Synaptic mechanism underlying serotonin modulation of transition to cocaine addiction

Abstract

Prevention of compulsive cocaine taking Over time, about 20% of chronic cocaine users lose control and become addicted. There are indications that the differential efficacy of the brain serotonin (5-HT) system may be involved in the vulnerability to drug addiction. However, the relevant circuits and underlying cellular processes remain elusive. Li et al . discovered a synaptic mechanism in mice that underlies the modulatory role of 5-HT in reducing the likelihood of transition to compulsion and eventually addiction (see the Perspective by Miyazaki and Miyazaki). Cocaine binds to 5-HT transporters to block 5-HT reuptake. The elevated extracellular 5-HT activates 5-HT 1B receptors and causes presynaptic depression of a projection from the orbitofrontal cortex to the dorsal striatum. These changes reduce the likelihood of inducing postsynaptic potentiation at these synapses, which ultimately drives compulsion. —PRS

Leucine-Rich Repeat Kinase 2 limits dopamine D1 receptor signaling in striatum and biases against heavy persistent alcohol drinking

“…Additionally, while operant responses during quinine adulteration and punishment sessions were highly correlated, breakpoint responses were not. This dissociation between motivational salience and response to punishment is in line with the literature on pre-clinical models of AUD ( 72, 73 ).…”

Identification of Functional CircRNA–miRNA–mRNA Regulatory Network in Dorsolateral Prefrontal Cortex Neurons of Patients With Cocaine Use Disorder

“…Gene Ontology pathway enrichment analysis for the 82 genes aberrantly expressed in the patients with cocaine use disorder and indirectly regulated by circRNAs revealed that the 22 up-regulated genes participated in vital biological processes including positive regulation of axonogenesis (GO: 0050772) and cell junction organization (GO: 0034330) ( Figure 3A ), which is consistent with current reports on the relationship between cocaine addiction and the synaptic transmission ( Li et al, 2021 ; Wang et al, 2021 ; Zinsmaier et al, 2021 ). Moreover, the 62 down-regulated genes participated in vital biological processes including cellular response (GO:0032870, GO:0034605, and GO:0048511), protein modification and transport process (GO:0006986, GO:0046854, GO:0051258, GO:0031400, and GO:0017038), intracellular receptor and calcium-ion (GO:0030522, GO:0017156, and GO:0019722), cell and tissue morphogenesis (GO:0030099, GO:0001764, GO:0060538, GO:0048729, and GO:0030010), autophagy (GO:0006914), and positive regulation of cytokine production (GO:0001819) ( Figure 3B ), which implied that the etiology of cocaine use disorder may involve many biological processes.…”

“…Through the functional enrichment analysis of the mRNAs in the network, we found that the up-regulated mRNAs were mainly involved in regulation of axonogenesis and cell junction, which suggests that our up-regulated mRNA may have a close connection with synaptic transmission, and previous studies have confirmed that abnormal synaptic transmission is a very critical factor for cocaine addiction ( Khibnik et al, 2016 ; Martínez-Rivera et al, 2017 ; Li et al, 2021 ). Down-regulated mRNAs were found to be involved in many biological processes, including cellular response to hormone stimulus, response to unfolded protein, cellular response to heat, intracellular receptor signaling pathway, myeloid cell differentiation, calcium-ion regulated exocytosis, calcium-mediated signaling, and autophagy.…”

Striatal µ-Opioid Receptor Activation Triggers Direct-Pathway GABAergic Plasticity to Induce Negative Affect

“…These results suggest that withdrawal from non-contingent fentanyl administration induces depression-like behaviors. Unbiased cluster analysis ( Li et al, 2021b ) of the open field tests, social interaction tests (Supplementary Fig. 5), and sucrose splash tests yielded two clusters: non-depression-like and depression-like behaviors (Fig.…”