Written by 丨 莜
Responsible editor 丨 Yi Zhen
Morphine is a commonly used clinical analgesic and is limited in its use due to its high addictiveness [1]. According to the National Drug Abuse Testing Annual Report (2016) released by the State Drug Administration, morphine is one of the top 5 drugs with the most abuse/use for medical purposes, seriously endangering public health. The initial use of addictive drugs such as morphine and cocaine will bring euphoria and reward effects [2], that is, the positive reinforcing effect of addictive drugs; this euphoria drives individuals to further ingest the drug, and withdrawal will cause a series of uncomfortable physiological states (gastrointestinal symptoms, etc.) and negative emotions (anxiety, depression, etc.), and individuals will further obtain drugs in order to alleviate this discomfort, that is, negative reinforcement effects [3-4]. The cycle of positive and negative reinforcement alternately promotes a morphine-dependent state. The process of drug transition from initial reward to drug dependence is accompanied by changes in the plasticity of brain neural circuits, and it is of great scientific and social significance to analyze the mechanism of opioid morphine withdrawal inducing negative reinforcement, alleviate the negative emotions caused by withdrawal, and provide new intervention targets for the treatment of addiction and prevention of abuse.
On October 12, 2021, the team of academicians of the Institute of Brain Sciences of Fudan University published an article entitled CRHCeA→VTA inputs inhibit the positive ensembles to induce negative affect of opiate withdrawal online in Molecular Psychiatry. The study found that CRH neurons in central amygdala CeA undergo activation through inhibitory loops regulating clusters of neurons undergoing VTA morphine rewards, mediating opioid morphine withdrawal inducing negative intensification, and elaborating on the cell clustering and loop mechanisms of negative strengthening of the addictive drug morphine.
In the study, the authors used marker techniques for early gene drive to label clusters of neurons activated by initial exposure of morphine in important brain regions of the midbrain limbic system (VTA), and found that VTA morphine neuron clusters were biased towards the nucleus accumbens (NAc) brain regions, activating the VTA morphine neuron cluster could promote the release of NAc dopamine, triggering the self-sufficient light behavior of mice, and mediating the positive reinforcement effect of dopamine dependence. At the same time, electrophysiological records show that chronic morphine administration withdrawal enhances the inhibitory input received by morphine neuron clusters, inhibition of morphine neuronal activity aggravates conditional location aversion and anxiety behavior induced by morphine withdrawal, and activation of morphine neuron clusters relieves negative emotions of disgust and anxiety caused by morphine withdrawal, suggesting that the positive neuronal clusters encoding morphine rewards are inhibited and are responsible for the negative intensification of morphine.
So where does the inhibitory loop input for morphine reception come from? The authors found through electrophysiology and retrograde tracing that Adrenocorticotropic hormone-releasing CRH neurons in the CeA brain region were able to bias the regulation of VTA morphine neuron clusters, and that this biased inhibitory link was specifically enhanced after chronic administration of morphine, thereby mediating morphine withdrawal to induce negative emotions of disgust and anxiety. To explore the specific molecular mechanisms involved in the remodeling of this neural circuit, the authors used pharmacological interventions and CRISPR gene editing to inhibit the CRHR1 receptor on clusters of morphine neurons, and found that it was possible to significantly attenuate the inhibitory input of CRHCeA → VTA, thereby alleviating the negative reinforcement induced by morphine withdrawal.
Between good and evil thoughts, the VTA morphine neuron cluster that originally coded for the positive reward effect of the drug induced a negative emotional state due to the specific regulation of CRHCeA → VTA inhibitory input after chronic morphine administration. Taking opioid-activated neuronal clusters as the starting point, this study provides a new perspective on the pathological changes in mood and a new strategy for the treatment of opioid addiction from the perspective of abnormal remodeling of neural circuits.
Figure 1. Inhibitory loops regulate VTA morphine neuronal clusters mediate negative intensification
Jiang Changyou, postdoctoral fellow of the Institute of Brain Science of Fudan University, is the first author of this article, and Yang Xiao and He Guanhong, doctoral students of the School of Basic Medical Sciences, are the co-first authors of this article. Professor Ma Lan and Professor Feifei Wong of the Institute of Brain Science are the corresponding authors of this article. This paper was also co-authored by Professors Ying Mao and Wendong Xu from Huashan Hospital affiliated to Fudan University.
Original link:
https://www.nature.com/articles/s41380-021-01321-9
Model Maker: Eleven
bibliography
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