June 22, 2024

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Northwestern University: Anti-schizophrenia drug works differently than expected

Northwestern University: Anti-schizophrenia drug works differently than expected


Northwestern University: Anti-schizophrenia drug works differently than expected.

“Nature Neuroscience”: subvert cognition! Anti-schizophrenia drug works differently than expected, Northwestern University team finds.


Schizophrenia is a serious mental disorder in which patients experience severe disturbances in perception, thinking, and emotion that have a detrimental effect on daily life.


The dopamine hypothesis is one of the important hypotheses in the pathogenesis of schizophrenia. The dopamine hypothesis suggests that schizophrenia may be related to an overactive dopamine in the brain.

Overactive neurotransmitters lead to an imbalance in specific neural circuits, which can lead to symptoms such as hallucinations, delusions, disorganized thinking, and emotional detachment. Inhibition of dopamine activity is considered to be one of the main mechanisms of action of antipsychotic drugs.


Spinous projection neurons (SPNs) in the striatum region of the brain express dopamine receptors D1 (D1R) and dopamine receptors D2 (D2R), respectively, and the coupling of receptors to Gαs can increase or decrease SPN activity. By regulating the SPN, the purpose of balancing striatal output can be achieved.


In the past, scientists believed that antipsychotic drugs inhibit the activity of dopamine by binding to D2R. In fact, D2R is also expressed in brain cells other than the striatum, and the drug treatment effect predicted based on the receptor expression level is often wrong or even completely opposite to the actual existence.


Recently, a research team at Northwestern University in the United States has obtained a milestone discovery in the understanding of the neural basis of psychosis-it is not D2R but D1R that regulates striatal output in combination with antipsychotic drugs .

Studies have found that some drugs can normalize D2-SPN dynamics, but have no clinical effect. The antipsychotic efficacy of the drug is associated with a kinetic reversal of the D1-SPN. Selective inhibition of D1-SPN can attenuate amphetamine-driven hypermotility, hallucinations, and other symptoms .

The research was published in Nature Neuroscience.


Northwestern University: Anti-schizophrenia drug works differently than expected



The researchers recorded the activity of D1-SPN and D2-SPN in mouse brains by neural population imaging method. Using amphetamines to induce dopamine release, neuronal activity was consistent with previous observations, with increased levels of D1-SPN activity and decreased levels of D2-SPN activity.


Next, the researchers selected four antipsychotic drugs and evaluated their effects on neuronal activity. Among them, haloperidol has significant side effects of dyskinesia, clozapine and olanzapine have mild side effects of dyskinesia, and MP-10 is a candidate drug for schizophrenia that has failed clinically. According to the exercise ability of the mice after the drug, two drug doses, high and low, were set.


The results showed that all three clinically effective drugs could alleviate amphetamine-induced D1-SPN neuron dynamic disturbance, excessive movement, and abnormal sensorimotor gating (ie, dysregulation between sensation and movement) . In contrast, MP-10 attenuated the amphetamine-induced decrease in D2-SPN activity, but exacerbated D1-SPN hyperactivity and did not correct sensorimotor gating abnormalities in mice.


Northwestern University: Anti-schizophrenia drug works differently than expected

Antipsychotic drug improves hypermobility in mice




Such results remind us, is the correction of D1-SPN activity the key to the drug’s effect?

The researchers tested the compound with other novel antipsychotic drug candidates.

Although the mechanism of action of these compounds is not binding to dopamine receptors, all of the compounds that produced clinical efficacy attenuated amphetamine-induced D1-SPN hyperactivity .

Inhibition of D1-SPN activity by chemical methods can also reduce the auditory hallucinations induced by amphetamine in mice .


Northwestern University: Anti-schizophrenia drug works differently than expected

Drug effects on D1-SPN better explain antipsychotic efficacy


Mice were treated with D1R partial agonist SKF38393 and D1R antagonist SCH23390/SCH39166, respectively.

The results showed that the three compounds could alleviate amphetamine-induced hypermotor and sensorimotor gating abnormalities.

Among them, SKF38393 promotes D1-SPN activity under baseline conditions and inhibits D1-SPN activity under conditions of excessive dopamine release, exhibiting dopamine state-dependent selective inhibition of D1-SPN.


Collectively, the studies demonstrate that the efficacy of antipsychotic drugs is linked to their restoration of normal activity in the D1-SPN , opening up new options for the development of drugs with fewer side effects. “This is a landmark discovery that revolutionizes our understanding of the neural basis of psychosis,” the researchers said.






Northwestern University: Anti-schizophrenia drug works differently than expected

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