Maurel S, Schreiber R, De Vry J
CNS Research, Bayer AG, Cologne, Germany.
Behav Pharmacol. 1998 Jul;9(4):337-43.
Although accumulating evidence suggests that serotonergic drugs are able to substitute for the ethanol (EtOH) cue in rats, it is still unclear which 5-HT receptor subtypes are responsible for this phenomenon, and whether these receptors are critically involved in the EtOH cue. In the present study, rats were trained to discriminate EtOH (1000 mg/kg, i.p., t-15 min) from saline in a two-lever food-reinforced procedure, and it was investigated to which extent serotonergic compounds with a certain level of specificity for either 5-HT1B, 5-HT2A or 5-HT2C receptors generalized to the EtOH cue. Subsequently, the involvement of these receptor subtypes was ascertained by the use of selected 5-HT receptor antagonists. The 5-HT1B receptor agonist CP 94,253 (0.3-5 mg/kg, i.p.) and the mixed 5-HT(2C/1B) receptor agonist mCPP (0.1-1 mg/kg, i.p.), but not the preferential 5-HT2A receptor agonist DOI (0.3-1 mg/kg, i.p.), completely generalized to the EtOH cue. Complete generalization of the former two compounds coincided with a decrease in response rate. In antagonism studies, it was shown that the 5-HT1B receptor antagonist GR 127935 (10 mg/kg, i.p.) completely blocked generalization of CP 94,253 to the EtOH cue, suggesting that stimulation of 5-HT1B receptors produces discriminative stimulus effects which are similar to those of EtOH. GR 127935 (10 mg/kg, i.p.), as well as the mixed 5-HT(1B/2C) receptor antagonist metergoline (1 mg/kg, i.p.), and the 5-HT2C receptor antagonist SB 206,553 (1 mg/kg, i.p.) completely blocked generalization of mCPP to the EtOH cue. This suggests that 5-HT1B and 5-HT2C receptors are required for the generalization of mCPP to the EtOH cue. The present findings indicate that activation of 5-HT1B and 5-HT2C, but not of 5-HT2A receptors, mimics the EtOH cue. However, the finding that neither metergoline, nor the 5-HT2A receptor antagonist MDL 100,907 blocked the EtOH cue, suggests that these receptors play only a minor role in the discriminative stimulus effects of a moderately low dose of EtOH.
尽管越来越多的证据表明，血清素能药物能够替代大鼠体内的乙醇（EtOH）线索，但目前仍不清楚是哪些5-羟色胺（5-HT）受体亚型导致了这一现象，以及这些受体是否在EtOH线索中起关键作用。在本研究中，通过双杠杆食物强化程序训练大鼠区分EtOH（1000毫克/千克，腹腔注射，t-15分钟）和生理盐水，并研究了对5-HT1B、5-HT2A或5-HT2C受体具有一定特异性水平的血清素能化合物对EtOH线索的泛化程度。随后，通过使用选定的5-HT受体拮抗剂来确定这些受体亚型的参与情况。5-HT1B受体激动剂CP 94,253（0.3-5毫克/千克，腹腔注射）和5-HT(2C/1B)混合受体激动剂mCPP（0.1-1毫克/千克，腹腔注射），而非优先的5-HT2A受体激动剂DOI（0.3-1毫克/千克，腹腔注射），能完全泛化到EtOH线索。前两种化合物的完全泛化与反应率的降低相吻合。在拮抗研究中，结果表明5-HT1B受体拮抗剂GR 127935（10毫克/千克，腹腔注射）完全阻断了CP 94,253对EtOH线索的泛化，这表明刺激5-HT1B受体产生的辨别性刺激效应与EtOH相似。GR 127935（10毫克/千克，腹腔注射）以及5-HT(1B/2C)混合受体拮抗剂美替拉酮（1毫克/千克，腹腔注射）和5-HT2C受体拮抗剂SB 206,553（1毫克/千克，腹腔注射）完全阻断了mCPP对EtOH线索的泛化。这表明5-HT1B和5-HT2C受体是mCPP泛化到EtOH线索所必需的。目前的研究结果表明，激活5-HT1B和5-HT2C受体，而非5-HT2A受体，可模拟EtOH线索。然而，美替拉酮和5-HT2A受体拮抗剂MDL 100,907均未阻断EtOH线索这一发现表明，这些受体在中等低剂量EtOH的辨别性刺激效应中仅起次要作用。
