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Article | Drug addiction (Drug addiction) refers to the characteristics of specific, compensatory and adaptive changes in the body due to the long-term interaction of drugs with the body.
Once the drug is stopped, it will cause severe discomfort and/or psychology in the body The urgent need for the above is manifested as a strong desire for drugs and compulsive drug-seeking behavior
.
Drug addiction is extremely harmful to individuals, families and society.
To solve the problem of addiction from the root, we urgently need to know the specific mechanism of action of these substances in the brain
.
Cocaine is one of the most addictive substances known at present.
It regulates the level of dopamine by interfering with the transmission of dopamine (DA) in the brain to neurons (increased DA level is a typical feature of all addictive drugs [ 1]) Stimulate the cerebral cortex, and then generate excitement and pleasure, and finally make people addicted to it
.
Studies have shown that cocaine can also change the level of 5-HT in the striatum by inhibiting the serotonin (5-hydroxytryptamine, 5-HT) transporter SERT; the use of drugs to reduce 5-HT in the forebrain will enhance cocaine addiction [2] , Indicating that the 5-HT system may be related to drug addiction, but its related neural circuits and potential cellular mechanisms are still unclear
.
On September 10, 2021, the Christian Lüscher team from the University of Geneva, Switzerland, published a research paper titled Synaptic mechanism underlying serotonin modulation of transition to cocaine addiction in Science magazine online
.
Researchers found that cocaine blocked the reabsorption of 5-hydroxytryptamine (5-HT) by binding to the serotonin transporter SERT, which caused the extracellular 5-HT levels to increase, which in turn activated 5-HT1B receptors and induced the orbitofrontal cortex (orbitofrontal cortex, OFC) terminal presynaptic inhibition reduces the possibility of inducing post-synaptic enhancement at OFC-DS (Dorsal striatum) synapses, and ultimately drives compulsive drug-seeking behavior
.
This paper uses detailed data to reveal the neural mechanism of serotonin regulating drug addiction, and proposes new targets and therapeutic mechanisms for the development of related therapeutic drugs.
For this reason, Science issued a special review at the same time: Increased serotonin prevents compulsion in addiction
.
In order to explore the regulatory role of 5-TH, the SERT Met172 knock-in (SertKI) mouse model was cited in the study [3]
.
In SertKI mice, SERT loses its ability to bind cocaine.
Therefore, intraperitoneal injection of cocaine (15 mg/kg ip) will not cause changes in 5-HT in the dorsal striatum (DS) of mice (Figure 1)
.
Subsequently, the researchers conducted cocaine self-administration (SA) experiments, which were mainly divided into two stages: Acquisition sessions-through training to enable mice to obtain the ability to perform cocaine SA through the button (0.
5 mg/kg per injection ); Punishment sessions- Give mice 0.
2 mA foot electric shocks (4 times in total)
.
The test results showed that SertKI and wild-type (WT) mice did not show any difference in the acquisition (learning) stage
.
However, after the penalty was added, the cocaine SA behavior of the two groups of mice changed significantly.
The authors classified these mice as "abandoners" (decreased SA) and "persistents" (increased SA)
.
Of the 25 SertKI mice, 14 (56%) were classified as "stickers", while only 3 (12%) of the 26 WT mice in the litter control were classified as "stickers" , Indicating that SertKI mice showed stronger compulsive cocaine SA behavior
.
Figure 1.
Detection of 5-TH changes in DS in mice after intraperitoneal injection of cocaine.
Next, the author let the mice receive optogenetic DA neuron self-stimulation (oDASS, which induces neuronal adaptation) Sex, to simulate drug addiction), and use citalopram (a selective 5-HT reuptake inhibitor) to up-regulate 5-HT levels
.
The authors observed that, regardless of the use of drugs, there was no difference in the behavior of all mice in the learning phase, and the behavior of the mice changed after the introduction of punishment
.
Of the 26 mice treated with citalopram, only 4 (15%) were classified as "stickers", while in the control group, 60% were "stickers", indicating that citalopram can reduce small Rat obsessive oDASS
.
Studies have shown that oDASS is mainly driven by the synaptic enhancement of the afferent nerve from OFC to DS [4], then whether cocaine SA is the same mechanism
.
As shown in Figure 2, the author selectively stimulated the OFC-DS projection to induce excitatory postsynaptic currents (EPSC) by stimulating the nerve ends in the DS brain slices
.
The results showed that the AMPA/NMDA ratio of "persistents" was significantly higher than that of cocaine SA and oDASS "abandoners", indicating that the enhancement of OFC-DS pathway was caused by the increase in the number of AMPA receptors
.
Subsequently, the authors examined the effect of 5-HT on synaptic transmission in the OFC-DS pathway
.
5-HT (4 μM) immersion can induce presynaptic inhibition of excitatory transmission.
This effect can be blocked by the 5-HT1B receptor antagonist NAS181 (20 μM), but cannot be blocked by the 5-HT1A receptor antagonist WAY100635 ( 1 μM) blocking
.
Further analysis revealed that presynaptic inhibition was mainly caused by the reduced probability of glutamate release
.
Figure 2.
5-HT regulates OFC-DS pathway.
In order to explore the causal relationship between 5-HT-induced presynaptic inhibition and compulsive cocaine SA, the authors specifically knocked out 5-HT in OFC neurons targeting DS.
HT1B receptor
.
Subsequently, cocaine SA experiments were performed in mice lacking 5-HT1B receptors
.
Consistent with the previous results, during the learning phase, there was no significant difference between the 5-HT1B receptor-deficient group and the control group; during the punishment phase, the cocaine SA behavior of mice changed.
Compared with the control group (13%), 5-HT1B loss was less The proportion of "persistents" in mice is higher (57%), indicating that the loss of 5-HT1B receptor promotes compulsive cocaine SA
.
Finally, the researchers analyzed and discussed the experimental results: In WT mice, the combination of cocaine and SERT blocked 5-HT reuptake, resulting in increased levels of extracellular 5-HT, which in turn activated 5-HT1B receptors and induced OFC Presynaptic inhibition at the end reduces the possibility of OFC-DS synapses to induce post-synaptic enhancement, and ultimately drives compulsive drug-seeking behavior; in SertKI mice, cocaine cannot bind to SERT, and extracellular 5-HT is not affected by cocaine Due to the impact of injection, OFC-DS delivery that has not undergone presynaptic inhibition may increase the possibility of LTP induction, and ultimately manifest as a higher proportion of compulsive drug-seeking individuals; in 5-HT1B knockout mice, although Cocaine still inhibits 5-HT reuptake, but OFC-DS transmission is not inhibited, so it is beneficial to LTP induction
.
The authors believe that this synaptic mechanism helps overcome the limitations of current 5-HT reuptake inhibitor treatments, and also helps design selective agonists to treat addiction
.
Original link: https://science.
org/doi/10.
1126/science.
abi9086 Plate maker: Eleven references [1] C.
Lüscher, MA Ungless, PLOS Med.
3, e437 (2006).
[2] Y.
Pelloux, R.
Dilleen, et.
al, Neuropsychopharmacology 37, 2505–2514 (2012).
[3] BJ Thompson et al.
, Proc.
Natl.
Acad.
Sci.
USA 108, 3785–3790 (2011).
[4] V.
Pascoli et al.
, Nature 564, 366–371 (2018).
Reprinting instructions [Original Articles] BioArt original articles, personal reposting and sharing are welcome, reprinting is prohibited without permission, the copyright of all published works is owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
Once the drug is stopped, it will cause severe discomfort and/or psychology in the body The urgent need for the above is manifested as a strong desire for drugs and compulsive drug-seeking behavior
.
Drug addiction is extremely harmful to individuals, families and society.
To solve the problem of addiction from the root, we urgently need to know the specific mechanism of action of these substances in the brain
.
Cocaine is one of the most addictive substances known at present.
It regulates the level of dopamine by interfering with the transmission of dopamine (DA) in the brain to neurons (increased DA level is a typical feature of all addictive drugs [ 1]) Stimulate the cerebral cortex, and then generate excitement and pleasure, and finally make people addicted to it
.
Studies have shown that cocaine can also change the level of 5-HT in the striatum by inhibiting the serotonin (5-hydroxytryptamine, 5-HT) transporter SERT; the use of drugs to reduce 5-HT in the forebrain will enhance cocaine addiction [2] , Indicating that the 5-HT system may be related to drug addiction, but its related neural circuits and potential cellular mechanisms are still unclear
.
On September 10, 2021, the Christian Lüscher team from the University of Geneva, Switzerland, published a research paper titled Synaptic mechanism underlying serotonin modulation of transition to cocaine addiction in Science magazine online
.
Researchers found that cocaine blocked the reabsorption of 5-hydroxytryptamine (5-HT) by binding to the serotonin transporter SERT, which caused the extracellular 5-HT levels to increase, which in turn activated 5-HT1B receptors and induced the orbitofrontal cortex (orbitofrontal cortex, OFC) terminal presynaptic inhibition reduces the possibility of inducing post-synaptic enhancement at OFC-DS (Dorsal striatum) synapses, and ultimately drives compulsive drug-seeking behavior
.
This paper uses detailed data to reveal the neural mechanism of serotonin regulating drug addiction, and proposes new targets and therapeutic mechanisms for the development of related therapeutic drugs.
For this reason, Science issued a special review at the same time: Increased serotonin prevents compulsion in addiction
.
In order to explore the regulatory role of 5-TH, the SERT Met172 knock-in (SertKI) mouse model was cited in the study [3]
.
In SertKI mice, SERT loses its ability to bind cocaine.
Therefore, intraperitoneal injection of cocaine (15 mg/kg ip) will not cause changes in 5-HT in the dorsal striatum (DS) of mice (Figure 1)
.
Subsequently, the researchers conducted cocaine self-administration (SA) experiments, which were mainly divided into two stages: Acquisition sessions-through training to enable mice to obtain the ability to perform cocaine SA through the button (0.
5 mg/kg per injection ); Punishment sessions- Give mice 0.
2 mA foot electric shocks (4 times in total)
.
The test results showed that SertKI and wild-type (WT) mice did not show any difference in the acquisition (learning) stage
.
However, after the penalty was added, the cocaine SA behavior of the two groups of mice changed significantly.
The authors classified these mice as "abandoners" (decreased SA) and "persistents" (increased SA)
.
Of the 25 SertKI mice, 14 (56%) were classified as "stickers", while only 3 (12%) of the 26 WT mice in the litter control were classified as "stickers" , Indicating that SertKI mice showed stronger compulsive cocaine SA behavior
.
Figure 1.
Detection of 5-TH changes in DS in mice after intraperitoneal injection of cocaine.
Next, the author let the mice receive optogenetic DA neuron self-stimulation (oDASS, which induces neuronal adaptation) Sex, to simulate drug addiction), and use citalopram (a selective 5-HT reuptake inhibitor) to up-regulate 5-HT levels
.
The authors observed that, regardless of the use of drugs, there was no difference in the behavior of all mice in the learning phase, and the behavior of the mice changed after the introduction of punishment
.
Of the 26 mice treated with citalopram, only 4 (15%) were classified as "stickers", while in the control group, 60% were "stickers", indicating that citalopram can reduce small Rat obsessive oDASS
.
Studies have shown that oDASS is mainly driven by the synaptic enhancement of the afferent nerve from OFC to DS [4], then whether cocaine SA is the same mechanism
.
As shown in Figure 2, the author selectively stimulated the OFC-DS projection to induce excitatory postsynaptic currents (EPSC) by stimulating the nerve ends in the DS brain slices
.
The results showed that the AMPA/NMDA ratio of "persistents" was significantly higher than that of cocaine SA and oDASS "abandoners", indicating that the enhancement of OFC-DS pathway was caused by the increase in the number of AMPA receptors
.
Subsequently, the authors examined the effect of 5-HT on synaptic transmission in the OFC-DS pathway
.
5-HT (4 μM) immersion can induce presynaptic inhibition of excitatory transmission.
This effect can be blocked by the 5-HT1B receptor antagonist NAS181 (20 μM), but cannot be blocked by the 5-HT1A receptor antagonist WAY100635 ( 1 μM) blocking
.
Further analysis revealed that presynaptic inhibition was mainly caused by the reduced probability of glutamate release
.
Figure 2.
5-HT regulates OFC-DS pathway.
In order to explore the causal relationship between 5-HT-induced presynaptic inhibition and compulsive cocaine SA, the authors specifically knocked out 5-HT in OFC neurons targeting DS.
HT1B receptor
.
Subsequently, cocaine SA experiments were performed in mice lacking 5-HT1B receptors
.
Consistent with the previous results, during the learning phase, there was no significant difference between the 5-HT1B receptor-deficient group and the control group; during the punishment phase, the cocaine SA behavior of mice changed.
Compared with the control group (13%), 5-HT1B loss was less The proportion of "persistents" in mice is higher (57%), indicating that the loss of 5-HT1B receptor promotes compulsive cocaine SA
.
Finally, the researchers analyzed and discussed the experimental results: In WT mice, the combination of cocaine and SERT blocked 5-HT reuptake, resulting in increased levels of extracellular 5-HT, which in turn activated 5-HT1B receptors and induced OFC Presynaptic inhibition at the end reduces the possibility of OFC-DS synapses to induce post-synaptic enhancement, and ultimately drives compulsive drug-seeking behavior; in SertKI mice, cocaine cannot bind to SERT, and extracellular 5-HT is not affected by cocaine Due to the impact of injection, OFC-DS delivery that has not undergone presynaptic inhibition may increase the possibility of LTP induction, and ultimately manifest as a higher proportion of compulsive drug-seeking individuals; in 5-HT1B knockout mice, although Cocaine still inhibits 5-HT reuptake, but OFC-DS transmission is not inhibited, so it is beneficial to LTP induction
.
The authors believe that this synaptic mechanism helps overcome the limitations of current 5-HT reuptake inhibitor treatments, and also helps design selective agonists to treat addiction
.
Original link: https://science.
org/doi/10.
1126/science.
abi9086 Plate maker: Eleven references [1] C.
Lüscher, MA Ungless, PLOS Med.
3, e437 (2006).
[2] Y.
Pelloux, R.
Dilleen, et.
al, Neuropsychopharmacology 37, 2505–2514 (2012).
[3] BJ Thompson et al.
, Proc.
Natl.
Acad.
Sci.
USA 108, 3785–3790 (2011).
[4] V.
Pascoli et al.
, Nature 564, 366–371 (2018).
Reprinting instructions [Original Articles] BioArt original articles, personal reposting and sharing are welcome, reprinting is prohibited without permission, the copyright of all published works is owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
