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

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.

可卡因药理作用与环境刺激的条件化关联，被认为是该药物长期成瘾潜力的关键影响因素。与可卡因相关的刺激可通过诱发药物渴求提升复吸风险，脑成像研究已将杏仁核与伏隔核（NAcc）确定为可卡因线索介导上述效应的潜在神经解剖学底物。为探究环境刺激在消退的可卡因寻求行为恢复过程中的作用，研究人员对雄性Wistar大鼠进行训练，使其将辨别刺激（SΔs）与反应依赖性给药的静脉注射可卡因或生理盐水建立联结。随后，大鼠接受反复消退训练，期间不给予可卡因、生理盐水及相应的SΔs，直至大鼠连续3个训练周期内的按压反应次数≤4次，达到消退标准。后续再次暴露于可卡因相关SΔ时（而非非奖赏性SΔ），即使未额外给予药物，大鼠先前活跃杠杆的按压反应也出现显著恢复。在为期8天的测试周期内，可卡因相关SΔ的效应效能与行为选择性未发生改变。通过另一组大鼠的颅内微透析检测发现，暴露于可卡因相关SΔ可显著升高伏隔核与杏仁核内的多巴胺外流水平，而非奖赏性SΔ则不会改变脑内多巴胺水平。上述结果表明，可预测可卡因出现的刺激可诱发稳定且持久的可卡因寻求行为，该效应可能涉及伏隔核与杏仁核内多巴胺递质传递的激活。