Schizophrenia which neurotransmitter

Deficits in PPI can be produced in rodents by administering psychotomimetics such as dopaminergic and serotonergic agonists and glutamatergic antagonists 31 — Furthermore, dopaminergic stabilizers have been shown to restore social behavior in a rat model of schizophrenia 35 , and regulatory feedback loops exist among serotonergic, GABAergic, and dopaminergic neurotransmitters Pregnenolone, a neurosteroid in the central nervous system CNS , works by improving cognitive deficits through GABA, and pregnenolone improves PPI deficits in dopamine transporter knockout mice Activation of GABA-receptors in the rat brain results in various receptor interactions with glutamate 40 , 41 , and modulation of GABA A a5 receptors improves cognitive deficits in rats In a rat model of schizophrenia, the increase in dopamine is caused by hyperactivity of the ventral hippocampus Changes in dopamine receptors D-2 caused by antipsychotic drugs, such as quinpirole, have been demonstrated in a validated rodent model of schizophrenia 44 , However, recent work by Bay-Richter et al.

An up-regulation of D2-high receptors is a consistent feature in animal models of schizophrenia However, alterations in D 3 dopamine receptors caused by novel antipsychotic drugs, such as cariprazine, decrease cognitive deficits in knockout mice Therefore, D 3 -receptor antagonists are recommended as a new pharmacological strategy to improve cognitive function in schizophrenia [review by Nakajima et al.

Social isolation rearing in rats, which is a valid neurodevelopmental model of schizophrenia, reduces dopamine levels in the frontal cortex Cognitive deficits in schizophrenia affect working memory, language and executive function, episodic memory, processing speed, attention inhibition, and sensory processing The prefrontal region is affected in cognitive discrepancies connected with working memory [see the systematic review by Smieskova et al.

Episodic memory discrepancies in schizophrenia involve the medial temporal cortex, particularly the hippocampus, and the prefrontal cortex, particularly the ventral and dorsolateral prefrontal regions Additionally, auditory processing involving memory procedures is impaired in the working memory of schizophrenia patients Cognitive deficits correlate with a decline in dopamine in the prefrontal cortex, primarily at the level of D 1 -receptors 54 — 59 but also due an imbalance of D 1 and D 2 -receptors in the prefrontal cortex [review by Durstewitz and Seamans 60 ; Takahashi 61 ].

Several studies have proposed that an inverted U-shaped relation between working memory and activation of the prefrontal cortex exists in schizophrenia patients There is ongoing discussion regarding the involvement of D 1 - and D 2 -receptors in cognition in schizophrenia patients 63 — Cognitive discrepancies and working memory deficits in the prefrontal cortex are associated with an increase in dopamine and D 1 -receptors in the prefrontal cortex in schizophrenia patients 67 , Atypical antipsychotics such as clozapine block D 2 -receptors in the striatum and 5-HT 1A -receptors in the prefrontal cortex, which results in increased dopamine activity 69 , By blocking D 2 -receptors through antipsychotics, the apoptotic mechanisms in the brain regions involved in cognition are impaired The disturbed activity of working memory in the DLPFC in schizophrenia patients is influenced by the release of dopamine in the midbrain in schizophrenia patients, which is regulated by a deficit in glutamatergic projection from the DLPFC to midbrain dopamine neurons Extrastriatal dopamine transmission is necessary for attention and working memory, and these deficits in the fronto—striato—thalamic pathway are involved in cognition in schizophrenia Newer antipsychotic drugs such as olanzapine and clozapine, which have a better affinity for dopamine receptors and blocking 5-HT 2A receptors, decrease the hyperactivity of the mesolimbic dopaminergic pathway and improve the activity of D 1 -receptors in the prefrontal cortex Furthermore, nicotine improves cognition in schizophrenia patients Interactions between dopaminergic and methylation mechanisms may result in cognitive deficits in schizophrenia patients.

The COMT Met-allele results in lower COMT-activity, leading to greater production of dopamine and increased D 1 -receptor activity in the prefrontal cortex and, subsequently, better cognitive abilities in carriers of the Met-allele 76 — A link between Met-carriers and smoking has been recently reviewed 83 , and an association between COMT and cognitive dysfunction in bipolar disorder has also been discussed Middle-aged healthy women with H-COMT who carry the Val allele show better cognitive abilities, including executive processing and cognitive flexibility, than carriers of the Met allele Dopamine receptors are G-protein-coupled receptors and can be divided into D 1 , D 2 , D 3 , and D 4 -receptors D 1 receptors in the prefrontal cortex are decreased in schizophrenia patients and are unaffected by chronic treatment of typical neuroleptics [review by Friedmann et al.

In contrast, D 1 -receptors are increased in the parieto-temporal cortex in schizophrenia patients Increased D2 mRNA has been found in the frontal cortex in schizophrenia patients when compared with neuropsychiatric healthy control subjects Both the classic and -current antipsychotic drugs act primarily by increasing high-affinity D 2 -receptor expression 92 — Haloperidol has been shown to increase high-affinity D 2 -receptors in dopamine-sensitive rats in an animal of schizophrenia Dopamine agonists bind to D 2 -high and D 2 -low-receptors 93 , This D 2 two-state model is still controversial, although discussions tend to doubt its validity, as demonstrated by in vitro binding experiments The action of dopamine agonists is related to dopamine hyperactivity in psychosis Dopamine antagonists and, to a lesser extent, dopamine agonists increase the D 2 -high-receptors This increase in D 2 -high-receptors is a necessary basic requirement for the development of a psychosis that correlates with dopamine supersensitivity This specific increase in D 2 -receptors and dopamine supersensitivity might result in antipsychotic treatment failure , Although D 2 -receptor antagonists induce dopamine activity , the mechanisms underlying the action of dopamine D 2 -receptor antagonists are not entirely clear.

The low therapeutic advantage of dopamine D 2 -receptor antagonists and their high pharmacological selectivity require future research Antipsychotic drugs block D 2 receptors and increase the release of glutamate in the striatum , particularly on the right side of the striatum, which is a brain region involved in cognition and reward motivation Glutamate agonists have an effect on D 2 high-receptors in schizophrenia , For example, alterations in D 2 -receptor function caused by antipsychotic medication in a rodent model of schizophrenia 44 or by the application of an amphetamine in schizophrenia patients have been recently demonstrated.

Lower doses of antipsychotics such as risperidone are effective and do not induce EPSs , This specific D 2 -receptor occupancy in the striatum in schizophrenia patients interacts with the antagonistic effects of 5-HT 2A receptors [review by Pani et al. D 1 -receptors and NMDA-receptors cooperate with each other Furthermore, the intensification of D 2 -receptor antagonists by D 1 -receptor agonists results in better NMDA transmission, exemplified by the action of clozapine as a partial D 1 -receptor agonist NMDA and D 1 dopamine receptor interaction occurs through signal transduction and phosphorylation and dephosphorylation mechanisms D 1 -receptors are present in GABAergic interneurons For example, valproic acid affects GABA and, subsequently, dopamine A slightly increased density of D 2 -receptors in basal condition and a significant increase in D 2 -receptors in the striatum of schizophrenia patients has been found This increase of striatal dopamine D 2 -receptors in schizophrenia has also been demonstrated in neuroimaging and molecular imaging studies , Specific neurotransmitter pathways such as those of glutamate, GABA, and acetylcholine lead to a high-affinity of the D 2 -receptor Dopamine receptors such as the D 2 -receptor contain receptor mosaics i.

Decreased D 2 -receptors in the thalamus and anterior cingulate cortex in schizophrenia might suggest that they are involved in abnormalities in dopamine transmission from the thalamus to the prefrontal cortex Low doses of D 2 -receptor antagonists and signaling enhancers of NMDA-receptors are recommended as new treatments in schizophrenia [review by Fuxe et al. In the associative striatum, an increased D 2 -receptor availability has been found in schizophrenia patients Increased dopamine release in the striatum is linked to substance dependence, such as amphetamine dependency, in schizophrenia However, the role of dopamine in the dysfunction of the striatum in schizophrenia patients requires future research It can be summarized that, to date, the mechanism of every effective antipsychotic medication in schizophrenia involves dopamine and its interaction with other neurochemical pathways such as those of glutamate, GABA, serotonin, and acetylcholine.

Deviations in dopamine and glutamate have been reported in the prefrontal cortex of schizophrenia patients NMDA-receptors are involved in releasing dopamine into the striatum and frontal cortex in schizophrenia patients [Ref.

These interactions are accompanied by calcium-dependent changes and exchanges between DAT and G72 in various brain regions In contrast to dopamine receptors, glutamate receptors are found in the subcortical and cortical brain regions The activity of dopamine is regulated by GABA and glutamate. For example, corticostriatal glutamatergic pathways interact with dopamine terminals , , and specific glutamate receptors in the striatum, such as mGlu2, are sensitive to dopamine High glutamate levels have been found in the dorsal caudate nucleus of schizophrenia patients It can be summarized that NMDA-receptors and D 1 -receptors in cortical brain areas such as the prefrontal cortex and an excess of D 2 -receptors in subcortical brain areas such as the striatum are interconnected with each other through a positive feedback mechanism However, through its presynaptic action, dopamine reduces the release of glutamate in the pyramidal neurons of layer V in the prefrontal cortex Dopamine dysregulation in the basal ganglia of schizophrenia patients is an important intrinsic feature in the pathology of schizophrenia and not a medication side effect [review by Perez-Costas et al.

The finding by Brisch et al. Furthermore, Sokoloff et al. Indeed, injection of NMDA-antagonists such as MK increases glutamate concentration in the frontal, retrosplenial, and cingulate cortices Glutamate dysfunction in the prefrontal cortex and hippocampus causes the release of dopamine in the striatum A new focus on glutamatergic signaling mediated by NMDA and metabotropic receptors may benefit new drug developments [review by Field et al.

The review by Bernstein et al. The enzyme glutamine synthetase, which degrades glutamate into glutamine, is located in glial cells and is decreased in schizophrenia patients Additionally, the glutamate transporter for astrocytes, GLT-1, is increased in schizophrenia patients Although Arai et al.

Moreover, the atypical antipsychotic agent risperidone increases glutamine synthetase levels A synergistic interaction of adenosine and glutamate affecting the ventral striato-pallidal GABA pathway has been demonstrated in a rat model The interactions of pyramidal neurons with dopamine receptors on their dendrites and pyramidal cells with glutamate on their spines, and GABAergic interneurons in the prefrontal cortex in schizophrenia patients might offer new insights into receptor-targeted therapies [Ref.

In the nucleus accumbens, neurotensin NT inhibits dopamine discharge, which increases glutamate release and activates the ventral striato-pallidal GABA pathway, leading to a subsequent increase in glutamate transport from the mediodorsal thalamus to the prefrontal cortex Another interaction between dopamine in the prefrontal cortex and glutamate in the mediodorsal thalamus might be responsible for the effects of zotepine, which increases the extracellular levels of noradrenaline, dopamine, glutamate, and GABA GABA interacts with acetylcholine by constraining its excitatory contribution to cholinergic interneurons, which are decreased in the striatum of schizophrenia patients, resulting in prefrontal deviations in schizophrenia Dopamine also interacts with acetylcholine, which increases with smoking frequency in schizophrenia patients Acute nicotine administration might have positive effects on cognition in schizophrenia patients [Ref.

Dopamine neurons in the midbrain release serotonin, which is important during combined drug treatment with serotonin to prevent the so-called serotonin syndrome, a surplus of serotonin in some brain regions Atypical antipsychotics involving serotonin receptors include 5-HT 1A receptor agonists or antagonists, 5-HT 2A receptor antagonists, 5-HT 2c receptor inverse or partial agonists or neutral antagonists, 5-HT 6 receptor antagonists, and 5-HT 7 receptor antagonists Antipsychotics such as clozapine and aripiprazole possessing 5-HT- 1A agonist properties induce hippocampal neurogenesis and increase dopamine in the prefrontal cortex [review by Schreiber and Newman-Tancredi ].

It can be summarized that various serotonin—dopamine interactions, which include both direct and indirect feedback mechanisms, contribute to the pathology of schizophrenia [Ref. Novel antipsychotic drugs, such as asenapine, increase dopamine and glutamate levels in various subcortical and cortical areas New antipsychotic drugs with novel mechanisms induce alterations in both dopamine and glutamate [review by Paz et al.

For example, metabotropic glutamate and NMDA-receptors are future targets for new drugs , Future drug development should target signaling molecules involved in dopamine, glutamate, and serotonin neurotransmission such as Akt and glycogen synthase kinase-3 98 , , as well as the control of presynaptic dopamine synthesis and release Stress in schizophrenia patients causes an increased release of dopamine in the prefrontal cortex, which cannot be counteracted by reduced GABA A receptor complex activity, as well as dendritic spine loss in the prefrontal cortex , When used in schizophrenic patients, cannabis induces hyperdopaminergic and hypoglutamatergic activities with both positive and negative symptoms In particular, cannabis increases dopamine transmission in the nucleus accumbens, which might cause or aggravate psychoses A high-low activity polymorphism in COMT interacts with adolescent cannabis abuse, increasing the risk for schizophrenia Further, genes such as disrupted-in-schizophrenia-1 DISC1 play a role in stress pathways and the metabolism of dopamine in schizophrenia [review by Hains and Arnsten ; Lipina et al.

The role of dopamine in human evolution has hitherto received little theoretical attention. It is still unclear to what extent dopaminergic expansion in hominin evolution was due to genetic adaptations or epigenetic factors. Dopamine has expanded throughout primate and hominin evolution and that dopamine is especially concentrated in the prefrontal cortex, which is involved in higher order functioning.

The dopaminergic hypothesis contends that climatic changes occurring in sub-Saharan Africa during the Pliocene and Pleistocene periods, which resulted in increases of the Savannah belt expanded hominin locomotory range. It is also speculated that some human groups ventured to the more habitable African southern coast leading to dietary changes i. Dopamine increase may have also been linked with a concomitant elevation in thyroid hormone production.

Higher T4 found in Homo may have represented an early endocrinological difference between humans and other primates In humans, T4 concentration is associated with tyrosine conversion to dopa a precursor to dopamine ; deficiencies of T4 concentrations are linked with various neurological impairments Recent research suggests that from Homo erectus onward, humans became persistence hunters, requiring various morphological and thermo-regulatory modifications i.

From Homo erectus onward there is an evident increase in stride size, which also optimized ergonomic requirements of bipedalism while diminishing energy requirements. Greater mass of slow twitch muscles would have also assisted long distance locomotion. Long distance locomotion in conjunction with greater hunting activities in ancestral hominins incorporated all aspects of the CNS such as retention and memory recall of large geographic areas, which maximized resource acquisition.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. National Center for Biotechnology Information , U. Journal List Front Psychiatry v. Front Psychiatry.

Published online May Author information Article notes Copyright and License information Disclaimer. Edited by: Thomas W. This article was submitted to Schizophrenia, a section of the journal Frontiers in Psychiatry.

Received Jan 20; Accepted Apr The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.

No use, distribution or reproduction is permitted which does not comply with these terms. This article has been corrected. See Front Psychiatry. This article has been cited by other articles in PMC. Abstract Dopamine is an inhibitory neurotransmitter involved in the pathology of schizophrenia. Keywords: dopamine, schizophrenia, cognition, glutamate, dopamine receptors, cannabis, animal models of schizophrenia, evolution of the human brain.

Brief History of Dopamine Hypothesis in Schizophrenia Dopamine, adrenaline, and noradrenaline are neurotransmitters that belong to the catecholamine family. Recent Animal Models Implicating Dopamine in Schizophrenia The prepulse inhibition PPI of the acoustic SR ASR is a neurophysiologic measurement of sensorimotor gating and a marker for information-processing deficits in neuropsychiatric disorders such as schizophrenia 27 — Cognition in Schizophrenia Cognitive deficits in schizophrenia affect working memory, language and executive function, episodic memory, processing speed, attention inhibition, and sensory processing Alternate Neurochemical Models in Schizophrenia and Their Interactions with Dopamine Deviations in dopamine and glutamate have been reported in the prefrontal cortex of schizophrenia patients Dopamine and Human Evolution The role of dopamine in human evolution has hitherto received little theoretical attention.

Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References 1. A morphometric study of the dopamine-containing cell groups in the mesencephalon of normals, Parkinson patients, and schizophrenics.

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Michael F. Green Michael F. Katharine J. Nelson Katharine J. Google Preview. Read More. Your current browser may not support copying via this button. Subscriber sign in You could not be signed in, please check and try again. Username Please enter your Username. Password Please enter your Password. Forgot password? Don't have an account? The cause of schizophrenia is still unclear.

Genetics Heredity : Scientists recognize that the disorder tends to run in families and that a person inherits a tendency to develop the disease. Similar to some other genetically-related illnesses, schizophrenia may appear when the body undergoes hormonal and physical changes like those that occur during puberty in the teen and young adult years or after dealing with highly stressful situations. Chemistry: Scientists believe that people with schizophrenia have an imbalance of the brain chemicals or neurotransmitters: dopamine, glutamate and serotonin.

These neurotransmitters allow nerve cells in the brain to send messages to each other. This problem in processing different sounds, sights, smells and tastes can also lead to hallucinations or delusions. Structure: Some research suggests that problems with the development of connections and pathways in the brain while in the womb may later lead to schizophrenia.

Viral Infections and Immune Disorders: Schizophrenia may also be triggered by environmental events, such as viral infections or immune disorders. For instance, babies whose mothers get the flu while they are pregnant are at higher risk of developing schizophrenia later in life.

People who are hospitalized for severe infections are also at higher risk. The signs of schizophrenia are different for everyone. Symptoms may develop slowly over months or years, or may appear very abruptly. The disease may come and go in cycles of relapse and remission.

Anyone who experiences several of these symptoms for more than two weeks should seek help immediately. A medical or mental health professional may use the following terms when discussing the symptoms of schizophrenia. A quick, easy and confidential way to determine if you may be experiencing a mental health condition is to take a screen.

Take a psychosis screen here. If you suspect someone you know is experiencing symptoms of schizophrenia, encourage them to see a medical or mental health professional immediately. Early treatment--even as early as the first episode--can mean a better long-term outcome. While no cure for schizophrenia exists, many people with this illness can lead productive and fulfilling lives with the proper treatment. Recovery is possible through a variety of services, including medication and rehabilitation programs.

Rehabilitation can help a person recover the confidence and skills needed to live a productive and independent life in the community. Types of services that help a person with schizophrenia include:.