Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
Biochem Biophys Res Commun. 2010 Jan 1;391(1):773-7. doi: 10.1016/j.bbrc.2009.11.136. Epub 2009 Nov 26.
Pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient mice display remarkable behavioral changes including increased novelty-seeking behavior and reduced hypothermia induced by either serotonin (5-HT)(1A) receptor agonists or ethanol. Because 5-HT(1A) receptors have been implicated in the development of alcohol dependence, we have examined ethanol preference in PACAP-deficient mice using a two-bottle choice and a conditioned place preference test, as well as additive effects of ethanol and 5-HT(1A) receptor agents on hypothermia. PACAP-deficient mice showed an increased preference towards ethanol compared with wild-type mice. However, they showed no preference for the ethanol compartment after conditioning and neither preference nor aversion to sucrose or quinine. The 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) restored the attenuated hypothermic response to ethanol in the mutants to similar levels in wild-type mice, with no effect in wild-types. In contrast, the 5-HT(1A) receptor antagonist WAY-100635 attenuated the ethanol-induced hypothermia in wild-type mice, with no effect in the mutants. These results demonstrate increased ethanol preference in PACAP-deficient mice that may be mediated by 5-HT(1A) receptor-dependent attenuation of ethanol-induced central inhibition.
垂体腺苷酸环化酶激活肽（PACAP）缺陷型小鼠表现出显著的行为变化，包括增加新奇寻求行为和减少 5-羟色胺（5-HT）（1A）受体激动剂或乙醇诱导的体温降低。因为 5-HT（1A）受体被认为与酒精依赖的发展有关，所以我们使用双瓶选择和条件性位置偏好测试检查了 PACAP 缺陷型小鼠对乙醇的偏好，以及乙醇和 5-HT（1A）受体药物对体温降低的附加作用。PACAP 缺陷型小鼠与野生型小鼠相比，对乙醇的偏好增加。然而，它们在条件作用后对乙醇隔室没有偏好，也没有对蔗糖或奎宁的偏好或厌恶。5-HT（1A）受体激动剂 8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）使突变体中对乙醇的减弱的体温降低反应恢复到与野生型小鼠相似的水平，而对野生型小鼠没有影响。相反，5-HT（1A）受体拮抗剂 WAY-100635 减弱了野生型小鼠中乙醇引起的体温降低，而对突变体没有影响。这些结果表明，PACAP 缺陷型小鼠对乙醇的偏好增加，这可能是通过 5-HT（1A）受体依赖性减弱乙醇引起的中枢抑制来介导的。
