Behavioral Changes and Neuronal Damage in Rhesus Monkeys after 10 Weeks of Ketamine Administration Involve Prefrontal Cortex Dopamine D2 Receptor and Dopamine Transporter

Sun, Zongbo; Ma, Ye; Xie, Lei; Huang, Jinzhuang; Duan, Shan; Guo, R. S.; Xie, Yi; Lv, Jidong; Lin, Zhiyong; Ma, Shuhua

doi:10.1016/j.neuroscience.2019.07.022

Cited by 8 publications

(7 citation statements)

References 42 publications

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“…Interestingly, SCH and HAL inhibited the 4‐F‐PCP‐ and 4‐Keto‐PCP‐induced CPP alongside KET, indicating the involvement of the DA system in their rewarding effects. Drugs that stimulate the mesolimbic DA system have been shown to induce CPP and/or SA 28,29 . This also corresponds with the previous findings showing that the antagonistic effect of DRD1 and DRD2 blocked the KET reward 30 .…”

Section: Discussionsupporting

confidence: 91%

“…This is in line with a previous study on KET, which showed no changes in DAT protein after treatment 5,41 . In another study, a decrease in DAT expression was only seen after a 10‐week‐treatment with KET 29 . Further research is needed to understand why DAT showed no activity changes during the short treatment days.…”

Section: Discussionsupporting

confidence: 89%

“…Drugs that stimulate the mesolimbic DA system have been shown to induce CPP and/or SA. 28,29 This also corresponds with the previous findings showing that the antagonistic effect of DRD1 and DRD2 blocked the KET reward. 30 Additionally, another study also points out the involvement of dopaminergic system in PCP-induced place preference.…”

Section: Methodssupporting

confidence: 91%

“…5,41 In another study, a decrease in DAT expression was only seen after a 10-week-treatment with KET. 29 Further research is needed to understand why DAT showed no activity changes during the short treatment days. Nevertheless, such findings suggest that 4-F-PCP and 4-Keto-PCP can alter the dopaminergic reward system of the brain in response to the addictive properties of the drug.…”

Section: Methodsmentioning

confidence: 99%

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The dopaminergic alterations induced by 4‐F‐PCP and 4‐Keto‐PCP may enhance their drug‐induced rewarding and reinforcing effects: Implications for abuse

et al. 2020

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Novel psychoactive substances remain the popular recreational drugs of use over the years. They continue to bypass government restrictions due to their synthesis and modifications. Recent additions to the lists are the 4‐F‐PCP and 4‐Keto‐PCP, analogs of the drug phencyclidine (PCP) known to induce adverse effects and abuse potential. However, studies on the abuse potential of 4‐F‐PCP and 4‐Keto‐PCP remain scarce. The rewarding and reinforcing effects of the drugs were assessed using conditioned place preference (CPP), self‐administration, and locomotor sensitization tests. Dopamine (DA) receptor antagonists (SCH23390 and haloperidol) were administered during CPP to evaluate the involvement of the mesolimbic dopaminergic system. DA‐related protein expression in the nucleus accumbens (NAcc) and ventral tegmental area (VTA) was measured. Additionally, phosphorylated cyclic‐adenosine monophosphate‐activated protein (AMP) response element‐binding (p‐CREB) protein, deltaFosB (∆FosB), and brain‐derived neurotrophic factor (BDNF) protein levels in the NAcc were measured to assess the addiction neural plasticity effect of the drugs. Both 4‐F‐PCP and 4‐Keto‐PCP‐induced CPP and self‐administration; however, only 4‐F‐PCP elicited locomotor sensitization. Treatment with DA receptor antagonists (SH23390 and haloperidol) inhibited the 4‐F‐ and 4‐Keto‐induced CPP. Both substances altered the levels of DA receptor D1 (DRD1), thyroxine hydroxylase (TH), DA receptor D2 (DRD2), p‐CREB, ∆FosB, and BDNF. The results suggest that 4‐F‐PCP and 4‐Keto‐PCP may induce abuse potential in rodents via alterations in dopaminergic system accompanied by addiction neural plasticity.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

Section: Methodssupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

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The dopaminergic alterations induced by 4‐F‐PCP and 4‐Keto‐PCP may enhance their drug‐induced rewarding and reinforcing effects: Implications for abuse

et al. 2020

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“…In our study, however, the terminal gene networks (PFC and striatum) were strong moderators of the association between early adversity and the co-morbidities, while the VTA co-expression network showed no significant associations. mRNA axonal transport and protein synthesis at the terminal is an important mechanism for regulation of neurotransmitter synthesis and reuptake 72 , and could explain the presence of DAT1 mRNA at the terminals, consistently detected in numerous human postmortem studies 38,[73][74][75] . Indeed, one of the central nodes of our network is HNRNPA1 (Figure 1E), a gene associated with mRNA transport and synthesis 76 , suggesting that DAT1 mRNA transport to terminals may be a key mechanistic feature of our DAT1 mesocorticolimbic gene network.…”

Section: Discussionmentioning

confidence: 99%

Striatal dopamine gene network moderates the effect of early adversity on the risk for adult psychiatric and cardiometabolic comorbidity

Barth

Mar

Filho

et al. 2022

Preprint

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Psychiatric and cardio-metabolic conditions are commonly comorbid, being a leading cause of disability. Early adversity is a risk factor for both conditions, however, biological pathways remain unknown. The dopamine (DA) system is sensitive to early adversity and influences the development of comorbidities. We hypothesized that early life adversity would functionally link these conditions with the mesocorticolimbic dopamine system as a critical moderator pathway. We computed a co-expression based polygenic score (ePRS) reflecting variations in the function of the dopamine transporter (DAT) gene network in the prefrontal cortex and striatum, the final targets of the mesocorticolimbic pathway. We explored the interaction effects of the ePRS with a score of early life adversity on presence of psychiatric and cardio-metabolic comorbidities in adults (UK Biobank, N= 60016) and adolescents (ALSPAC, N= 910). In adults we also explored genetic and environment effects on gray matter density variations. As predicted, the mesocorticolimbic DAT1 ePRS significantly moderated the impact of early life adversity on the risk for both psychiatric (schizophrenia, neuroticism, mood and substance use disorders) and cardio-metabolic (type 2 diabetes, atherosclerosis, cardiovascular disease) comorbidities in adults and adolescents. Brain gray matter densities in the insula and prefrontal cortex were significantly associated with SNPs from the DAT1 ePRS implicating these regions as critical dopaminergic targets for psychiatric/cardio-metabolic comorbidities. These results reveal that psychiatric and cardio-metabolic comorbidities share common developmental pathways and underlying biological mechanisms.

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A Multifunctional Nanocarrier System for Highly Efficient and Targeted Delivery of Ketamine to NMDAR Sites for Improved Treatment of Depression

Tan

Gao

et al. 2023

Adv Healthcare Materials

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Ketamine (KA), commonly used as an anesthetic, is now widely studied as an antidepressant for the treatment of depression. However, due to its side effects, such as addiction and cognitive impairment, the dosage and frequency of (S)‐ketamine approved by the FDA for the treatment of refractory depression is very low, which limits its efficacy. Here, a new multifunctional nanocarrier system (AC‐RM@HA‐MS) with specific targeting capabilities is developed to improve the efficacy of KA treatment. KA‐loaded NPs (AC‐RM@HA‐MS‐KA) are constructed with a multilayer core–shell structure. KA‐loaded mesoporous silica NPs are prepared, conjugated with hyaluronic acid (HA) as pore gatekeepers, and sheathed with an RBC‐membrane (RM) for camouflage. Finally, the surface is tagged with bifunctional peptides (Ang‐2‐Con‐G, AC) to achieve specific targeting. One peptide (Ang‐2) is acted as a guide to facilitate the crossing of the blood–brain barrier (BBB), while the other (Con‐G) is functioned as a ligand for the targeted delivery of KA to the N‐methyl‐D‐aspartate receptor sites. Animal experiments reveal that AC‐RM@HA‐MS‐KA NPs effectively cross the BBB and directionally accumulate in the curing areas, thereby alleviating the depressive symptoms and improving the cognitive functions of depressed mice. After treatment, the depressed mice almost completely return to normal without obvious symptoms of addiction.

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Behavioral Changes and Neuronal Damage in Rhesus Monkeys after 10 Weeks of Ketamine Administration Involve Prefrontal Cortex Dopamine D2 Receptor and Dopamine Transporter

Cited by 8 publications

References 42 publications

The dopaminergic alterations induced by 4‐F‐PCP and 4‐Keto‐PCP may enhance their drug‐induced rewarding and reinforcing effects: Implications for abuse

The dopaminergic alterations induced by 4‐F‐PCP and 4‐Keto‐PCP may enhance their drug‐induced rewarding and reinforcing effects: Implications for abuse

Striatal dopamine gene network moderates the effect of early adversity on the risk for adult psychiatric and cardiometabolic comorbidity

A Multifunctional Nanocarrier System for Highly Efficient and Targeted Delivery of Ketamine to NMDAR Sites for Improved Treatment of Depression

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