducted by Arnold et al. (1973); Friedman & Wo (1974) concluded that depletion of dopamine results in a loss of movement control. These kinds of symptoms are similar to the clinical indications perceived in neurological sickness, Parkinsonism (Holmes et al., 2001).

Investigations relating to dopamine never ended there. Researchers such as Carlson (1993); Anorld (1973) found out that L-dopa, an antecedent of dopamine, could effectively treat Parkinsonism symptoms, and this is still one of the drug treatments today.

In 1977, the dopamine theory was developed by several researchers (Carlson, 1993; Fagius et al., 1983) who emphasized on the role of dopamine in the advancement of extrapyramidal side-effects of neuroleptic drugs. The inhibition of primary dopamine function is a fundamental element common to various neuroleptic medications. The reward and dopaminergic pathways of the dopaminergic system are majorly the targets for the psychosomatic and the extrapyramidal activities, respectively, of these medications. Even though the significant intrusion in dopamine function in dementia cannot be excluded, the direct association between dopaminergic and other neuronal coordination needs to be investigated in more detail.

Today, dementia with Lewy bodies is the origin of neurodegenerative dementia of older people with a projected occurrence of 16% to 25% of incidents as per autopsy studies (McCleery et al., 2015). Community prevalence projections differ more widely with percentages of between zero to five among the healthy elderly and zero to thirty percent among older people with dementia (Walker & Walker, 2009).

Today, the medication strategies employed on dementia are based on the neurotransmitter replacement approaches used for other neurodegenerative illnesses such as Parkinsonism and Alzheimer’s. Hopefully, with the increased attention to studying dementia, especially with the effects of neurotransmitters such as dopamine, finding medication would be easier.

The usage of neurotransmitter –based approaches for the medication in dementia is among the current issues affecting current studies today. Evidence claims that these neurotransmitter strategies might lessen the behavioral symptoms of dementia; however, their safety, efficiency, and long-term effects are yet to be known. Besides, even when particular disease processes on dementia are created, drugs based on supplementing neurotransmitter systems will much likely to help improve the symptoms.

Behavioral and psychological symptoms

The behavioral defects that are linked with dementia disrupt patient care and pose a management challenge to the care provider. Some of the behavioral and mental symptoms associated with dementia are psychotic traits such as delusions and hallucinations along with those behaviors without psychotic characteristics, including depression, anxiety, aggressiveness, and uncooperativeness (Cummings & Mega, 2003). Patients with dementia exhibit some forms of disrupted agitated behaviors at some point in the course of their illness (Holmes et al., 2001). According to Herrmann et al. (2004­­­), 18 to 65 percent of dementia patients experience aggressive behaviors, which has a detrimental impact on them and also to the caregivers.

The treatment of behavioral syndromes in dementia patients has focused on the use of psychotropic drugs (Cummings & Mega, 2003). Studies conducted in nursing homes and hospitals and also in the community (Mathews et al., 2002; Garcia-Alloza et al., 2006; Engelborghs et al., 2008) have confirmed that psychotropic drugs are usually used in elderly patients with dementia. Because of this constant use, guidelines governing the use of psychiatric medications in such institutions have been developed (Mathews et al., 2002).

Norepinephrine is one of the major neurotransmitters located in the sympathetic nervous system in the periphery and is also predominant in the brain (Herrmann et al., 2004­­­). This neurotransmitter is mediated and controlled by other neurochemicals in the human brain, most of them are known to influence human behavior (Walker & Walker, 2009). Any damage or alteration to any of the neurotransmitters is most likely to distress other neurotransmitters and possibly lead to behavior deviations (Garcia-Alloza et al., 2006).

The noradrenergic system networks with several neurotransmitters that aid in the function of the human brain such as acetylcholine, serotonin, and aminobutyric acid to modulate its tissues, eventually releasing other hormones such as somatostatin. Most of these neurotransmitters have been linked behaviors, including depression, anxiety, and aggression in most people. Therefore, any alteration in some of these neurotransmitters might result in a role in exasperating already disrupted neurotransmitter systems (Cummings & Mega, 2003). Besides, several neurochemical systems are known to be aggravated in dementia patients, such kind of alteration might amplify behavioral instabilities.

Post-mortem examinations have reliably shown noradrenergic system participation in dementia disease process accompanied by shrunk Norepinephrine levels being found in several brain areas. Most of these studies identify decreased levels of cortical and subcortical Norepinephrine levels in the anterior medial gyrus, thalamus, and other connected parts of the brain (Teri et al., 1992; Herrmann et al., 2004).

Damage of noradrenergic neurons in the locus coeruleus, which is the primary noradrenergic resource in the human brain in patients with dementia; these alterations might account for a deficiency in the noradrenergic system in the progression of the disease of dementia (Cummings & Mega, 2003). Nevertheless, epinephrine (NE) in the brain tissue might not directly connect with functional noradrenergic diffusion. Instead, noradrenergic increase and neuronal activity presumed via dimensions of comparative concentrations of NE and its prevalent intraneuronal metabolite offer a more precise demonstration of actual noradrenergic function.

In other post-mortem studies, when both 3-methoxy-4-hydroxyphenylglycol (MHPG) and Epinephrine were measured collaboratively, even though epinephrine in the brain was decreased, MPHG remained unchanged or high in patients with Alzheimer’s illness compared to control participants (Mann et al., 1982; Bierer et al., 1995). These results imply that neuronal damage or alteration might lead to an escalation of epinephrine metabolism, hence fuelled noradrenergic activity indeed as a compensatory system for locus coeruleus epinephrine loss. According to Hoogendijk et al., (1999) there is a substantial inverse relationship between the MHPG- epinephrine ratio and the quantity of residual pigment locus coeruleus neurons in Dementia or Alzheimer’s patients; further, they conclude that there is an overactivity or stimulation of the remnant locus coeruleus neurons to balance cerebral epinephrine damage. From this work, it, however, remains unclear whether this counterbalance mechanism happens in the noradrenergic neuron terminuses in the projection regions in the locus coeruleus cell bodies or all of them.

Albeit, these results imply that neuronal loss might lead to consequent amplified epinephrine metabolism that will increase noradrenergic activity, probably as a balancing reaction mechanism for locus coeruleus epinephrine loss.

Neurotransmitters and behavior

The association between neurotransmitters, such as dopamine, has been researched in various psychiatric disturbances such as anxiety, aggression, and depression. For instance, in depression, evidence shows dysfunction in α2 receptor failure together with postsynaptic α₂ receptor suppression (Charney et al., 1982), amplified presynaptic α₂ receptor reaction and density in locus coeruleus (Ordway et al., 1994).

Additionally, there is an observation of a decrease in noradrenergic receptor sensitivity and amplified noradrenergic quantity noted in patients with anxiety, aggressiveness, and posttraumatic stress (Geracioti Jr et al., 2001). High amounts of the release of neurotransmitters such as dopamine have been linked with high levels of aggression in animals, in healthy mature people, and also in depressed people (Redmond et al., 1986).

In animals, neurotransmitters such as dopamine and epinephrine boost aggression, while β-adrenoreceptor inhibitors have been shown to reduce aggression levels (Charney et al., 1982). Besides, the neurotransmitters, such as dopamine and epinephrine metabolite levels, have been shown to have a positive association with aggression in patients with personality disorders (Gerra et al., 1996). The involvement of the noradrenergic system in several psychiatric and behavioral disorders in animals and demented people has been widely studied, and results show a positive correlation between the two variables (Charney et al., 1982; Ordway et al., 1994; Garcia-Alloza et al., 2006).

Depression in Demented people

Depression complicates personality disorders in people and is common in people suffering from mild severity of dementia (Bierer et al., 1995). Besides, dementia and Alzheimer’s have similar symptoms, such as loss of appetite and compassion and sleep disturbances. According to Matthews et al. (2002), demented people suffering from comorbid depression possess higher levels of locus coeruleus deterioration as compared with patients who are not depressed. Nevertheless, some studies contradict this assumption, such as Hoogendijk et al., (1999), who finds no significant difference in the locus coeruleus degeneration between these types of patients.

Nevertheless

Zubenko & Moossy (1988) note that such disparity can be due to the differences in methodology, including confounding the level of dementia or depression. Besides, a decrease in dopamine has also been evidenced in the cortex of depressed demented people, which further backs the altered role of noradrenergic system undertaking in inducing depressive symptoms (Matthews et al., 2002). Therefore, the current literature supports the influence of dopamine and other neurotransmitters such as epinephrine and depression in dementia.

A post-mortem study conducted on the anterior cortex, hypothalamus and cerebellum (parts of the brain innervated by locus coeruleus neurons) in patients who were extremely aggressive, non-aggressive and elderly healthy control subjects found a substantially increased level of  α₂ receptors in the cerebellum or agitated patients representing 70% level higher than non-agitated patients (Russo-Neustadt & Cotman,1997).  The intensities of α₂ receptors present in unagitated demented people were slightly high as compared with the levels present in the healthy control subjects. Also supporting this evidence is Zubenko & Moossy (1988), who argue that there is an association between motor agitation and amplified MHPG levels.

Psychosis and dopamine

Psychosis is described as a set of clinically unruly behavior typical in dementia patients Aarsland et al., (1996). Both studies supporting the connection of psychotic behaviors and noradrenergic safeguarding and studies presenting no evidence of linkage between psychosis and neurotransmitters have been recorded. For instance, Zubenko & Moossy (1988) established a higher epinephrine level in the substantia nigra of dementia patients with psychotic behavior as compared to patients without psychotic behaviors.  Also, Förstl et al., (1994) documents that patients with Alzheimer’s with auditory illusions had significantly higher neurons count in the gyrus and trend towards lower dorsal raphe nucleus neuron count as compared with patients without psychosis, nevertheless, Förstl and counterparts did not observe this in locus coeruleus. Albeit, the association between noradrenergic system and psychotic behaviors, remains unclear, which needs further research.

In conclusion, evidence from various researches in both animal and human subjects supports an association between noradrenergic dysfunction and behavior. More particularly, patients with personality disorders such as dementia and have anxiety disorders all show a blunted growth hormone, including dopamine, which actively disrupts noradrenergic control. In comparison between demented patients with aggressive behaviors and non-aggressive patients, there are higher levels of aggression when dopamine levels are overproduced and under-produced or altered in this case. Nevertheless, the exact knowledge of what happens during each of these situations i.e., low levels and high levels of dopamine, need further research to assess the association of dopamine and behavior in dementia patients.

References

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