ArticleInternational journal of molecular sciences2024
The Mechanism of the Nucleus Accumbens-Ventral Pallidum Pathway Mediated by Drug Withdrawal-Induced High-Seeking Motivation in Cocaine Addiction.
Article in International journal of molecular sciences, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
The reinforcement of drug-seeking motivation following drug withdrawal is recognized as a significant factor contributing to relapse. The ventral pallidum (VP) plays a crucial role in encoding and translating motivational aspects of reward. However, current research lacks a clear understanding of how the VP mediates drug-seeking motivation and the feedback modulation between the VP and the nucleus accumbens (NAc) following drug withdrawal. Therefore, utilizing a rat model of cocaine self-administration, we investigated the circuitry mechanisms underlying drug-seeking behavior post-drug withdrawal involving the NAc-VP pathway. Initially, we observed a significant enhancement in drug-seeking behavior 14 days after cocaine withdrawal. Subsequently, we identified the feedback mechanism through which the NAc-VP regulates this behavior. Immunofluorescence results indicated an increase in c-Fos expression levels in the ventral pallidum ventromedial (VPvm) and ventrolateral ventral pallidum (VPvl) following drug withdrawal. Calcium fiber photometry further elucidated that during the expression of high motivational drug-seeking behavior, there was a specific enhancement in VPvm neuronal activity, and retrograde tracing techniques suggested a weakened transmission function in the NAc-VPm pathway. Additionally, chemical genetic techniques demonstrated that inhibiting the activity of the NAc-VP pathway could increase the motivational level of drug-seeking behavior. These findings indicate that the reduced inhibitory function of the NAc-VP pathway following prolonged cocaine withdrawal forms the basis for heightened reactivity in VPvm neurons, thus regulating the expression of high motivational behavior triggered by drug-related cues. Our study results suggest that maintaining normal NAc-VP pathway functionality may decrease drug-seeking motivation post long-term drug withdrawal, offering new insights for interventions targeting relapse.
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