Reddy D S, Zeng Y-C
Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina 27606, USA.
Methods Find Exp Clin Pharmacol. 2007 Dec;29(10):659-64. doi: 10.1358/mf.2007.29.10.1147766.
Progesterone affects the function of the brain by multiple mechanisms. The physiological effects of progesterone are mediated by the interaction of the hormone with progesterone receptors (PRs), which are widely expressed in the hypothalamus, hippocampus and limbic areas. The PR is composed of two protein isoforms, PR-A and PR-B, which are expressed from a single PR gene. In addition, progesterone influences neuronal activity through its conversion to allopregnanolone, a neurosteroid that acts as a positive allosteric modulator of GABA(A) receptors. However, the role of PRs in the sedative-hypnotic action of neurosteroids is unclear. In this study, PR knockout (PRKO) mice were used as model to study the sedative-anesthetic actions of the progesterone-derived neurosteroid allopregnanolone and the noncompetitive NMDA receptor antagonist ketamine. Mice were confirmed to be PR deficient by genotyping and immunohistochemistry of PR expression in the brain. Anesthetic potency was evaluated by the loss of the righting reflex paradigm. Allopregnanolone-induced anesthetic activity was similar in PRKO mice and their wild-type littermates, suggesting that PRs are not involved in the anesthetic response to allopregnanolone. However, the noncompetitive NMDA receptor antagonist ketamine has significantly reduced anesthetic potency in PRKO mice, suggesting a possible developmental plasticity of glutamate receptors. There was no marked gender-related difference to ketamine response in both genotypes. In conclusion, these results suggest that the neurosteroid allopregnanolone and ketamine produce differential anesthetic response in mice lacking PRs.
孕酮通过多种机制影响大脑功能。孕酮的生理作用是由该激素与孕酮受体（PRs）相互作用介导的，PRs在下丘脑、海马体和边缘区域广泛表达。PR由两种蛋白质异构体PR-A和PR-B组成，它们由单个PR基因表达。此外，孕酮通过转化为别孕烯醇酮来影响神经元活动，别孕烯醇酮是一种神经甾体，作为GABA(A)受体的正变构调节剂发挥作用。然而，PRs在神经甾体的镇静催眠作用中的作用尚不清楚。在本研究中，PR基因敲除（PRKO）小鼠被用作模型，以研究孕酮衍生的神经甾体别孕烯醇酮和非竞争性NMDA受体拮抗剂氯胺酮的镇静麻醉作用。通过基因分型和大脑中PR表达的免疫组织化学确认小鼠PR缺陷。通过翻正反射消失范式评估麻醉效能。别孕烯醇酮诱导的麻醉活性在PRKO小鼠及其野生型同窝小鼠中相似，表明PRs不参与对别孕烯醇酮的麻醉反应。然而，非竞争性NMDA受体拮抗剂氯胺酮在PRKO小鼠中的麻醉效能显著降低，表明谷氨酸受体可能具有发育可塑性。两种基因型对氯胺酮反应均无明显的性别相关差异。总之，这些结果表明，神经甾体别孕烯醇酮和氯胺酮在缺乏PRs的小鼠中产生不同的麻醉反应。
