Overstreet D H, Rezvani A H, Knapp D J, Crews F T, Janowsky D S
Skipper Bowles Center for Alcohol Studies, University of North Carolina School of Medicine at Chapel Hill 27599-7178, USA.
Psychiatr Genet. 1996 Fall;6(3):107-17. doi: 10.1097/00041444-199623000-00002.
It was previously reported that selection for differences in the hypothermic effects to the selective 5-HT-1A agonist, 8-OH-DPAT, occurred rapidly, with very substantial differences present by the fourth generation. The present communication summarizes the findings from the next five generations of selection and from behavioral and other functional studies on these rats. The rats which were more sensitive to 8-OH-DPAT (High DPAT Sensitive-HDS) exhibited decreases in temperature of 4 degrees C or more and the distribution did not overlap with that of the rats which were less sensitive to 8-OH-DPAT (Low DPAT Sensitive-LDS) which exhibited decreases in temperature of 1.5 degrees C or less. The randomly bred control group (Random DPAT Sensitive-RDS) exhibited intermediate temperature decreases (means of 1.6-1.8 degrees C), with time overlap with the distributions of the selected groups. Pretreatment with pindolol, a 5-HT-1A antagonist, reduced the hypothermic response to 8-OH-DPAT, but pretreatment with ritanserin, a 5-HT-7 and 5-HT-2A/C antagonist, had no effect, confirming that the hypothermic response to 8-OH-DPAT is mediated predominantly by 5-HT-1A receptors. The HDS rats were less mobile in a forced swim test and drank more saccharin solution in a two-bottle choice paradigm than the LDS or RDS rats over several generations. In contrast, there were no consistent differences among the groups for open field activity or performance in an elevated plus maze. There were no differences among the groups for voluntary alcohol intake, but the HDS rats exhibited greater suppression of alcohol and saccharin intake after injection of 8-OH-DPAT (0.125 mg kg-1). The HDS rats were also found to have a higher number of 5-HT-1A binding sites in cortical regions than the LDS or RDS rats, but there were no 5-HT-1A binding site differences in the raphe nuclei. These findings clearly show that consistent behavioral differences do occur in the 8-OH-DPAT-selected lines of rats, but only for behaviors related to possible depression or reward, not anxiety. The pattern of binding results suggests that these behavioral correlates of 8-OH-DPAT selection may be related to changes in cortical 5-HT-1A receptors rather than raphe autoreceptors.
此前有报道称，针对选择性5-羟色胺-1A（5-HT-1A）激动剂8-羟基二丙基氨基四氢吡啶（8-OH-DPAT）的低温效应差异进行的选择迅速发生，到第四代时就出现了非常显著的差异。本通讯总结了接下来五代选择的结果以及对这些大鼠进行的行为和其他功能研究的结果。对8-OH-DPAT更敏感的大鼠（高DPAT敏感性-HDS）体温下降4摄氏度或更多，其分布与对8-OH-DPAT不太敏感的大鼠（低DPAT敏感性-LDS）不重叠，后者体温下降1.5摄氏度或更少。随机繁殖的对照组（随机DPAT敏感性-RDS）体温下降幅度居中（平均1.6 - 1.8摄氏度），其分布与所选组有时间上的重叠。用5-HT-1A拮抗剂吲哚洛尔预处理可降低对8-OH-DPAT的低温反应，但用5-HT-7和5-HT-2A/C拮抗剂利坦色林预处理则无效果，这证实了对8-OH-DPAT的低温反应主要由5-HT-1A受体介导。在几代实验中，HDS大鼠在强迫游泳试验中活动较少，在两瓶选择范式中比LDS或RDS大鼠饮用更多的糖精溶液。相比之下，在旷场活动或高架十字迷宫表现方面，各组之间没有一致的差异。各组在自愿酒精摄入量方面没有差异，但HDS大鼠在注射8-OH-DPAT（0.125毫克/千克）后对酒精和糖精摄入的抑制作用更强。还发现HDS大鼠皮质区域的5-HT-1A结合位点数量比LDS或RDS大鼠多，但中缝核中的5-HT-1A结合位点没有差异。这些发现清楚地表明，在8-OH-DPAT选择的大鼠品系中确实存在一致的行为差异，但仅针对与可能的抑郁或奖赏相关的行为，而非焦虑相关行为。结合结果的模式表明，8-OH-DPAT选择的这些行为相关性可能与皮质5-HT-1A受体的变化有关，而非中缝自身受体的变化。
