Department of Neuropharmacology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Transl Psychiatry. 2022 Feb 11;12(1):58. doi: 10.1038/s41398-022-01815-2.
Previous findings have proposed that drugs targeting 5-HT receptors could be promising candidates in the treatment of trauma- and stress-related disorders. However, the reduction of conditioned freezing observed in 5-HT receptor knock-out (KO) mice in previous studies could alternatively be accounted for by increased locomotor activity. To neutralize the confound of individual differences in locomotor activity, we measured a ratio of fear responses during versus before the presentation of a conditioned stimulus previously paired with a footshock (as a fear measure) by utilizing a conditioned licking suppression paradigm. We first confirmed that 5-HT receptor gene KO attenuated fear responses to distinct types of single conditioned stimuli (context or tone) independently of locomotor activity. We then assessed the effects of 5-HT receptor gene KO on compound fear responses by examining mice that were jointly conditioned to a context and a tone and later re-exposed separately to each. We found that separate re-exposure to individual components of a complex fear memory (i.e., context and tone) failed to elicit contextual fear extinction in both 5-HT receptor gene KO and wild-type mice, and also abolished differences between genotypes in tone-cued fear extinction. This study delineates a previously overlooked role of 5-HT receptors in conditioned fear responses, and invites caution in the future assessment of molecular targets and candidate therapies for the treatment of PTSD.
先前的研究结果表明，针对 5-HT 受体的药物可能是创伤和应激相关障碍治疗的有前途的候选药物。然而，在之前的研究中，5-HT 受体敲除（KO）小鼠的条件性冻结减少，这也可能是由于运动活性增加所致。为了消除运动活性个体差异的干扰，我们利用条件性舔抑制范式，通过测量条件刺激呈现期间与之前与足部电击配对的条件刺激（作为恐惧测量）之间的恐惧反应比率来测量。我们首先证实 5-HT 受体基因 KO 减弱了对不同类型的单一条件刺激（情境或音调）的恐惧反应，而与运动活性无关。然后，我们通过检查联合条件作用于情境和音调并随后分别重新暴露于每个音调的小鼠，评估了 5-HT 受体基因 KO 对复合恐惧反应的影响。我们发现，在 5-HT 受体基因 KO 和野生型小鼠中，对复杂恐惧记忆的单个成分（即情境和音调）的单独重新暴露均不能引起情境恐惧消退，并且也消除了基因型之间在音调提示的恐惧消退方面的差异。这项研究描绘了 5-HT 受体在条件性恐惧反应中的先前被忽视的作用，并在未来对 PTSD 治疗的分子靶标和候选疗法的评估中引起了警惕。
