High-Phenolic Cocoa Enhances Drug-Induced Reinstatement of Cocaine-Conditioned Place Preference Independently of Increasing Adult Hippocampal Neurogenesis

Abstract

Cocaine is a powerful psychostimulant that disrupts brain function, affecting both physical and mental health. Natural cocoa, rich in polyphenols, influences neuroplasticity and cognitive processes. This study examined the effects of a high-phenolic cocoa-enriched diet on mice previously exposed to cocaine in a conditioned place preference (CPP) paradigm, assessing CPP maintenance, cognitive and emotional behavior, and adult hippocampal neurogenesis (AHN) after protracted abstinence. Forty-two male and female C57BL/6JRj mice were divided into saline (VEH) and cocaine (COC) groups. The CPP paradigm included pre-conditioning, 2 weeks of conditioning with alternating cocaine (20 mg/kg) and saline pairings, and a post-conditioning test. COC mice then received either a 10% cocoa-enriched diet or regular diet. After 24 days, mice underwent a second CPP test session and a cocaine-induced reinstatement session (10 mg/kg). Behavioral assessments and immunohistochemistry for AHN-related markers followed. While cocaine did not produce long-term emotional and cognitive changes, it reduced the survival of adult-born cells differentiating into mature neurons. Cocoa consumption did not influence the long-term CPP maintenance but significantly increased cocaine-induced reinstatement and heightened subsequent anxiety-like behavior in the COC mice. Additionally, cocoa-fed mice showed enhanced AHN; however, mediation analysis confirmed that neurogenesis did not influence drug-seeking. No sex differences were observed. These findings suggest that a cocoa-rich diet may modulate addiction-related behavior through pathways independent of AHN. Although cognitive, emotional, and neuroprotective benefits are associated with cocoa consumption, its role in cocaine addiction requires further investigation, as there is a potential risk of cocoa interacting with drug reward or drug-seeking.