Dopamine paradox in schizophrenia

Dopamine paradox in schizophrenia

We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

If there is more dopamine action in the mesocortical pathway in schizophrenia, then schizophrenics should always be in euphoric state. Instead, schizophrenics often lack motivation and do not experience pleasure. Why?

Short answer
The dopamine (DA) hypothesis suggests that excessive DA transmission in the mesolimbic pathway in schizophrenia leads to hallucinations and other positive symptoms. It explains the negative symptoms of schizophrenia (flattened affect, reduced motivation) by reduced DA activity in the mesocortical pathway affecting the frontal cortical regions.

You are referring to the dopamine hypothesis of schizophrenia.

The initial dopamine (DA) hypothesis focused primarily on the positive symptoms of schizophrenia, namely the active psychoses, which includes periods of hallucinations and delusions. These effects can be attributed to hyperactivity in subcortical dopaminergic pathways. Specifically, excessive subcortical release of dopamine is thought to increase D2 receptor activation, disturbing the cortical pathway through the nucleus accumbens (Brisch et al., 2014), called the mesolimbic pathway (Fig. 1). These positive effects can be treated quite effectively with the classical, first-generation anti-dopaminergic antipsychotics such as haloperidol and chlorpromazine.

However, there is another important aspect on schizophrenia, which are the negative symptoms. While the full-blown psychoses occur in waves, these negative symptoms are a more continuous and persistent phenomenon. The symptoms include a flattened affect and dysphoria (reduced pleasure in life). These symptoms are thought to occur due to altered prefrontal cortex (PFC) functioning. Specifically, they are thought to be induced by hypoactivity in dopaminergic D1 transmission (Brisch et al., 2014) in the mesocortical pathway (Fig. 1).

Fig. 1. The dopamine pathways in the brain, including the mesolimbic and mesocortical pathway, implicated in the positive and negative symptoms of schizophrenia, respectively. source: Wikipedia.

These two sides of schizophrenia point to an imbalance in DA activity in the brain, namely hyperactive subcortical mesolimbic D2 activity leading to positive symptoms, and hypoactive mesocortical D1 activity in the PFC resulting in negative symptoms. This imbalance hypothesis is the revised DA hypothesis and it is still an accepted working model (Brisch et al., 2014).

However, as noted by others, schizophrenia is a complex disease and it is thought that besides DA, also serotonin, glutamate and GABA play a role (Olijslagers et al., 2006). The current first line of treatment of schizophrenia are atypical neuroleptics, such as Clozapine. Clozapine is a selective monoaminergic antagonist with high affinity for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), 1 and 2 adrenergic, and H1 histaminergic receptors. Clozapine acts as an antagonist at other receptors, but with lower potency. The broad effects of Clozapine are thought to underlie its potent antipsychotic therapeutic effect. It is believed it mainly works through a combination of antagonistic effects at D2 receptors in the mesolimbic pathway and 5-HT2A receptors in the frontal cortex. D2 antagonism relieves positive symptoms while 5-HT2A antagonism alleviates negative symptoms.

- Brisch et al., Front Psychiatry (2014); 5: 47
- Olijslagers et al., Curr Neuropharmacol (2006); 4(1): 59-68

No. Schizophrenia isn't a single disease. It is class of psychotic disorders. Dopamine isn't the single cause of psychotic type diseases including schizotype. Many other pathways play a part in the various diseases; Serotonin, Glutamate, Histamine… ect.ect.ect. Genetic, Expressive and developmental factors are all known to play a role too.

Moreover you're not even describing typical symptomatic schizophrenia but a version of schizo that contains depressive features as well. Apathy caused by schizophrenia is a negative symptom a lack of interest in this life. Often we become preoccupied with the pleasures of delusions or hallucinations. The large dose of dopamine associate with a not "evil" hallucination is pleasurable on the order of cocaine. Delusions feel like antidepressants. Apathy caused by antipsychotics is entirely different.

New insights into biological underpinnings of schizophrenia

Researchers have implicated 10 new genes in the development of schizophrenia using a method called whole exome sequencing, the analysis of the portion of DNA that codes for proteins. Working with a global consortium of schizophrenia research teams, Tarjinder Singh, PhD, a postdoctoral fellow affiliated with the Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard, Massachusetts General Hospital, and Harvard Medical School, and colleagues completed one of the largest of such studies so far, incorporating genetic data from over 125,000 people to gain deeper insights into the genetic underpinnings of schizophrenia. The research was presented as a featured plenary presentation at the American Society of Human Genetics 2019 Annual Meeting in Houston, Texas

"The main aim of our research is to understand the genetic causes of schizophrenia and motivate the development of new therapeutics," said Dr. Singh. "Drug development for schizophrenia has had limited progress in the last 50 years, but in the last decade, we have started to make genetic discoveries that help us better understand the mechanisms underlying the disorder."

Schizophrenia is a severe psychiatric disorder, the risk of which can be dramatically increased by the disruption of certain protein-coding genes. Since these changes are so strongly selected against in every generation, Dr. Singh explained, they are rare in the population and researchers need a very large sample size to study them with enough statistical power to draw robust conclusions. As part of the Schizophrenia Exome Sequencing Meta-Analysis Consortium, they analyzed the genomes of 25,000 people with schizophrenia and 100,000 people without disease from five continental populations.

"For the first time, we were able to identify 10 genes that when disrupted, dramatically increase risk for schizophrenia," said Dr. Singh. He noted that two of the 10 genes coded for glutamate receptors, a type of protein known to be crucial in communication among brain cells. By pinpointing glutamate receptors as genetically involved in disease, this finding strongly suggests that decreased function of these receptors drives disease symptoms, and that this system can potentially be a target for future therapies.

"Furthermore, our analyses showed us that there are many more such genes our search is just beginning," he added.

Dr. Singh and colleagues also noted that they found shared genetic connections with neurodevelopmental delay and autism spectrum disorder. By comparing these conditions, the researchers hope to find how specific the genes they found are to schizophrenia, and what their wider biological effects are.

"Overall, this method is a powerful way to look at complex traits, and combining results from genome-wide association studies and exome sequencing will teach us a lot about the biology underlying human diseases," said Dr. Singh. "Now that we know how to do it, the biological work is what comes next."

Dopamine, Schizophrenia, and. Creativity?


I have heard of Schizophrenia a ton, but I wasn't as aware of how exactly it works in the brain. It was also super interesting that you connected it to how a creative persons mind works.

I totally agree with Madeline. This topic is so so interesting. I think that mentally ill people, specifically schizophrenics, are so fascinating because of how their brains work. Not only that, but the fact that schizophrenia has to do with dopamine is interesting, because typically dopamine makes people happy, and in the case of schizophrenia, it's peculiarly the opposite.

This was really cool to read. Before reading this, I was familiar with schizophrenia, but I had no idea how it operated.

Learned about this at Rutgers, it was refreshing to see some neurotransmitters here.

Wow, this is fascinating! I love how you described the positive and negative symptoms first as well as schizophrenia as a whole it is a diverse disorder which is stigmatized I think because many people are only told one thing about those with it and are not educated on the true depth of the subject. I think the link between creativity and schizophrenia is so interesting, I wonder if it's different for those in the prodromal phase, or maybe it's the same and could be a predictor? Overall, great read!

This topic is so cool. Schizophrenia is something I never really knew too much about, so it is great to learn more. Also, it was interesting learning about the positive and negative symptoms.

The Dopamine Hypothesis of Schizophrenia


The dopamine hypothesis of schizophrenia , which was formulated in the 1960s after the discovery of the antipsychotic actions of chlorpromazine, was extremely successful as a heuristic principle for interpreting aspects of the phenomenology of schizophrenia. The development of improved antipsychotic medications was guided by a search for dopamine blockers based on the concept that schizophrenia is, in part, a hyperdopaminergic state. Molecular imaging studies performed over the past 25 years strongly support an association of increased subcortical dopamine transmission with the positive symptoms of schizophrenia, with the caveat that this finding is not pathognomonic due to neurochemical heterogeneity of populations of schizophrenia patients. Although subcortical hyperdopaminergia contributes importantly to aberrant salience (manifesting in positive symptoms), the original dopamine hypothesis must be extended to include contributions of other neurotransmitter systems, with glutamate being particularly implicated in the pathophysiology of schizophrenia.

Related Links

References: Schizophrenia risk from complex variation of complement component 4. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose SA, Handsaker RE Schizophrenia Working Group of the Psychiatric Genomics Consortium, Daly MJ, Carroll MC, Stevens B, McCarroll SA. Nature. 2016 Jan 27. doi: 10.1038/nature16549. [Epub ahead of print]. PMID: 26814963.

Funding: NIH’s National Institute of Mental Health (NIMH), National Human Genome Research Institute (NHGRI), National Institute of General Medical Sciences (NIGMS) and the Stanley Center for Psychiatric Research.

Psychosis: a consequence of network dysfunction

Psychosis is a condition that features a range of behavioural alterations that relate to a loss of contact with reality and a loss of insight. People with psychosis experience hallucinations (primarily auditory in schizophrenia 53 ) and delusions. In schizophrenia, auditory hallucinations have been associated with altered connectivity between the hippocampus and thalamus 54 . During hallucinations, increased activation of the thalamus, striatum and hippocampus have also been observed 55 . Thus, altered thalamocortical connectivity, especially with the hippocampus, may impede internal/external representations of auditory processing 56 . In contrast, delusions in people with schizophrenia have been associated with overactivation of the prefrontal cortex (PFC) and diminished deactivation of striatal and thalamic networks 57 . Thus, the complexity of psychotic symptoms is congruent with the highly connected nature of implicated brain regions.

Although we still know little about the underlying neurobiology of psychosis, focal brain lesions allow for a better understanding of the networks involved without the confounds of medication and unrelated neuropathology. Generally speaking, lesions that induce hallucinations are often in the brain networks associated with the stimulus of the hallucination (i.e., auditory, visual or somatosensory) 58 . Visual hallucinations have been associated with dysfunction of the occipital lobe, striatum and thalamus, whereas auditory hallucinations are associated with dysfunction of the temporal lobe, hippocampus, amygdala and thalamus 58 . Insight is generally maintained after focal brain lesions that produce hallucinations and subcortical dopamine function is normal 59 , unlike what is observed in schizophrenia 58 . In contrast, a loss of insight (which can manifest as delusionary beliefs) is associated with alterations in cortico-striatal networks. For example, people with basal ganglia or caudate lesions can present with both hallucinations and delusions 60, 61 . Furthermore, a case study of religious delusions in a patient with temporal lobe epilepsy was associated with overactivity of the PFC 62 , and there are multiple lines of evidence suggesting that the PFC is integral for delusionary beliefs 63 . Therefore, while impairing networks specific to certain sensory modalities can lead to hallucinations, dysfunctional integration of PFC input to the associative striatum may be especially important for delusional symptoms in schizophrenia.

Central to the networks involved in psychosis and schizophrenia, the thalamus acts as a relay for most information going to the cortex 64 . Brain imaging studies have demonstrated that medication-naive patients with schizophrenia have significantly reduced thalamic and caudate volumes relative to healthy controls and medicated patients 65 . Moreover, reduced thalamic volumes has also been observed in UHR subjects 66 . A simplified schematic of the networks that may be especially relevant to psychotic symptoms in schizophrenia is presented in Fig. 2. The thalamus forms a circuit with the associative striatum and PFC whereby impairments in any of these regions can impair the functionality of the network as a whole. In addition, the hippocampus and amygdala, which are both involved in sensory perception and emotional regulation, can affect this network via their connectivity with the thalamus (but other indirect pathways also exist). Although this is an over simplification, it highlights how psychotic symptoms could arise from multiple sources of neuropathology/dysfunction or abnormal connectivity.

Dysfunction in a variety of brain regions can elicit psychotic symptoms. A primary circuit involved in psychosis includes the thalamus and prefrontal cortex (yellow) feeding into the associative striatum. Alterations in the thalamus and prefrontal cortex are involved in hallucinations and also insight for delusional symptoms. Expression of psychotic symptoms in most cases requires increased activity in the associative striatum and specifically excessive D2 receptor stimulation (red). Other limbic regions such as the hippocampus and amygdala (green) can feed into this circuit contributing to altered sensory perception and emotional context

Advances in Understanding the Genetic Etiology of Schizophrenia

The dopamine hypothesis ‘version II’ was published before the Human Genome Project and the huge advances in genetic research in schizophrenia. After over 1200 studies, it seems clear that no one gene “encodes” for schizophrenia. 63 Rather, in common with many other complex diseases, there are a number of genes each of small effect size associated with schizophrenia. 63 The gene database on the Schizophrenia Research Forum ( provides a systematic and regularly updated meta-analysis of genetic association studies. As of autumn 2008, 4 of the top 10 gene variants most strongly associated with schizophrenia are directly involved in dopaminergic pathways. The strongest association is with a gene variant affecting the vesicular monoamine transporter protein (rs2270641, odds ratio 1.63). This protein acts to accumulate dopamine and other monoamines into vesicles, which fits with the PET studies that show elevated radiolabeled dopamine accumulation into striatal vesicles in schizophrenia. Additionally, other gene variants in the list of the strongest associations, such as in the genes for methylenetetrahydrofolate reductase and V-akt murine thymoma viral oncogene homolog 1, indirectly affect the dopaminergic system among other effects. 64 Many of the other gene variants in the top list are involved in brain development, such as the gene for dysbindin, or influence more ubiquitous brain transmitters such as glutamate or γ-aminobutyric acid (GABA). 63, 64 While recent findings have breathed great interest in the copy number variations in schizophrenia—the early evidence there also suggests that they are rare, tend to be unique to families, and are unlikely to account for more than a few percent of schizophrenia. 63, 65–67 It would be premature to try and synthesize these genes into a pathway leading to dopamine abnormality because the precise number, nature, function, and association of these genes to schizophrenia is evolving. The most parsimonious statement that can be made today is that while a number of genetic associations have been identified, none of them accounts for the majority of schizophrenia and most of them are likely to be susceptibilities. Of the ones that have been identified, some have already been tied to altered dopamine transmission. 68 However, the functional relevance of most of them to dopamine function is not known. 68 This view of schizophrenia genetics then reemphasizes a critical role for other interacting factors—particularly the environmental risk factors for schizophrenia.

Variables In Dopamine Upon Schizophrenia Biology Essay

Dopamine [ 4- (2-aminoethyl) benzene-1,2-diol) ] is a catecholamine monoamine neurotransmitter (Neve, 2009, p. 24) formed in the encephalon ‘s dopamine nerve cells from the amino acid precursor Laˆ‘tyrosine it is so stored in cysts within the nervus terminuss, let go ofing the Dopastat into the synaptic cleft. It is synthesized chiefly in the adrenal secretory organ myelin foremost by the hydroxylation of the amino acid L-tyrosine to Laˆ‘3,4aˆ‘dihydroxyphenylalanine (L-DOPA) via the enzyme tyrosine 3-monooxygenase (tyrosine hydroxylase) and so by the decarboxylation of Laˆ‘DOPA by aromatic L-amino acid decarboxylase (Myers, 2007, p.

105).This release is controlled by a assortment of factors, including the firing rate-the impulse-dependent release (von Bohlen & A Halback, 2006, p. 64) -of the Dopastat nervus cell and the release and subsequent synthesis-modulating presynaptic Dopastat receptors because presynaptic Dopastat receptors are sensitive to the cell ‘s ain neurotransmitter, they are called dopamine autoreceptors. The function of these autoreceptors is to supervise extracellular Dopastat concentrations, modulating the impulse-dependent release rate and besides to command dopamine synthesis (Powis & A Bunn, 1995, p.

330). Once released the dopamine Acts of the Apostless at postsynaptic receptors to act upon behaviour. These autoreceptors are found at dendrites and haoma (von Bohlen & A Halback, 2006, p. 66).Adhering to the postsynaptic receptors induces a alteration in the constellation of these receptors which so causes membrane permeableness to ions and initiates a complex alteration of intracellular postsynaptic events (von Bohlen & A Halback, 2006, p.

64). The result is an activation or suppression of the postsynaptic nerve cell (Stahl, 2008, p. 346).

The actions of Dopastat in the synapse are terminated chiefly by the reuptake of neurotransmitter into the presynaptic terminus by agencies of an active Dopastat transporter, where it is stored and can be reused (Eshlemann & A Janowsky, 2003, p. 439).The Dopastat transporter is a glycoprotein of 619 amino acids that show a 12-span transmembrane design (von Bohlen & A Halback, 2006, p. 64). The intent of the transporter is to roll up extracellular Dopastat and topographic point into the presynaptic terminus to modulate its life-cycle. This uptake procedure depends upon Na and chlorine ions its efficiency can be measured at 80 % (von Bohlen & A Halback, 2006, p. 64).

Dopamine is either returned to synaptic cysts for rerelease or degraded by monoamine oxidase (MAO) and aldehyde dehydrogenase to dihydroxiphenylacetic acid (Kuhar, et al., 1990, p. 18).

Alternatively, it can be metabolized by catechol-0-methyltransferase to organize 3-methoxytryptamine (von Bohlen & A Halback, 2006, p. 64). The conveyance mechanism is non located in an active country, but instead in a perisynaptic country, connoting that Dopastat diffuses off from the intersynaptic cleft (Memo et al., 1986, p. 19).Although it was foremost thought that Dopastat occurred merely as an intermediate merchandise formed in the biogenesis of two other catecholamine neurotransmitters, noradrenaline and adrenaline, Dopastat is now recognized as a neurotransmitter in its ain right. Several distinguishable dopamine neural systems have been identified in the encephalon (Memo et al.

, 1986, p. 22). These include systems within the hypothalamus and the pituitary secretory organ systems within the mesencephalon that undertaking to a assortment of cortical and limbic parts and basal ganglia the retinal system and the olfactory system. The mesencephalon Dopastat nerve cells which project to a assortment of forebrain constructions are critically involved in normal behavioural attending and rousing abnormalcies in the normal operation of these systems have been implicated in a assortment of upsets.

Dopamine receptors are classified into two groups: D1 and D2. The following table depicts the belongingss of dopaminergic receptors. [ 1 ] Per Neve (2009, p. 24) these receptors belong to the category of G protein-coupled receptors. The G proteins interact with Dopastat to direct secondary messager Cascadess (Steiner & A Tseng, 2010, p. 448).

Amino Acid SequenceLocation on the Human ChromosomeProtagonistsAdversariesD1 householdD1 (1A)446Sq-34-35A-G8930CY-208-245DihydrexidineHydroxybenzazepineHalobenzazepineThioxantheneD5 (1B)4774p-15.

1-3HydroxybenzazepineHalobenzazepineD2 householdD2L (2AI±)44311q-22-23AminotetralineBenzamideD2S (2AI?)41411qErgolineBenzamideD3 (2B)4003q-13.1(+) -7-OH-DPATS-14297D4 (2C)387+11p-15.5Ergoline(+) -AporphineClozapineDopaminergic hyperactivity leads to an accretion of the neurotransmitter in the synaptic cleft (von Bohlen & A Halback, 2006, p. 70). This hyperactivity consequences in an increased sensitiveness to emphasize associated with a predominace of noradrenergic over dopaminergic hyperactivity (Yui et al., 2000, pp.

343-349). The excitant feedback cringle from the thalamus to the striate body, arising from the centromedian-parafascicular composite and the midplane thalamic karyon can take to dopaminergic hyperactivity dysregulating sensorimotor and limbic circuits within the basal ganglia taking to thalamic hyperactivity, which would take to extended stimulation of the cerebral mantle (Visser-Vandewalle, 2007, p. 218).

Dopaminergic hypoactivity consequences in motor disfunction (von Bohlen & A Halback, 2006, p.A 70): the basal ganglia has an of import function in motion. Antagonism of presynaptic D2 receptors increases the release of norephinephrine, while hostility of postsynaptic D2 receptors consequences in choice vascular relaxation (Brent, 2005, p. 307).SchizophreniaSchizophrenia was foremost classified as a separate mental upset by Kraepelin in 1890 (Kraepelin, 1911).

Historically, nevertheless, as compared to other psychopathic provinces, description, categorization and causing has been obscure. In 1952, the first edition of the Diagnostic and Statistical Manual of Mental Disorders was published by the American Psychiatric Association in an attempt to standardise diagnosing and etiology (Wilson, 1993, p. 400).From a psychological position, no individual personality type has been systematically found in premorbid histories of schizophrenics (Cancro, 1985, p. 635). One of the nucleus research surveies used to place a familial function in the causing of an unwellness is the household or blood kinship method. This method compares the prevalence rate of a patient ‘s upset with their relations vis-a-vis the general population.

This, along with duplicate surveies, provided ambiguous consequences (Cancro, 1985, pp.A 635-637).No specific bodily manifestations exist in schizophrenic disorder nevertheless, in its early phases, patients report multiple symptoms, including concern, arthritic strivings in the shoulders, back hurting, failing and dyspepsia (Weiner, 1985, p. 691). A patient sing an acute schizophrenic reaction on a regular basis nowadayss dilated students, damp thenars and moderate tachycardia (Weiner, 1985, p. 691). Pneumoencephaographic information, nevertheless, showed grounds for ventricular expansion in a statistically important per centum of schizophrenics (Cancro, 1985, p.

639). Over the old ages, the immune systems, plasma factors, and blood flow surveies had been conducted on schizophrenics with the consequence of nonspecific findings (Cancro, 1985, p. 639). However, surveies of Dopastat degrees have been assuring. Dopamine degrees in schizophrenic encephalons post-mortem are higher in the caudate karyon and the karyon accumbens.

It has been repeatedly shown that schizophrenic ‘s postmortem encephalons had an addition in the figure of D2 type Dopastat receptor adhering sites (Cancro, 1985, p. 639).Discussion refering the etiology of schizophrenic disorder is complicated by a cardinal conceptual issue: what are the theories supposed to explicate about the disease. These theories are often stated in footings of individual causes which become manifest merely through their interaction with other systems. A individual factor will non account for all of the aetiologic discrepancy.

Correlations are mistaken for causal accounts. If it were to go apparent that chemical production, response or metamorphosis were the link for schizophrenic disorder, a functional account would go the implicit in premiss for the status to be. Perturbations in attending are a outstanding characteristic of schizophrenic disorder.

On the footing of reaction clip experiments, schizophrenics tend to be affected or distracted by irrelevant facets in the context of the stimulation (Weiner, 1985, p. 664). They may hold some trouble in keeping a province of preparedness to do a response to a stimulation and in forming their response in clip, which is “ an inability to keep a major set ” (Weiner, 1985, p. 664). The aetiologic theory most subscribed to is that schizophrenic disorder is a physical disease due to a structural or functional defects in some organ system. Having observed that schizophrenics have low emphasis tolerance, the adrenocortical endocrines were investigated, with unnatural degrees found, merely to subsequently emerge as covariants of the patient ‘s behaviour and the grade of break of psychological operation (Weiner, 1985, p.

669). A similar decision can be drawn about the findings that 30 % of schizophrenics have an unnatural Decadron suppression trial (Weiner, 1985, p. 669).For a figure of old ages now, the plausible hypothesis is that dopamine interactions can explicate schizophrenic disorder. This is based chiefly upon contrary technology, based upon the encephalon ‘s reaction to antipsychotic drugs and projecting their impact upon Dopastat degrees this is the theoretical account ‘s implicit in failing this theoretical account does non extinguish all of the immaterial variables such as other chemical reactions, genetic sciences, environment,A figure of articles have been published refering increased degrees of enzymes in the blood of acutely psychotic patients, including creatine phosphokinase (CPK), aldolase, and platelet MAO-B (Akasaki, et al., 1993, pp. 843-846 Gosling, et al.

, 1972, pp. 351-355 Matthysse & A Lipinski, 1975, pp. 551-565 Meltzer, 1973, pp. 589-593).

What is interesting here is that CPK is derived from musculus, non from the encephalon. In acute psychosis, there are many sorts of anatomic alterations in the subterminal motor nervus terminations in skeletal musculus and in the musculus itself. In the vastus lateralis or gastrocnemius musculuss of 57 % of ascertained psychotic patients, myofibrillar alterations occurred, including their devolution (Weiner, 1985, p. 674).

Another hypothesis is that pathogenesis of schizophrenic disorder is the consequence of unnatural metamorphosis these merchandises are described as holding psychomimetic belongingss (Weiner, 1985, p. 675). The implicit in hypothesis is that metabolic perturbation is the consequence of methylated Dopastat. Agents that increase or mobilize effectual sums of catecholamines in the encephalon addition psychotic symptoms L-DOPA, the precursor to dopamine, noradrenaline and adrenaline may make so. But Dopastat may non be the lone perpetrator. Norepinephrine, widely distributed throughout the limbic, paramedian thalamic and hypothalamic constructions of the encephalon, play a major function in many behaviours, including eating, aggression, motion, memory and the sleep-wake rhythm.

As such, it may move as a neuromodulator instead than that of a neurotransmitter (Castro-Alamancos and Calcagnotto, 2001, pp. 1489-1497 Harik, 1984, pp. 699-707 Hu, et al.

, 2009, pp. 160-173). Tassin found that stimulation of cortical alpha-1 sympathomimetic receptors inhibits cortical Dopastat transmittal at D1 receptors (Tassin, 1992, pp. 135-162).The psychological abnormalcies and cognitive troubles in schizophrenic disorder precede and outlast the psychosis. The hypothesis of dopamine dysregulation is the best account for the psychotic episode in schizophrenic disorder the pathophysiology of other psychological and cognitive abnormalcies in schizophrenic disorder remains ill-defined.

A combination of susceptibleness cistrons (Brzustowica, et al., 2000, pp. 678-682) and other factors contributes to schizophrenia, and the net consequence dysregulates the Dopastat neurotransmission system, taking to high release of Dopastat, more D2 receptors, and an evident predomination of monomer signifiers of D2 (Kapur & A Mamo, 2003, pp. 1081-1090).

This dopamine dysregulation leads to the psychotic episode.Abnormal synchronism of nervous activity between distal encephalon parts has been proposed to underlie schizophrenic disorder. A survey investigated whether unnatural synchronism occurs between the median prefrontal cerebral mantle and the hippocampus, two encephalon parts implicated in schizophrenic disorder, utilizing the maternal immune activation theoretical account.

It is induced through a individual injection of the man-made immune system activator polyriboinosinic-polyribocytidylic acid, a man-made parallel of double-stranded RNA, a molecular form associated with viral infection, in pregnant rats. It was based on epidemiological grounds of increased hazard of schizophrenic disorder in maturity after antenatal exposure to infection (Dickerson, et al., 2010, p.

12424). EEG coherency and neural phase-locking to underlying EEG were measured. EEG coherency correlated with reduced prepulse suppression of jump, a step of centripetal gating and a feature of schizophrenic behaviour.

Changes in the synchronism of neural fire to the underlying EEG were apparent in the theta and low-gamma frequences. Produced was a cardinal break in long-range neural synchronism in the encephalons of the grownup offspring that theoretical accounts the break of synchronism observed in schizophrenic disorder (Dickerson, et al., 2010, p.

12431).In 2003 a survey was performed of an initial subset of calcineurin-related cistrons. Transmission disequilibrium surveies detected association with the PPP3CC cistron, which encodes calcineurin I? catalytic fractional monetary unit, located at 8p21.3 as a possible schizophrenic disorder susceptible cistron (Gerber, et al., 2003, p. 8997). In a follow-on survey, verification of 1,140 instances supported the old familial association of altered calcineurin signaling with schizophrenia pathogenesis (Yamada, et al.

, 2006, p. 2819). This was reinforced by a similar survey conducted in 2008 (Mathieu, et al.

, 2008, p. 1186). Another 2008 survey posited that schizophrenic disorder was a familial upset and has identified a specific cistron as a precursor to schizophrenia (Takao, et al., 2008, p.

11).Further research needs to bring out implicit in mechanisms that predispose the encephalon to the dysregulation of the Dopastat system (Bertolino, et al., 2000, pp. 125-132) and to farther consider and extinguish outlying variables, plus developing a heuristic psychological/biochemical attack to schizophrenia (Howes & A Kapur, 2009, p.

Dopamine is key to the mystery of metabolic dysfunction in psychiatric patients

PITTSBURGH, Feb. 15, 2021 - Why do patients who receive antipsychotic medications to manage schizophrenia and bipolar disorder quickly gain weight and develop prediabetes and hyperinsulemia? The question remained a mystery for decades, but in a paper published today in Translational Psychiatry, researchers from the University of Pittsburgh School of Medicine finally cracked the enigma.

Antipsychotic drugs, scientists showed, not only block dopamine signaling in the brain but also in the pancreas, leading to uncontrolled production of blood glucose-regulating hormones and, eventually, obesity and diabetes.

"There are dopamine theories of schizophrenia, drug addiction, depression and neurodegenerative disorders, and we are presenting a dopamine theory of metabolism," said lead author Despoina Aslanoglou, Ph.D., a postdoctoral fellow at Pitt's Department of Psychiatry. "We're seeing now that it is not only interesting to study dopamine in the brain, but it is equally interesting and important to study it in the periphery."

Dopamine is a neurotransmitter that acts as a chemical messenger between neurons and is commonly known to play a role in pleasure, motivation and learning. And antipsychotic medications--such as clozapine, olanzapine and haloperidol--relieve hallucinations and delirium by blocking a subtype of dopaminergic receptors in the brain called D2-like receptors and preventing dopamine molecules from causing neurological effects.

But, as Aslanoglou and senior author Zachary Freyberg, M.D., Ph.D., assistant professor of psychiatry and cell biology at Pitt, found, it's not so simple.

"We still don't really understand how dopamine signals biologically," said Freyberg. "Even decades after dopamine receptors have been discovered and cloned, we still deploy this 'magical thinking' approach: something happens that's good enough. We use drugs that work on dopamine receptors, but how they intersect with this 'magical system' is even less understood."

The human pancreas contains miniature structures called pancreatic islets, which are made up of alpha and beta cells whose function is to produce and secrete hormones that regulate blood glucose. Alpha cells produce glucagon to raise blood glucose, and beta cells produce insulin to lower blood glucose back to normal.

If even one player in the glucose-regulating machinery breaks, our bodies begin to suffer. Low blood glucose makes us feel dizzy and faint, while high blood glucose--when sustained for a long time--causes diabetes and other complications in the cardiovascular system.

And, as it turns out, dopamine can tip the scales.

Freyberg's team found that both pancreatic alpha and beta cells can make their own dopamine, confirming that its effects aren't limited to the brain. What's more, while beta cells primarily rely on the uptake of the dopamine precursor L-DOPA, alpha cells can make L-DOPA from scratch and ramp up its production in response to glucose. This raises the possibility that alpha cells can use dopamine to not only signal at their own receptors, but also supply it to beta cells, where it acts on D2-like receptors and inhibits secretion of glucose-lowering insulin.

And unexpectedly, the researchers discovered that pancreatic dopamine also can act on receptors designed to recognize other molecules, such as "fight-or-flight" messengers adrenaline and noradrenaline.

At a low concentration, scientists showed, dopamine primarily binds to inhibitory D2-like dopamine receptors and blocks insulin or glucagon release. At high concentrations, however, dopamine also can bind to beta-adrenergic receptors and become stimulatory, pushing hyperglycemic effects of glucagon release in alpha cells while at the same time inhibiting insulin release in beta cells through inhibitory alpha-adrenergic receptors.

Together, these findings finally explain how psychiatric patients develop metabolic syndrome after getting treatment. Blocking inhibitory dopamine receptors with antipsychotics causes a vicious circle--the brake comes off and insulin and glucagon release become unchecked, quickly desensitizing the body and further propagating hyperinsulimia, hyperglycemia and, eventually, obesity and diabetes.

"When you identify something so important, you have to make sure you find an application for it and improve people's lives," said Aslanoglou. "Our discovery can inform us of how to better formulate drugs to target dopamine signaling. This might be a novel pathway to therapeutics in both psychiatry and metabolism."

Additional authors of the paper include Suzanne Bertera, Ph.D., Massimo Trucco, M.D., and Rita Bottino, Ph.D., all of the Allegheny Health Network Research Institute Marta Sánchez-Soto, Ph.D., Benjamin Free, Ph.D., and David Sibley, Ph.D., all of the National Institutes of Health (NIH) Jeongkyung Lee, Ph.D., Wei Zong, Ph.D., Xiangning Xue, Ph.D., and Vijay K. Yechoor, M.D., all of Pitt Shristi Shrestha, Ph.D., and Marcela Brissova, Ph.D., both of the Vanderbilt University Medical Center Ryan Logan, Ph.D., of The Jackson Laboratory and Claes B. Wollheim, M.D., of the University of Geneva, Switzerland.

This research was supported by the Department of Defense (grant # PR141292), the John F. and Nancy A. Emmerling Fund of The Pittsburgh Foundation, the Intramural Research Program of the National Institute of Neurological Disorders and Stroke in the NIH (grant # R01DK097160), and U.S. Department of Veterans Affairs grant VA-ORD-BLR&D I01BX002678.

To read this release online or share it, visit http://www. upmc. com/ media/ news/ 021521-Freyberg-Aslanoglou [when embargo lifts].

About the University of Pittsburgh Schools of the Health Sciences

The University of Pittsburgh Schools of the Health Sciences include the schools of Medicine, Nursing, Dental Medicine, Pharmacy, Health and Rehabilitation Sciences and the Graduate School of Public Health. The schools serve as the academic partner to the UPMC (University of Pittsburgh Medical Center). Together, their combined mission is to train tomorrow's health care specialists and biomedical scientists, engage in groundbreaking research that will advance understanding of the causes and treatments of disease and participate in the delivery of outstanding patient care. Since 1998, Pitt and its affiliated university faculty have ranked among the top 10 educational institutions in grant support from the National Institutes of Health. For additional information about the Schools of the Health Sciences, please visit http://www. health. pitt. edu .

Contact: Anastasia Gorelova
Mobile: 412-491-9411
E-mail: [email protected]

Contact: Ashley Trentrock
Mobile: 412-529-9092
E-mail: [email protected]

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

Dopamine paradox in schizophrenia - Biology

For many years, the science of schizophrenia seemed stuck at the level of neurotransmitters and receptors. Decades of research had apparently proven the singular importance of dopamine and dopamine receptors to the understanding of schizophrenia and its treatment. Unfortunately, this awareness had brought us only so far in understanding the underlying pathophysiology and the ways in which we could improve outcomes in our patients. While the positive symptoms of schizophrenia, including hallucinations, delusions, and disorganized thinking, were often effectively ameliorated with typical antipsychotics -- with a singular mechanism action of D2 blockade, the negative and cognitive symptoms were left untouched and understudied.

The identification of clozapine as an effective treatment for previously untreatable patients with schizophrenia brought a paradigm shift in several important areas. First, other neurotransmitters, specifically serotonin, became important in the understanding of schizophrenia. Second, the benefits of clozapine for negative and cognitive symptoms led to an increased realization of their importance in affecting quality of life and other important outcomes. The evolution in understanding of the pathophysiology of schizophrenia, however, remained at the level of neurotransmitters and their receptors.

Analogous to the era of phrenology, the "bumps" that were seen on neurons only hinted at the dysfunction in the flesh below. With advances in techniques of molecular genetics, functional neuroimaging, and other research methods, the calvaria has been removed and the underlying function of the brain is becoming increasingly better understood. An emerging theme in schizophrenia research that was evident at this year's American Psychiatric Association annual meeting is that parallel lines of research are rapidly progressing beyond the level of simple transmitters to define neuroanatomical and neurophysiological circuits that lie at the heart of cerebral dysfunction in schizophrenia.

Nicotinic Receptor Model
To further broaden the number of neurotransmitters found to be important in understanding the pathophysiology and the complex neurocircuitry in schizophrenia, research over the last several years has provided clues to the impact of dysfunction of both cholinergic and glutamatergic neurotransmitter systems. The work of Robert Freedman, MD,[1] Chairman of the Department of Psychiatry at the University of Colorado Health Sciences Center, Denver, has progressed from early studies showing deficits in auditory information processing in schizophrenia to a well-described model of cortical dysfunction in schizophrenia related to dysfunction of a specific nicotinic receptor using molecular genetic techniques. By tracing the deficits in auditory information processing through families that included patients with schizophrenia and unaffected relatives, Dr. Freedman's group was able to show that a relatively common genetic mutation in nicotinic receptors, found in 10% of the population, caused difficulties in sensory gating and could be a predisposing factor for the impaired cognition and psychosis seen in schizophrenia. His research indicates a deficit in inhibitory interneuronal function, involving the alpha7-nicotinic receptor, as an integral feature of the altered neurocircuitry in schizophrenia. Such impaired nicotinic receptor function could be at the heart of the dramatically increased use of nicotine in patients with schizophrenia.

Glutamate Model
With all the emphasis in psychiatric research on neurotransmitters, it seems odd that the most prevalent and possibly most important neurotransmitter of them all was ignored. Glutamate, by virtue of the fact that it is found in high concentrations in the brain with much of it not acting as a neurotransmitter, was difficult to see as a neurotransmitter at all. However, it is now widely understood that glutamate is the most prevalent excitatory neurotransmitter in the brain and that dysfunction of glutamate receptors, which are likely present on every cell in the brain, lies at the heart of many neurologic, and possibly psychiatric, diseases.

Carol Tamminga, MD,[2] Professor of Psychiatry and Pharmacology at the University of Maryland School of Medicine, Baltimore, has published several studies measuring effects of certain compounds on a specific glutamate receptor, the NMDA receptor. The NMDA receptor is most known for its involvement as a mechanism of action of the hallucinogenic properties of phencyclidine, or PCP. Dr. Tamminga and colleagues have used PCP and ketamine in humans as a model of the pathophysiology of schizophrenia. PCP and ketamine were both initially used as anesthetic agents, and ketamine is still commonly used in dental procedures. Both PCP and ketamine antagonize the action of the NMDA receptor by blocking the ion channel and can cause perceptual disturbance and cognitive dysfunction similar to that seen in schizophrenia. In addition, when these compounds are given to patients with schizophrenia their symptoms are magnified. Using positron emission tomography (PET) studies, Dr. Tamminga's group has shown that ketamine increases regional cerebral blood flow in the anterior cingulate cortices and decreases flow in the hippocampus and cerebellum, all areas that had previously been shown to be abnormal in schizophrenia. A hypoglutamatergic state beginning in the hippocampus could inhibit excitatory transmission to the anterior cingulate and temporal cortex. The complicated neurocircuitry could include GABA and cholinergic interneurons that regulate pyramidal cell firing as well, thereby expanding pharmacological targets for treatment to glutamatergic, cholinergic, and GABA-ergic modulators.

Role of Dopamine
Returning to the importance of dopamine in the pathophysiology of schizophrenia, Daniel Weinberger, MD,[3] Chief of the Clinical Brain Disorders Branch at the National Institute of Mental Health, has conducted research into the importance of catechol-O-methyl transferase, or COMT, in the pathophysiology of schizophrenia. COMT is an enzyme that degrades dopamine in the synaptic cleft. Interestingly, unlike the striatum, the prefrontal cortex has no dopamine transporters. Dopamine transporters are reuptake sites similar to those found on serotonin receptors. When these reuptake sites are blocked, like with serotonin reuptake inhibitors, or don't exist, as is the case in the prefrontal cortex for dopamine, the effects of neurotransmitter-degrading enzymes are extremely important. Hence the contraindication of concurrent serotonin reuptake inhibitors and monoamine oxidase inhibitor use. Therefore, the effect of COMT in the action of dopamine in the prefrontal cortex is substantial. In fact, animal studies have shown that COMT is responsible for more than 60% of dopamine degradation in the prefrontal cortex. And dopamine action in the prefrontal cortex is supremely important for cognition. Dopamine activity in the prefrontal cortex, through studies done in patients with Parkinson's disease, has been shown to dramatically increase the "efficiency" of neurocognitive performance. This, in essence, allows the brain to focus more of its energy on brain regions that are important for processing information. This effect of dopamine, and its disruption, is possibly responsible for the deficits in attention and executive functioning commonly found in patients with schizophrenia.

Genetic Techniques
Using molecular genetic techniques similar to those used by Dr. Freedman, Dr. Weinberger and colleagues[3] have shown that a single point mutation in the COMT gene causes a 75% reduction in the activity of COMT. This genetic "defect," which increases dopamine activity in the prefrontal cortex, has been shown, using the Wisconsin Card Sort Test, to significantly improve executive functioning. In fact, this "defect," which is responsible for 4% of the human variation of attention and executive functioning and is not found in great apes, was proposed as a potential factor in the evolution of the cortex, and, therefore, of mankind itself. And the gene encoding the more effective form of COMT has been shown to be significantly more prevalent in patients with schizophrenia than in normal controls. This line of evidence makes a convincing argument that the gene encoding the more effective form of COMT is a susceptibility gene for schizophrenia. With the elucidation of the importance of COMT, another target for psychopharmacology is delineated.

Glia and White Matter
With all the focus on neurons, it is easy to forget that the vast majority of the cells in our brains are not neurons, but glia. Glia, including astrocytes and oligodendrocytes, make up more than half the brain's weight and outnumber neurons by a factor of more than 101. Their actions of support to neurons are crucial to proper brain function. Astrocytes are believed to provide structural support for the neurons of the brains and aid in the repair of neurons following damage to the brain. Oligodendrocytes produce myelin, which surrounds the axons of many neurons and is the identifying component of white matter. Taking the research into the pathophysiology of schizophrenia into a heretofore-neglected area, Kenneth L. Davis, MD,[4] Chairman of the Department of Psychiatry at Mount Sinai School of Medicine, New York, NY, presented data indicating that alterations in white matter may be intimately involved.

Moving forward from an atheoretical presupposition, measuring gene expression changes detected by microarray DNA-chip analysis of postmortem tissue from the dorsolateral prefrontal cortex of patients with schizophrenia -- analogous to a scientifically sound "fishing expedition" into altered genetic expression, Dr. Davis found that one can differentiate schizophrenic from normal brains solely on the basis of expression of myelin genes. Following this exciting finding, several investigators have utilized different methods to show the dramatic damage to oligodendrocytes in the brains of patients with schizophrenia. Not only are oligodendrocyte counts in functionally important areas of the cortex significantly reduced, but electron microscope findings show that such areas exhibit abnormal inclusions between myelin sheath lamellae, showing evidence for cellular dysfunction. Anisotropy, a measure of the coherence of white matter, has also been shown to be reduced in frontal and temporal lobes of patients with schizophrenia. Such "frayed wires" are further evidence for altered neuronal structure and connectivity in schizophrenia.

Given this, dramatic alterations in oligodendrocyte function appear to be present in schizophrenia, with reduced numbers, impaired function, and disrupted cytoarchitecture. Decades of research have consistently shown increased ventricular size in the brains of people with schizophrenia, but reductions in gray matter volume have been small and inconsistently found, outside of specific thalamic nuclei. Could it be that, all along, the lost brain volume in schizophrenia has come from loss of white matter?

One exciting possibility that could link several of these parallel lines of research involves glutamate hyperactivity. Bita Moghaddam, PhD,[5] Associate Professor in Psychiatry at Yale University, New Haven, Connecticut, published an important paper in 1997 showing that ketamine, an NMDA antagonist, actually increased glutamate outflow in the prefrontal cortex to non-NMDA receptors. Overactivation of AMPA and kainate receptors, 2 important non-NMDA glutamate receptors, has been linked to subsequent excitotoxic oligodendroglial death.[6] Thus, endogenous alterations in the glutamate system, mimicked by drugs such as PCP and ketamine as in the work by Dr. Tamminga, could lead to excessive glutamate release onto oligodendrocytes -- leading to impaired function, cell death, and loss of white matter.

Such a model that includes both known neurophysiological and neuroanatomical deficits found in the brains of people with schizophrenia offers hope that we are ever closer to answering a question deserving of the Nobel prize: what is the pathophysiology of schizophrenia and how do we treat it?

Freedman R. Nicotinic receptors and the genetics of schizophrenia and bipolar disorder. Program and abstracts of the American Psychiatric Association 155th Annual Meeting May 18-23, 2002 Philadelphia, Pennsylvania. Industry-supported Symposium No. 24B.
Tamminga CA. Glutamatergic transmission in schizophrenia. Program and abstracts of the American Psychiatric Association 155th Annual Meeting May 18-23, 2002 Philadelphia, Pennsylvania. Industry-supported Symposium No. 24C.
Weinberger DR. Molecular biology and genetics of cortical function in schizophrenia. Program and abstracts of the American Psychiatric Association 155th Annual Meeting May 18-23, 2002 Philadelphia, Pennsylvania. Industry-supported Symposium No. 24E.
Davis KL. White-matter abnormalities in schizophrenia. Program and abstracts of the American Psychiatric Association 155th Annual Meeting May 18-23, 2002 Philadelphia, Pennsylvania. Industry-supported Symposium No. 24D.
Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 199717:2921-2927.
McDonald JW, Althomsons SP, Hyrc KL, Choi DW, Goldberg MP. Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity. Nat Med. 19984:291-297.