Fredriksson Ida, Adhikary Sweta, Steensland Pia, Vendruscolo Leandro F, Bonci Antonello, Shaham Yavin, Bossert Jennifer M
Cellular Neurobiology Branch, IRP-NIDA, NIH, Baltimore, MD, USA.
Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm, Sweden.
Neuropsychopharmacology. 2017 Apr;42(5):1001-1011. doi: 10.1038/npp.2016.209. Epub 2016 Sep 21.
The gateway hypothesis posits that initial exposure to legal drugs promotes subsequent addiction to illicit drugs. However, epidemiological studies are correlational and cannot rule out the alternative hypothesis of shared addiction vulnerability to legal and illegal drugs. We tested the gateway hypothesis using established rat alcohol exposure procedures and cocaine self-administration and reinstatement (relapse) procedures. We gave Wistar or alcohol-preferring (P) rats intermittent access to water or 20% alcohol in their homecage for 7 weeks (three 24-h sessions/week). We also exposed Wistar rats to air or intoxicating alcohol levels in vapor chambers for 14-h/day for 7 weeks. We then tested the groups of rats for acquisition of cocaine self-administration using ascending cocaine doses (0.125, 0.25, 0.5, 1.0 mg/kg/infusion) followed by a dose-response curve after acquisition of cocaine self-administration. We then extinguished lever pressing and tested the rats for reinstatement of drug seeking induced by cocaine-paired cues and cocaine priming (0, 2.5, 5, 10 mg/kg, i.p.). Wistar rats consumed moderate amounts of alcohol (4.6 g/kg/24 h), P rats consumed higher amounts of alcohol (7.6 g/kg/24 h), and Wistar rats exposed to alcohol vapor had a mean blood alcohol concentration of 176.2 mg/dl during the last week of alcohol exposure. Alcohol pre-exposure had no effect on cocaine self-administration, extinction responding, and reinstatement of drug seeking. Pre-exposure to moderate, high, or intoxicating levels of alcohol had no effect on cocaine self-administration and relapse to cocaine seeking. Our data do not support the notion that alcohol is a gateway drug to cocaine.
通路假说认为，最初接触合法药物会促使随后对非法药物成瘾。然而，流行病学研究只是相关性的，无法排除对合法和非法药物存在共同成瘾易感性的另一种假说。我们使用既定的大鼠酒精暴露程序以及可卡因自我给药和复吸（复发）程序来检验通路假说。我们让Wistar大鼠或偏爱酒精的（P）大鼠在其饲养笼中间歇性地接触水或20%的酒精，持续7周（每周三个24小时时段）。我们还将Wistar大鼠每天暴露于蒸汽室中的空气或致醉酒精水平下，持续7周，每天14小时。然后，我们使用递增的可卡因剂量（0.125、0.25、0.5、1.0毫克/千克/输注）对大鼠组进行可卡因自我给药的习得测试，在习得可卡因自我给药后再进行剂量反应曲线测试。然后我们停止杠杆按压，并测试大鼠对由可卡因配对线索和可卡因激发（0、2.5、5、10毫克/千克，腹腔注射）诱导的觅药行为的复吸情况。Wistar大鼠摄入适量酒精（4.6克/千克/24小时），P大鼠摄入较高量酒精（7.6克/千克/24小时），并且在酒精暴露的最后一周，暴露于酒精蒸汽的Wistar大鼠平均血液酒精浓度为176.2毫克/分升。酒精预先暴露对可卡因自我给药、消退反应和觅药行为的复吸没有影响。预先暴露于中度、高度或致醉水平的酒精对可卡因自我给药和复吸可卡因觅药行为没有影响。我们的数据不支持酒精是可卡因的通路药物这一观点。
