Parsons L H, Weiss F, Koob G F
Department of Neuropharmacology, Division of Psychopharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.
J Neurosci. 1998 Dec 1;18(23):10078-89. doi: 10.1523/JNEUROSCI.18-23-10078.1998.
The effects of serotonin1B [5-hydroxytryptamine1B (5-HT1B)] receptor activation on cocaine reinforcement were investigated using intravenous cocaine self-administration by rats. The 5-HT1B receptor agonists 5-methoxy-3-1,2,3,6-tetrahydro-4-pyridinyl-1H-indole (RU 24969) (0.3-3 mg/kg), 3-(1,2,5, 6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94,253) (0.3-3 mg/kg), and 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3, 2-b]pyridine (CP 93,129) (3 and 10 micrograms, i.c.v.) each dose-dependently reduced the self-administration of a cocaine dose on the descending limb of the fixed-ratio 5 (FR-5) cocaine dose-effect function, in a manner similar to the effect produced by increasing the unit dose of cocaine. In addition, each of these 5-HT1B agonists lowered the threshold dose of cocaine that supported self-administration. These results are consistent with a 5-HT1B agonist-induced potentiation of cocaine reinforcement. On a progressive ratio schedule of reinforcement, RU 24969 and CP 94,253 dose-dependently (0.3-3 mg/kg) increased the highest completed ratio for cocaine self-administration, again by producing behavioral alterations similar to those induced by increasing the unit dose of cocaine. The effect of CP 94,253 was dose-dependently blocked by the 5-HT1B/1D receptor partial agonist 2'-methyl-4'-(5-methyl[1,2, 4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid[4-methodoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127, 935) (0.3-10 mg/kg) but was unaffected by the 5-HT1A receptor antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl- benzamide (p-MPPI; 1-10 mg/kg). Self-administration behavior was not maintained when either RU 24969 or CP 94,253 was substituted for cocaine, indicating that these 5-HT1B agonists do not produce significant reinforcing effects alone. Together, these findings indicate that 5-HT1B receptor stimulation facilitates the reinforcing properties of cocaine. These results are in opposition to recent findings with 5-HT1B receptor knock-out mice and may have important ontogenic implications in the area of drug abuse research.
采用大鼠静脉注射可卡因自身给药法，研究了5-羟色胺1B[5-羟色胺1B（5-HT1B）]受体激活对可卡因强化作用的影响。5-HT1B受体激动剂5-甲氧基-3-（1,2,3,6-四氢-4-吡啶基）-1H-吲哚（RU 24969）（0.3 - 3毫克/千克）、3-（1,2,5,6-四氢-4-吡啶基）-5-丙氧基吡咯并[3,2-b]吡啶（CP 94,253）（0.3 - 3毫克/千克）和3-（1,2,5,6-四氢吡啶-4-基）吡咯并[3,2-b]吡啶（CP 93,129）（3和10微克，脑室内注射）均剂量依赖性地降低了固定比率5（FR - 5）可卡因剂量效应函数下降支上可卡因剂量的自身给药量，其方式类似于增加可卡因单位剂量所产生的效果。此外，这些5-HT1B激动剂中的每一种都降低了支持自身给药的可卡因阈值剂量。这些结果与5-HT1B激动剂诱导的可卡因强化作用增强一致。在渐进比率强化程序中，RU 24969和CP 94,253剂量依赖性地（0.3 - 3毫克/千克）增加了可卡因自身给药的最高完成比率，同样是通过产生与增加可卡因单位剂量所诱导的行为改变相似的改变来实现的。CP 94,253的作用被5-HT1B/1D受体部分激动剂2'-甲基-4'-（5-甲基[1,2,4]恶二唑-3-基）-联苯-4-羧酸[4-甲氧基-3-（4-甲基-哌嗪-1-基）-苯基]-酰胺（GR 127,935）（0.3 - 10毫克/千克）剂量依赖性地阻断，但不受5-HT1A受体拮抗剂4-碘-N-[2-[4-（甲氧基苯基）-1-哌嗪基]乙基]-N-2-吡啶基-苯甲酰胺（p-MPPI；1 - 10毫克/千克）的影响。当用RU 24969或CP 94,253替代可卡因时，自身给药行为无法维持，这表明这些5-HT1B激动剂单独不会产生显著的强化作用。总之，这些发现表明5-HT1B受体刺激促进了可卡因的强化特性。这些结果与最近关于5-HT1B受体基因敲除小鼠的发现相反，并且可能在药物滥用研究领域具有重要的个体发生学意义。
