Compulsive drug seeking that is associated with addiction is hypothesized to follow a heuristic framework that involves three stages (binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation) and three domains of dysfunction (incentive salience/pathologic habits, negative emotional states, and executive function, respectively) via changes in the basal ganglia, extended amygdala/habenula, and frontal cortex, respectively. This review focuses on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the addiction cycle. Hyperkatifeia provides an additional source of motivation for compulsive drug seeking via negative reinforcement. Negative reinforcement reflects an increase in the probability of a response to remove an aversive stimulus or drug seeking to remove hyperkatifeia that is augmented by genetic/epigenetic vulnerability, environmental trauma, and psychiatric comorbidity. Neurobiological targets for hyperkatifeia in addiction involve neurocircuitry of the extended amygdala and its connections via within-system neuroadaptations in dopamine, enkephalin/endorphin opioid peptide, and γ-aminobutyric acid/glutamate systems and between-system neuroadaptations in prostress corticotropin-releasing factor, norepinephrine, glucocorticoid, dynorphin, hypocretin, and neuroimmune systems and antistress neuropeptide Y, nociceptin, endocannabinoid, and oxytocin systems. Such neurochemical/neurocircuitry dysregulations are hypothesized to mediate a negative hedonic set point that gradually gains allostatic load and shifts from a homeostatic hedonic state to an allostatic hedonic state. Based on preclinical studies and translational studies to date, medications and behavioral therapies that reset brain stress, antistress, and emotional pain systems and return them to homeostasis would be promising new targets for medication development.

中文翻译：

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毒瘾：过度嗜食/负强化作为药物开发的框架


假设与成瘾相关的强迫性药物寻求遵循一个启发式框架，该框架涉及三个阶段（暴食/中毒、戒断/负面影响和全神贯注/预期）和三个功能障碍领域（激励显着性/病理习惯、负面情绪状态、和执行功能）分别通过基底神经节、扩展杏仁核/缰核和额叶皮层的变化。本综述重点关注导致过度兴奋症的神经化学/神经回路失调，过度兴奋症的定义是在成瘾周期的戒断/负面影响阶段戒断滥用药物期间出现更强烈的负面情绪/动机体征和症状。 Hyperkatifeia 通过负强化为强迫性药物寻求提供了额外的动机来源。负强化反映了消除厌恶刺激或寻求消除因遗传/表观遗传脆弱性、环境创伤和精神共病而增强的药物的反应的可能性增加。成瘾中过度嗜食症的神经生物学靶标涉及扩展杏仁核的神经回路及其通过多巴胺、脑啡肽/内啡肽阿片肽和γ-氨基丁酸/谷氨酸系统中的系统内神经适应的连接以及前应激促肾上腺皮质激素释放因子、去甲肾上腺素中的系统间神经适应、糖皮质激素、强啡肽、下丘脑分泌素和神经免疫系统以及抗应激神经肽 Y、伤害感受肽、内源性大麻素和催产素系统。 据推测，这种神经化学/神经回路失调会介导负享乐设定点，该设定点逐渐获得失衡负荷并从稳态享乐状态转变为失衡享乐状态。根据迄今为止的临床前研究和转化研究，重置大脑应激、抗应激和情绪疼痛系统并使它们恢复稳态的药物和行为疗法将成为药物开发的有希望的新目标。