3'-Deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome.

JOURNAL/nrgr/04.03/01300535-202410000-00028/figure1/v/2024-02-06T055622Z/r/image-tiff Methamphetamine addiction is a brain disorder characterized by persistent drug-seeking behavior, which has been linked with aberrant synaptic plasticity. An increasing body of evidence suggests that aberrant synaptic plasticity is associated with the activation of the NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome. 3'-Deoxyadenosin, an active component of the Chinese fungus Cordyceps militaris, has strong anti-inflammatory effects. However, whether 3'-deoxyadenosin attenuates methamphetamine-induced aberrant synaptic plasticity via an NLRP3-mediated inflammatory mechanism remains unclear. We first observed that 3'-deoxyadenosin attenuated conditioned place preference scores in methamphetamine-treated mice and decreased the expression of c-fos in hippocampal neurons. Furthermore, we found that 3'-deoxyadenosin reduced the aberrant potentiation of glutamatergic transmission and restored the methamphetamine-induced impairment of synaptic plasticity. We also found that 3'-deoxyadenosin decreased the expression of NLRP3 and neuronal injury. Importantly, a direct NLRP3 deficiency reduced methamphetamine-induced seeking behavior, attenuated the impaired synaptic plasticity, and prevented neuronal damage. Finally, NLRP3 activation reversed the effect of 3'-deoxyadenosin on behavior and synaptic plasticity, suggesting that the anti-neuroinflammatory mechanism of 3'-deoxyadenosin on aberrant synaptic plasticity reduces methamphetamine-induced seeking behavior. Taken together, 3'-deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome.

Construction and evaluation of an alcohol vapor chamber system.

An increasing number of studies demonstrated that alcohol vapor chamber is an effective way to model physical signs of alcohol use disorders. Although researchers are developing different vapor chambers to study chronic alcohol exposure model worldwide, few studies build and modify their own vapor chambers in China. Here, we designed and established an alcohol vapor chamber system for small animals. We described a paradigm showing how to control and monitor alcohol concentration in whole system. The vapor chamber system with several advantages including accommodating up to ten standard mouse cages. Furthermore, the system was tested by evaluating the blood alcohol concentration and neuron injury in mice. Importantly, the alcohol withdrawal after vapor exposure caused motor coordination impairment, anxiolytic- and depression-like behavior. Finally, the N-methyl-D-aspartate receptor (NMDAR)-mediated glutamatergic transmissions in the medial prefrontal cortex was changed after alcohol vapor exposure-induced behaviors. The frequency and amplitude of spontaneous excitatory postsynaptic currents between control and alcohol groups were not different, suggesting that alcohol exposure-induced behaviors are associated with the change in NMDAR response. Taken together, the new alcohol vapor chamber system was constructed, which would help to research the relationship between the stable alcohol exposure and withdrawal behaviors and to study chronic alcohol exposure-induced disorders in China.

NLRP3 deficiency decreases alcohol intake controlling anxiety-like behavior via modification of glutamatergic transmission in corticostriatal circuits.

BACKGROUND: Alcohol use disorders result from repeated binge and chronic alcohol consumption followed by negative effects, such as anxiety, upon cessation. This process is associated with the activation of NLRP3 inflammasome-mediated responses. However, whether and how inhibition of the NLRP3 inflammasome alters alcohol intake and anxiety behavior remains unclear. METHODS: A combination of drinking-in-the-dark and gavage was established in NLRP3-knockout and control mice. Behavior was assessed by open-field and elevated plus maze tests. Binge alcohol drinking was measured at 2 h and 4 h. A 2 h/4 h/24 h voluntary drinking was determined by a two-bottle choice paradigm. Western blotting and ELISA were applied to examine the levels of the NLRP3 inflammasome and- inflammatory factors, such as IL-1ß and TNF-α. Nissl staining was used to measure neuronal injury. The electrophysiological method was used to determine glutamatergic transmission in corticostriatal circuits. In vivo optogenetic LTP and LTD were applied to control the function of corticostriatal circuits on the behavior of mice. MCC950 was used to antagonize the NLRP3 inflammasome. RESULTS: The binge alcohol intake was decreased in NLRP3 KO mice compared to the control mice. During alcohol withdrawal, NLRP3 deficiency attenuated anxiety-like behavior and neuronal injury in the mPFC and striatum. Moreover, we discovered that glutamatergic transmission to striatal neurons was reduced in NLRP3 KO mice. Importantly, in vivo optogenetic induction of long-term potentiation (LTP) of corticostriatal circuits reversed the effects of NLRP3 deficiency on glutamatergic transmission and anxiety behavior. We also demonstrated that optogenetic induction of LTD decreased anxiety-like behavior and caused a reduction in glutamatergic transmission. Interestingly, NLRP3 deficiency or inhibition (MCC950 injection) attenuated the anxiety-like behavior, but it did not prevent DID + gavage paradigm-induced a persistent enhancement of drinking in a two-bottle choice at 2 and 4 days into withdrawal. CONCLUSION: Our results demonstrate that NLRP3 deficiency decreases binge alcohol intake and anxiety-like behavior through downregulation of glutamatergic transmission in corticostriatal circuits, which may provide an anti-inflammatory target for treating alcohol use disorders.