Przegaliński Edmund, Gołda Anna, Filip Małgorzata
Laboratory of Drug Addiction Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
Pharmacol Rep. 2008 Nov-Dec;60(6):798-810.
Numerous data indicated a significance for the brain dopaminergic pathways in the behavioral effects of cocaine, however recent research also demonstrated involvement of serotonin (5-HT) neurotransmission and particularly 5-HT(1B) receptors in the reinforcing, discriminative stimulus and sensitizing effects of cocaine. In order to substantiate a role of these receptors in incentive motivation for cocaine, we used the extinction/reinstatement model to examine the effects of the 5-HT(1B) receptor ligands on reinstatement of extinguished cocaine-seeking behavior and food-taking behavior. Rats trained to self-administer cocaine (0.5 mg/kg/infusion) subsequently underwent extinction procedures. They were then tested for the cocaine-primed or cocaine-associated cue-induced reinstatement of extinguished cocaine-seeking behavior. Other groups of rats were trained to self-administer food (sweet milk), and after extinction they were tested for the reinstatement of food-taking behavior induced by contingent food presentation. The 5-HT(1B) receptor antagonists SB 216641 (2.5-7.5 mg/kg) and GR 127935 (2.5-10 mg/kg) dose-dependently attenuated the cocaine (10 mg/kg)- and cocaine-associated cue-induced reinstatement of cocaine-seeking behavior whereas they failed to alter reinstatement of food-taking behavior. The 5-HT(1B) receptor agonist CP 94253 (2.5 or 5 mg/kg) combined with a subthreshold priming dose of cocaine (2.5 mg/kg) potentiated reinstatement of the drug seeking-behavior, but inhibited cocaine seeking induced by a submaximal dose (10 mg/kg) of cocaine or the cocaine-associated cue. Moreover, the 5-HT(1B) receptor agonist attenuated reinstatement of food-taking behavior. Facilitatory effect of CP 94253 on cocaine-seeking behavior and its inhibitory effect on food-taking behavior were blocked by SB 216641, but its inhibitory effect on cocaine-seeking behavior remained unaffected by this 5-HT(1B) receptor antagonist. Our results indicate that tonic activation of 5-HT(1B) receptors is involved in cocaine- and cue-induced reinstatement of cocaine-seeking behavior and that the inhibitory effects of 5-HT(1B) receptor antagonists on these phenomena are directly related to motivational aspects of cocaine abuse. The facilitatory 5-HT(1B) receptor-mediated effect of the 5-HT(1B) receptor agonist on cocaine seeking may be related to the earlier reported enhancement of the rewarding properties of cocaine, while its inhibitory effect on cocaine-seeking behavior, unrelated to the 5-HT(1B) receptor activation, may result from a general reduction of motivation.
大量数据表明大脑多巴胺能通路在可卡因的行为效应中具有重要意义，然而最近的研究也证明血清素（5-HT）神经传递，尤其是5-HT(1B)受体参与了可卡因的强化、辨别刺激和敏感化效应。为了证实这些受体在可卡因的动机激励中的作用，我们使用消退/恢复模型来研究5-HT(1B)受体配体对消退的可卡因觅求行为和进食行为恢复的影响。训练大鼠自我给药可卡因（0.5毫克/千克/注射），随后进行消退程序。然后测试它们对可卡因引发或与可卡因相关线索诱导的消退可卡因觅求行为的恢复情况。其他几组大鼠被训练自我给药食物（甜牛奶），消退后测试它们对因意外给予食物而导致的进食行为恢复情况。5-HT(1B)受体拮抗剂SB 216641（2.5 - 7.5毫克/千克）和GR 127935（2.5 - 10毫克/千克）剂量依赖性地减弱了可卡因（10毫克/千克）和与可卡因相关线索诱导的可卡因觅求行为的恢复，而它们未能改变进食行为的恢复。5-HT(1B)受体激动剂CP 94253（2.5或5毫克/千克）与阈下引发剂量的可卡因（2.5毫克/千克）联合使用增强了药物觅求行为的恢复，但抑制了由次最大剂量（10毫克/千克）可卡因或与可卡因相关线索诱导的可卡因觅求行为。此外，5-HT(1B)受体激动剂减弱了进食行为的恢复。CP 94253对可卡因觅求行为的促进作用及其对进食行为的抑制作用被SB 216641阻断，但其对可卡因觅求行为的抑制作用不受该5-HT(1B)受体拮抗剂的影响。我们的结果表明，5-HT(1B)受体的紧张性激活参与了可卡因和线索诱导的可卡因觅求行为的恢复，并且5-HT(1B)受体拮抗剂对这些现象的抑制作用与可卡因滥用的动机方面直接相关。5-HT(1B)受体激动剂对可卡因觅求行为的促进作用可能与早期报道的可卡因奖赏特性增强有关，而其对可卡因觅求行为的抑制作用，与5-HT(1B)受体激活无关，可能是由于动机的普遍降低所致。
