DOPAMINE
Dopamine in the Brain
People with schizophrenia have an over- or under-abundance of specific neurotransmitter receptors in the brain. While several neuromodulators are thought to be implicated in this disorder, the primary neural pathway involves receptors for the neuromodulator, dopamine. This is known as the “dopamine hypothesis of schizophrenia”. Specifically, there is too much of one receptor type known as D2.
There are several neural pathways that involve dopamine. The mesolimbic dopamine pathway in the brain is particularly associated with positive schizophrenia symptoms as a result of an overabundance of D2 receptors. This pathway connects the ventral tegmental area (where dopamine is produced) to the ventral striatum, which is involved in motivation, reinforcement, and fear. The mesocortical dopamine pathway is particularly associated with negative and cognitive schizophrenia symptoms as a result of low dopamine levels. This pathway connects the ventral tegmental area to the prefrontal cortex involved in cognition and emotional regulation. The nigrostriatal dopamine pathway connects the substantia nigra to the dorsal striatum, and helps produce movement. This pathway may be related to catatonia (slow movement) in schizophrenia, but it is also an important consideration for medications that affect dopamine, because reduction of dopamine in this area can cause motor-related side effects.
People with schizophrenia have an over- or under-abundance of specific neurotransmitter receptors in the brain. While several neuromodulators are thought to be implicated in this disorder, the primary neural pathway involves receptors for the neuromodulator, dopamine. This is known as the “dopamine hypothesis of schizophrenia”. Specifically, there is too much of one receptor type known as D2.
There are several neural pathways that involve dopamine. The mesolimbic dopamine pathway in the brain is particularly associated with positive schizophrenia symptoms as a result of an overabundance of D2 receptors. This pathway connects the ventral tegmental area (where dopamine is produced) to the ventral striatum, which is involved in motivation, reinforcement, and fear. The mesocortical dopamine pathway is particularly associated with negative and cognitive schizophrenia symptoms as a result of low dopamine levels. This pathway connects the ventral tegmental area to the prefrontal cortex involved in cognition and emotional regulation. The nigrostriatal dopamine pathway connects the substantia nigra to the dorsal striatum, and helps produce movement. This pathway may be related to catatonia (slow movement) in schizophrenia, but it is also an important consideration for medications that affect dopamine, because reduction of dopamine in this area can cause motor-related side effects.
What are the treatments involving dopamine (first generation antipsychotics)?
There are over 40 antipsychotics currently on the market. 30 of them are known as first-generation antipsychotics, and affect the dopamine receptor, D2. First generation antipsychotics (e.g. chlorpromazine, perphenazine, and haloperidol) are antagonists, meaning they target and block the D2 dopamine receptor. In the striatum, reducing dopamine improves positive symptoms of schizophrenia. In the nigro-striatal pathway, these medications cause “extrapyramidal” side effects which impact movement and speech such as through tremors and rigidity.
Blocking striatal D2 receptors is the most effective way to reduce psychotic symptoms. Antipsychotics are more effective in reducing psychosis if they have a stronger affinity for the D2 receptor. However, the more effective antipsychotics are also more likely to have extrapyramidal side effects on motor and speech. This is difficult because on average, 60-65% of the D2 receptors must be blocked to reduce symptoms, but blocking over 77% causes these side effects. Another big problem is that many of these first-generation medications DO NOT treat negative or cognitive symptoms, which provide the largest contribution to functional impairment.
There are over 40 antipsychotics currently on the market. 30 of them are known as first-generation antipsychotics, and affect the dopamine receptor, D2. First generation antipsychotics (e.g. chlorpromazine, perphenazine, and haloperidol) are antagonists, meaning they target and block the D2 dopamine receptor. In the striatum, reducing dopamine improves positive symptoms of schizophrenia. In the nigro-striatal pathway, these medications cause “extrapyramidal” side effects which impact movement and speech such as through tremors and rigidity.
Blocking striatal D2 receptors is the most effective way to reduce psychotic symptoms. Antipsychotics are more effective in reducing psychosis if they have a stronger affinity for the D2 receptor. However, the more effective antipsychotics are also more likely to have extrapyramidal side effects on motor and speech. This is difficult because on average, 60-65% of the D2 receptors must be blocked to reduce symptoms, but blocking over 77% causes these side effects. Another big problem is that many of these first-generation medications DO NOT treat negative or cognitive symptoms, which provide the largest contribution to functional impairment.
SEROTONIN
Serotonin in the Brain
Activity of the serotonin receptor, 5HT2A causes psychotic symptoms, and decreasing activity of this receptor lessens symptoms. Remember how neural pathways are highly connected? The serotonin receptor 5HT2A can affect dopamine in the cortical areas, which has too little dopamine, causing negative and cognitive symptoms. This is important because dopamine antagonists reduce too much dopamine in limbic areas, but do not improve too little dopamine in these areas.
Additionally, dopamine antagonists reduce activity in all of the dopamine pathways in the brain, including the nigrostriatal pathway and the mesocortical pathway, causing extrapyramidal side effects. Serotonin 5HT2A receptors can counteract this by increasing dopamine in these areas to reduce side effects (nigrostriatal pathway), and improve negative and cognitive symptoms (cortical area).
Activity of the serotonin receptor, 5HT2A causes psychotic symptoms, and decreasing activity of this receptor lessens symptoms. Remember how neural pathways are highly connected? The serotonin receptor 5HT2A can affect dopamine in the cortical areas, which has too little dopamine, causing negative and cognitive symptoms. This is important because dopamine antagonists reduce too much dopamine in limbic areas, but do not improve too little dopamine in these areas.
Additionally, dopamine antagonists reduce activity in all of the dopamine pathways in the brain, including the nigrostriatal pathway and the mesocortical pathway, causing extrapyramidal side effects. Serotonin 5HT2A receptors can counteract this by increasing dopamine in these areas to reduce side effects (nigrostriatal pathway), and improve negative and cognitive symptoms (cortical area).
How are treatments with serotonin (second generation antipsychotics) different?
Second generation antipsychotics target the serotonin receptor 5HT2A, and they are better at improving cognitive, mood, and negative symptoms of schizophrenia. The second generation antipsychotics also have high antagonism for the serotonin receptor, 5HT2A. This can actually increase dopamine in the prefrontal cortex, where negative symptoms arise from too little dopamine. However, medications that target serotonin receptors alone are less effective in reducing psychotic symptoms than those targeting dopamine D2 receptors. Therefore, these medications also antagonize D2 receptors, but have a lower affinity, so they produce fewer extrapyramidal side effects while still decreasing excessive dopamine in the mesolimbic areas to reduce positive symptoms of psychosis.
While extrapyramidal side effects for movement and speech are less common, these may instead cause problems involving the cardiovascular system and metabolism such as hypotension, weight gain, and excess lipids. Unfortunately, these medications are also not always effective, and have wide variability in their effects.
Second generation antipsychotics target the serotonin receptor 5HT2A, and they are better at improving cognitive, mood, and negative symptoms of schizophrenia. The second generation antipsychotics also have high antagonism for the serotonin receptor, 5HT2A. This can actually increase dopamine in the prefrontal cortex, where negative symptoms arise from too little dopamine. However, medications that target serotonin receptors alone are less effective in reducing psychotic symptoms than those targeting dopamine D2 receptors. Therefore, these medications also antagonize D2 receptors, but have a lower affinity, so they produce fewer extrapyramidal side effects while still decreasing excessive dopamine in the mesolimbic areas to reduce positive symptoms of psychosis.
While extrapyramidal side effects for movement and speech are less common, these may instead cause problems involving the cardiovascular system and metabolism such as hypotension, weight gain, and excess lipids. Unfortunately, these medications are also not always effective, and have wide variability in their effects.
GLUTAMATE
Glutamate in the Brain
It was later discovered that glutamate and dopamine may work together to cause overall symptoms of schizophrenia. Glutamate is an “excitatory” neuromodulator that has receptors on nearly all neurons. When these neurone are activated, they can in turn modulate the release of other neurotransmitters in the cortical and limbic areas.
The modulation of NDMA (a glutamate receptor) may be underactive in schizophrenia. This is known as the “glutamate hypothesis of schizophrenia.” When the NMDA receptor is underactive, there is less inhibition on serotonergic neurons in the cortex, causing cognitive and negative symptoms. This area also regulates dopamine production, and malfunction may result in excessive activity of areas that produce dopamine and project through the mesolimbic pathway, causing positive symptoms of schizophrenia indirectly.
Reduced NMDA receptor activity may also explain the overactivity of the serotonin receptor, 5HT2A in schizophrenia. In this modulatory network, reduced NDMA activity reduces serotonin 5HT1A receptors which increases global serotonin levels and leads to a signaling cascade that interrupts 5HT2A receptor function in the cortex, thus antagonizing 5HT2A and causing cognitive and negative symptoms as well.The role of NMDA is especially important because this underactivity may provide a cause of the negative and cognitive symptoms of schizophrenia (as well as the positive symptoms), as it can regulate activity at both dopamine and serotonin receptors.
It was later discovered that glutamate and dopamine may work together to cause overall symptoms of schizophrenia. Glutamate is an “excitatory” neuromodulator that has receptors on nearly all neurons. When these neurone are activated, they can in turn modulate the release of other neurotransmitters in the cortical and limbic areas.
The modulation of NDMA (a glutamate receptor) may be underactive in schizophrenia. This is known as the “glutamate hypothesis of schizophrenia.” When the NMDA receptor is underactive, there is less inhibition on serotonergic neurons in the cortex, causing cognitive and negative symptoms. This area also regulates dopamine production, and malfunction may result in excessive activity of areas that produce dopamine and project through the mesolimbic pathway, causing positive symptoms of schizophrenia indirectly.
Reduced NMDA receptor activity may also explain the overactivity of the serotonin receptor, 5HT2A in schizophrenia. In this modulatory network, reduced NDMA activity reduces serotonin 5HT1A receptors which increases global serotonin levels and leads to a signaling cascade that interrupts 5HT2A receptor function in the cortex, thus antagonizing 5HT2A and causing cognitive and negative symptoms as well.The role of NMDA is especially important because this underactivity may provide a cause of the negative and cognitive symptoms of schizophrenia (as well as the positive symptoms), as it can regulate activity at both dopamine and serotonin receptors.
Are there glutamate/NMDA receptor medications?
There are not many current medications that primarily target this receptor. Clozapine is one medication that does affect NMDA receptors, although indirectly, through a different glycine receptor that increases the activity of NMDA receptors. Medications that work on this receptor may improve both positive and negative symptoms, reduce side effects, and improve response to treatment. Siimilarly, the blood pressure medication, sodium nitroprusside may reduce schizophrenia symptoms by acting on the NMDA receptor, although more research is needed in this area.
References
Patel, K. R., Cherian, J., Gohil, K., & Atkinson, D. (2014). Schizophrenia: overview and treatment options. P & T : a peer-reviewed journal for formulary management, 39(9), 638–645.
Coyle, J. T., Basu, A., Benneyworth, M., Balu, D., & Konopaske, G. (2012). Glutamatergic synaptic dysregulation in schizophrenia: therapeutic implications. Handbook of experimental pharmacology, (213), 267–295. https://doi.org/10.1007/978-3-642-25758-2_10
Lieberman, J. A., & First, M. B. (2018). Psychotic disorders. New England Journal of Medicine, 379(3), 270-280.
Dokucu M. E. (2015). Neuromodulation Treatments for Schizophrenia. Current treatment options in psychiatry, 2(3), 339–348. https://doi.org/10.1007/s40501-015-0055-4
Tandon, R., & Fleischhacker, W. W. (2005). Comparative efficacy of antipsychotics in the treatment of schizophrenia: a critical assessment. Schizophrenia Research, 79(2-3), 145-155.
Nguyen, M., Little, L., & Nirmalan, V. (2015). FBN Case Study 2015 [PowerPoint Slides].
Trevlopoulou, A., Touzlatzi, N., & Pitsikas, N. (2016). The nitric oxide donor sodium nitroprusside attenuates recognition memory deficits and social withdrawal produced by the NMDA receptor antagonist ketamine and induces anxiolytic-like behaviour in rats. Psychopharmacology, 233(6), 1045-1054.
There are not many current medications that primarily target this receptor. Clozapine is one medication that does affect NMDA receptors, although indirectly, through a different glycine receptor that increases the activity of NMDA receptors. Medications that work on this receptor may improve both positive and negative symptoms, reduce side effects, and improve response to treatment. Siimilarly, the blood pressure medication, sodium nitroprusside may reduce schizophrenia symptoms by acting on the NMDA receptor, although more research is needed in this area.
References
Patel, K. R., Cherian, J., Gohil, K., & Atkinson, D. (2014). Schizophrenia: overview and treatment options. P & T : a peer-reviewed journal for formulary management, 39(9), 638–645.
Coyle, J. T., Basu, A., Benneyworth, M., Balu, D., & Konopaske, G. (2012). Glutamatergic synaptic dysregulation in schizophrenia: therapeutic implications. Handbook of experimental pharmacology, (213), 267–295. https://doi.org/10.1007/978-3-642-25758-2_10
Lieberman, J. A., & First, M. B. (2018). Psychotic disorders. New England Journal of Medicine, 379(3), 270-280.
Dokucu M. E. (2015). Neuromodulation Treatments for Schizophrenia. Current treatment options in psychiatry, 2(3), 339–348. https://doi.org/10.1007/s40501-015-0055-4
Tandon, R., & Fleischhacker, W. W. (2005). Comparative efficacy of antipsychotics in the treatment of schizophrenia: a critical assessment. Schizophrenia Research, 79(2-3), 145-155.
Nguyen, M., Little, L., & Nirmalan, V. (2015). FBN Case Study 2015 [PowerPoint Slides].
Trevlopoulou, A., Touzlatzi, N., & Pitsikas, N. (2016). The nitric oxide donor sodium nitroprusside attenuates recognition memory deficits and social withdrawal produced by the NMDA receptor antagonist ketamine and induces anxiolytic-like behaviour in rats. Psychopharmacology, 233(6), 1045-1054.
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