STRESS COMBINED WITH EXTINCTION PREVENTS COCAINE RELAPSE BY DISRUPTING MEMORY
Authors: Lee *Xue , Lu Tangsheng , Zheng Wei , Xue Yanxue 
Published: February 2025

Abstract

Background
Drug addiction is a chronic and recurrent brain disease. Addictive substances can cause changes in brain circuits and may be integrated into the memory system. Drug addiction consists of different phases, beginning when recreational use escalates to compulsive use and then cycles through withdrawal, and relapse. A relapse is a return to drinking or drug use after attempts have previously been made to stop. The prevention of relapses is perhaps the most fundamental task in addiction recovery. Repeated retrieval by the cue without reward stimulant reduces the behavioral response through a process called extinction. This learning is the fundamental principle underlying many cognitive- behavioral psychotherapeutic treatments. Yet behavioral change may be difficult to sustain, and relapse is not uncommon, even after successful treatment. Memory updating was applied to substance use problems by weakening the ability of drug-associated triggers to elicit substance use[1]. Stress can potentially affect all cognitive phases involved in memory function such as the process of memory storage, retrieval or/and consolidation. Stress prior to extinction might not only enhance the consolidation of extinction memory, like post-extinction stress does, but also make it less context- dependent[2].

Aims & Objectives
1) Whether stress combined with extinction learning disrupts consolidated memory to suppress cocaine relapse. 2) What is the mechanism of stress combined with extinction learning suppressing drug seeking behavior.

Method
The self-administration of cocaine was used as an animal model for addictive memory. A combination of techniques, including immunofluorescence, fiber optic recording, brain slice patch-clamp recordings, and Golgi staining, was employed to explore the mechanism of stress combined with extinction in addictive memory.

Results
(1) The drug-priming test following self-administration extinction training suggested that rats exposed to footshock before extinction training (FE group) had a lower number of active nosepokes compared to extinction group (E group). Interestingly, in conditioned place avoidance test, footshock did not elicit an aversive response. (2) Fiber optic recording results showed excitatory neuron in LHb were more active in FE group during drug-priming test. Electrophysiological in vitro results suggested a significant increase in action potential firing and reduction of the threshold of the injected current to trigger the action potential in LHb. (3) Chemogenetic activation of neuron activity in LHb combined with extinction training effectively facilitated the elimination of cocaine addiction memory and reduced psychological craving. (4) Chemogenetic activation of neuron activity in LHb increased cfos expression in RMTg. Activation of LHb-RMTg also facilitated extinction and inhibited relapse. Activation of LHb-RMTg circuit could mimic the effect of stress combined with extinction in inhibiting relapse.

Discussion & Conclusion
This study demonstrateed that stress combination with extinction training may promote the extinction of addictive memory and inhibit relapse by reshaping activity of neurons in the LHb-RMTg circuit.

References
1.Xue YX, Luo YX, Wu P, et al. A memory retrieval-extinction procedure to prevent drug craving and relapse. Science. 2012;336(6078):241-245. doi:10.1126/science.1215070
2.Sandi C, Pinelo-Nava MT. Stress and memory: behavioral effects and neurobiological mechanisms. Neural Plast. 2007;2007:78970. doi:10.1155/2007/78970