Post R M, Weiss S R
Biological Psychiatry Branch, NIMH, NIH, Bethesda, Maryland 20892-1272, USA.
Biol Psychiatry. 1998 Aug 1;44(3):193-206. doi: 10.1016/s0006-3223(98)00144-9.
A number of untreated or inadequately treated psychiatric illnesses often demonstrate syndrome progression manifested by either increasing frequency, severity, or spontaneity of episodes. Behavioral sensitization to psychomotor stimulants (and its cross sensitization to stress) and electrophysiological kindling provide two very different models for conceptualizing physiological and behavioral abnormalities that progress in severity in response to the same inducing stimulation over time. These models are highly indirect, and the behaviors induced and specific pharmacologic interventions do not directly parallel those in many of these psychiatric syndromes. Nonetheless, these preclinical models help us conceptualize potential mechanisms involved in syndrome progression based on experience-dependent modifications of the genome at the level of transcriptional regulation. In both preclinical models, agents that are effective in the earlier developmental phase of sensitization or kindling are not necessarily effective in amelioration of the full-blown syndromes, and vice versa. Thus these models also suggest a variety of intervention principles that can be directly tested in the clinic, such as differential efficacy of treatment as a function of stage of evolution of the given syndrome. Although serotonergic mechanisms do not appear central to the basic phenomena of sensitization and kindling, they appear capable of modulating their development and severity. As such, it becomes of considerable importance to assess whether serotonergic mechanisms that have been implicated in acute treatment of mood and anxiety syndromes are also involved in the longitudinal course and prevention of syndrome progression or occurrence. Identification of the more precise molecular mechanisms involved might provide a target for new therapeutic approaches to these recurrent and potentially disabling major psychiatric illnesses.
许多未经治疗或治疗不充分的精神疾病往往表现出综合征进展，其表现为发作频率增加、严重程度加重或发作更具自发性。对精神运动兴奋剂的行为敏感化（及其对应激的交叉敏感化）和电生理点燃为理解生理和行为异常提供了两种截然不同的模型，这些异常会随着时间推移，对相同的诱导刺激产生严重程度上的进展。这些模型具有高度间接性，所诱导的行为和特定的药物干预与许多此类精神综合征中的情况并不直接平行。尽管如此，这些临床前模型有助于我们基于转录调控水平上基因组的经验依赖性修饰，来理解综合征进展中涉及的潜在机制。在这两种临床前模型中，在敏感化或点燃的早期发展阶段有效的药物，不一定对改善全面发作的综合征有效，反之亦然。因此，这些模型还提出了多种可在临床上直接检验的干预原则，比如根据给定综合征演变阶段的不同，治疗效果也有所差异。虽然血清素能机制似乎并非敏感化和点燃基本现象的核心，但它们似乎能够调节其发展和严重程度。因此，评估在情绪和焦虑综合征急性治疗中涉及的血清素能机制是否也参与综合征进展或发生的纵向过程及预防，就变得相当重要。确定其中更精确的分子机制可能为这些复发性且可能导致残疾的主要精神疾病的新治疗方法提供靶点。
