Miczek K A, Weerts E M, Vivian J A, Barros H M
Tufts University, Medford, MA 02155, USA.
Psychopharmacology (Berl). 1995 Sep;121(1):38-56. doi: 10.1007/BF02245590.
A continuing challenge for preclinical research on anxiolytic drugs is to capture the affective dimension that characterizes anxiety and aggression, either in their adaptive forms or when they become of clinical concern. Experimental protocols for the preclinical study of anxiolytic drugs typically involve the suppression of conditioned or unconditioned social and exploratory behavior (e.g., punished drinking or social interactions) and demonstrate the reversal of this behavioral suppression by drugs acting on the benzodiazepine-GABAA complex. Less frequently, aversive events engender increases in conditioned or unconditioned behavior that are reversed by anxiolytic drugs (e.g., fear-potentiated startle). More recently, putative anxiolytics which target 5-HT receptor subtypes produced effects in these traditional protocols that often are not systematic and robust. We propose ethological studies of vocal expressions in rodents and primates during social confrontations, separation from social companions, or exposure to aversive environmental events as promising sources of information on the affective features of behavior. This approach focuses on vocal and other display behavior with clear functional validity and homology. Drugs with anxiolytic effects that act on the benzodiazepine-GABAA receptor complex and on 5-HT1A receptors systematically and potently alter specific vocalizations in rodents and primates in a pharmacologically reversible manner; the specificity of these effects on vocalizations is evident due to the effectiveness of low doses that do not compromise other physiological and behavioral processes. Antagonists at the benzodiazepine receptor reverse the effects of full agonists on vocalizations, particularly when these occur in threatening, startling and distressing contexts. With the development of antagonists at 5-HT receptor subtypes, it can be anticipated that similar receptor-specificity can be established for the effects of 5-HT anxiolytics.
抗焦虑药物临床前研究面临的一个持续挑战是，要捕捉焦虑和攻击行为的情感维度，无论是其适应性形式，还是当其成为临床关注问题时。抗焦虑药物临床前研究的实验方案通常涉及抑制条件性或非条件性的社交和探索行为（例如，受罚饮水或社交互动），并证明作用于苯二氮䓬 - γ-氨基丁酸A（GABAA）复合物的药物能逆转这种行为抑制。不太常见的是，厌恶事件会导致条件性或非条件性行为增加，而抗焦虑药物可逆转这种增加（例如，恐惧增强的惊吓反应）。最近，针对5-羟色胺（5-HT）受体亚型的假定抗焦虑药在这些传统方案中产生的效果往往不系统且不稳定。我们建议对啮齿动物和灵长类动物在社交对抗、与社交同伴分离或暴露于厌恶环境事件期间的发声表达进行行为学研究，以此作为了解行为情感特征的有前景的信息来源。这种方法关注具有明确功能有效性和同源性的发声及其他展示行为。作用于苯二氮䓬 - GABAA受体复合物和5-HT1A受体的抗焦虑药物能以药理学上可逆的方式系统且有力地改变啮齿动物和灵长类动物的特定发声；这些对发声的影响具有特异性，因为低剂量药物有效且不会损害其他生理和行为过程。苯二氮䓬受体拮抗剂可逆转完全激动剂对发声的影响，尤其是当这些发声出现在威胁、惊吓和痛苦情境中时。随着5-HT受体亚型拮抗剂的开发，可以预期5-HT抗焦虑药的作用也能建立类似的受体特异性。
