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Background and Objectives Chronic cocaine exposure has differential neural effects in Fischer 344 (F344) vs Lewis inbred rats that may explain strain‐dependent differences during acquisition vs maintenance of cocaine self‐administration. We assessed whether prior cocaine exposure alters operant responding for food across various phases (acquisition, maintenance, extinction, spontaneous recovery, reinitiation) in these strains. Methods Lewis and F344 rats (N = 12) were administered three cocaine (15 mg/kg) or saline injections at hourly intervals for 3 consecutive days. Beginning the next day for 24 days, rats had access to operant chambers in which one lever depression resulted in the delivery of a food pellet. Then, four extinction sessions were conducted in which food was no longer available, but other stimulus conditions remained the same. After a 2‐day break, spontaneous recovery was assessed over four sessions. Food delivery was then restored for 3 days to test reinitiation followed by a progressive ratio session. Results Lewis rats acquired the operant faster than F344 rats. F344 rats showed lower maintenance rates than Lewis rats but higher spontaneous recovery responding. Cocaine exposure caused persistence of responding during extinction in F344 but not Lewis rats. All groups reinitiated responding when food was available again and did not differ in final ratios completed under the progressive ratio schedule. Discussion and Conclusions That prior cocaine exposure led to persistence of responding in F344 rats during extinction may reflect heightened contextual conditioning that interferes with the ability to extinguish responding. Scientific Significance Results have implications for the genetic contribution to relapse‐like behaviors. (Am J Addict 2021;00:00–00)

Background and Objectives: A growing body of literature demonstrates that the human microbiota plays a crucial role in health and disease states, as well as in the body's response to stress. In addition, the microbiome plays a role in psychological well-being and regulating negative affect. Regulation of negative affect is a factor in psychostimulant abuse disorders. We propose a risk chain in which stress leads to negative affect that places an individual at risk to develop or relapse to psychostimulant abuse disorder. Stress, negative affect, and psychostimulant use all alter the gut microbiome.Methods: This review brings together the literature on affective disorders, stress, and psychostimulant abuse disorders to assess possible modulatory actions of the gut-brain axis to regulate these conditions.Results: Studies reviewed across the various disciplines suggest that the dysbiosis resulting from drug use, drug withdrawal, or stress may cause an individual to be more susceptible to addiction and relapse. Probiotics and prebiotics reduce stress and negative affect.Scientific Significance: Treatment during the withdrawal phase of psychostimulant abuse disorder, when the microbiome is altered, may ameliorate the symptoms of stress and negative affect leading to a reduced risk of relapse to psychostimulant use.