Control of cocaine-seeking behavior by drug-associated stimuli in rats: Effects on recovery of extinguished operant-responding and extracellular dopamine levels in amygdala and nucleus accumbens

TLDR

Cocaine’s long‑term addictive potential is driven by conditioning with environmental cues, which can trigger relapse by activating the amygdala and nucleus accumbens. The study examined how cocaine‑predictive cues influence recovery of extinguished cocaine‑seeking behavior in rats. Rats were trained with discriminative stimuli paired to cocaine or saline, then underwent repeated extinction sessions until responding dropped to ≤4 per session. Re‑exposure to the cocaine‑associated stimulus reinstated lever pressing and elevated dopamine in the nucleus accumbens and amygdala, while the nonreward stimulus had no effect, indicating that cocaine cues robustly and persistently trigger drug‑seeking via dopaminergic activation.

Abstract

The conditioning of the pharmacological actions of cocaine with environmental stimuli is thought to be a critical factor in the long-term addictive potential of this drug. Cocaine-related stimuli may increase the likelihood of relapse by evoking drug craving, and brain-imaging studies have identified the amygdala and nucleus accumbens (NAcc) as putative neuroanatomical substrates for these effects of cocaine cues. To study the significance of environmental stimuli in the recovery of extinguished cocaine-seeking behavior, male Wistar rats were trained to associate discriminative stimuli (SΔs) with response-contingent availability of intravenous cocaine vs. saline. The rats then were subjected to repeated extinction sessions during which cocaine, saline, and the respective SΔs were withheld until the animals reached an extinction criterion of ≤4 responses over three consecutive sessions. Subsequent re-exposure to the cocaine SΔ, but not the nonreward SΔ, produced strong recovery of responding at the previously active lever in the absence of any further drug availability. The efficacy and behavioral selectivity of the cocaine SΔ remained unaltered throughout an 8-day test period. Exposure to the cocaine SΔ significantly increased dopamine efflux in the NAcc and amygdala as measured by intracranial microdialysis in a separate group of rats. Dopamine levels remained unaltered in the presence of the nonreward SΔ. The results demonstrate that cocaine-predictive stimuli elicit robust and persistent cocaine-seeking behavior, and that this effect may involve activation of dopamine transmission in the NAcc and amygdala.