Hauser Sheketha R, Deehan Gerald A, Knight Christopher P, Waeiss Robert A, Engleman Eric A, Johnson Phillip L, McBride William J, Bell Richard L, Truitt William A, Rodd Zachary A
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States.
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States.
Front Psychiatry. 2025 Sep 3;16:1634350. doi: 10.3389/fpsyt.2025.1634350. eCollection 2025.
The ability of conditioned cues to evoke drug craving is considered a critical factor precipitating relapse of drug use. The nucleus accumbens shell (AcbSh) is a structure that mediates drug-seeking via the influence of associations formed between conditioned cues and drug reward.
In the present experiments, alcohol-preferring (P) rats were exposed to three conditioned odor cues; CS+ associated with alcohol self-administration, CS- associated with the absence of alcohol (extinction training), and a neutral stimulus (CS) presented in neutral environment with no association to alcohol. The experiments examined the effects of the conditioned cues on extracellular levels of dopamine (DA), serotonin (5-HT), and glutamate (GLU), as well as the pattern of activation of D1 receptor-containing neurons in the AcbSh. The involvement of 5-HT receptors within the AcbSh in regulating context- and cue-induced alcohol-seeking was also determined.
Presentation of the CS+ resulted in increased extracellular DA levels and reduced 5-HT levels in the AcbSh, as well as increased activation of D1 receptor-containing neurons. In contrast, presentation of the CS- decreased extracellular DA and GLU levels in the AcbSh. The conditioned cues did not affect DA levels in the Acb core. The intra-AcbSh administration of a 5-HT antagonist enhanced context- and cue-induced alcohol seeking, whereas a 5-HT agonist reduced these behaviors.
Overall, the data suggest that there are distinct neurocircuits within the AcbSh that mediating the effects of excitatory and inhibitory conditioned cues on motivated behavior. While this work highlights a complex interaction of several neurotransmitter systems, it may also suggest a potential role for behavioral therapies involving extinction training and 5-HT receptor activation as potential targets for the treatment of cue-induced drug-seeking behavior.
条件性线索引发药物渴望的能力被认为是促使药物使用复发的关键因素。伏隔核壳（AcbSh）是一个通过条件性线索与药物奖赏之间形成的关联影响来介导药物寻求行为的结构。
在本实验中，嗜酒（P）大鼠暴露于三种条件性气味线索；与酒精自我给药相关的CS +，与无酒精状态相关的CS -（消退训练），以及在与酒精无关联的中性环境中呈现的中性刺激（CS）。实验研究了条件性线索对多巴胺（DA）、5-羟色胺（5-HT）和谷氨酸（GLU）细胞外水平的影响，以及AcbSh中含D1受体神经元的激活模式。还确定了AcbSh内5-HT受体在调节情境和线索诱导的酒精寻求行为中的作用。
呈现CS +导致AcbSh中细胞外DA水平升高和5-HT水平降低，以及含D1受体神经元的激活增加。相比之下，呈现CS -降低了AcbSh中细胞外DA和GLU水平。条件性线索不影响Acb核心中的DA水平。在AcbSh内注射5-HT拮抗剂增强了情境和线索诱导的酒精寻求行为，而5-HT激动剂则减少了这些行为。
总体而言，数据表明AcbSh内存在不同的神经回路，介导兴奋性和抑制性条件性线索对动机行为的影响。虽然这项工作突出了几种神经递质系统的复杂相互作用，但它也可能提示涉及消退训练和5-HT受体激活的行为疗法作为治疗线索诱导的药物寻求行为潜在靶点的潜在作用。
