Schreiber R, Opitz K, Glaser T, De Vry J
Institute for Neurobiology, Department of Psychopharmacology, Cologne, Germany.
Psychopharmacology (Berl). 1993;112(1):100-10. doi: 10.1007/BF02247369.
The selective serotonin(5-HT)1A receptor agonists 8-OH-DPAT and ipsapirone were tested in selectively inbred Wistar rats, with high preference [70-90%: defined as the ratio of ethanol (EtOH) to total fluid intake] for EtOH (10% v/v) over water in a two-bottle free choice situation. Rats were injected shortly before the overnight test session (8:00 P.M.-8:00 A.M.). EtOH and water consumption were determined in 20-min intervals; food consumption after the session. 8-OH-DPAT (ED50: 2.4 mg/kg, SC) and ipsapirone (ED50: 12.5 mg/kg, SC) reduced EtOH preference in a dose-dependent manner. In addition, 8-OH-DPAT increased total fluid intake, whereas ipsapirone enhanced total food intake. The EtOH preference reduction was time-dependent and reached a maximum within the second 4 h after application of 8-OH-DPAT (-73%) and ipsapirone (-72%). The preference reducing effect of ipsapirone (20 mg/kg, PO) was completely blocked by the nonselective 5-HT1A antagonist spiperone (0.05 mg/kg, SC). Local application of 8-OH-DPAT (10 micrograms, 0.5 microliters) into the dorsal raphe nucleus (DRN, a brain area rich in somatodendritic 5-HT1A autoreceptors), reduced the EtOH preference significantly as compared to the saline injection in the same animal (-12%, 8:00-12:00 P.M.). Only marginal effects on ingestion behavior were observed after microinjection into the nucleus accumbens. Reduction of brain 5-HT levels by pretreatment with the 5-HT synthesis inhibitor pCPA (2 x 150 mg/kg, IP) resulted in a short lasting, marked reduction (-54%) and a long lasting, small attenuation of the EtOH preference. Total food consumption was strongly decreased but returned soon to normal; total fluid intake was only slightly decreased. The EtOH preference reducing effect of ipsapirone (5 and 20 mg/kg, SC) was attenuated in pCPA-pretreated rats. The present data suggest that 5-HT1A receptor ligands reduce EtOH preference via stimulation of 5-HT1A receptors in the DRN. The possibility of additional mechanism(s) is discussed.
在选择性近交的Wistar大鼠中对选择性5-羟色胺（5-HT）1A受体激动剂8-羟基二丙胺四乙酸（8-OH-DPAT）和伊沙匹隆进行了测试，这些大鼠在两瓶自由选择的情况下对10%（体积/体积）乙醇（EtOH）的偏好高于水，偏好度较高[70-90%：定义为乙醇与总液体摄入量的比率]。在夜间测试时段（晚上8:00至早上8:00）前不久给大鼠注射药物。每隔20分钟测定乙醇和水的消耗量；测试结束后测定食物消耗量。8-OH-DPAT（半数有效剂量：2.4毫克/千克，皮下注射）和伊沙匹隆（半数有效剂量：12.5毫克/千克，皮下注射）以剂量依赖的方式降低了对乙醇的偏好。此外，8-OH-DPAT增加了总液体摄入量，而伊沙匹隆增加了总食物摄入量。乙醇偏好的降低具有时间依赖性，在应用8-OH-DPAT（-73%）和伊沙匹隆（-72%）后的第二个4小时内达到最大值。伊沙匹隆（20毫克/千克，口服）的偏好降低作用被非选择性5-HT1A拮抗剂螺哌隆（0.05毫克/千克，皮下注射）完全阻断。将8-OH-DPAT（10微克，0.5微升）局部注射到中缝背核（DRN，一个富含体细胞树突状5-HT1A自身受体的脑区），与在同一动物中注射生理盐水相比，显著降低了乙醇偏好（-12%，下午8:00至12:00）。向伏隔核微量注射后，仅观察到对摄食行为的轻微影响。用5-羟色胺合成抑制剂对氯苯丙氨酸（2×150毫克/千克，腹腔注射）预处理降低脑5-羟色胺水平，导致乙醇偏好短暂显著降低（-54%）和长期轻微减弱。总食物消耗量大幅下降，但很快恢复正常；总液体摄入量仅略有下降。在对氯苯丙氨酸预处理的大鼠中，伊沙匹隆（5和20毫克/千克，皮下注射）的乙醇偏好降低作用减弱。目前的数据表明，5-HT1A受体配体通过刺激中缝背核中的5-HT1A受体降低乙醇偏好。还讨论了其他机制的可能性。
