Ramôa Carolina P, Doyle Susan E, Lycas Matthew D, Chernau Andrea K, Lynch Wendy J
Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA 22911.
Biol Psychiatry. 2014 Jul 1;76(1):8-14. doi: 10.1016/j.biopsych.2013.09.028. Epub 2013 Oct 4.
Although considerable evidence implicates dopamine D1-receptor signaling in the nucleus accumbens in motivation for cocaine during early stages of addiction, less is known with regard to its role after the development of addiction. Here, we examined its role in the development of an addicted phenotype in intact male and female rats, and in female rats that were either resistant or vulnerable to developing this phenotype.
Intact males, females, and ovariectomized (OVX) females with and without estradiol (vulnerable, OVX+E; resistant, OVX+Veh) were given either short access (ShA) (three fixed-ratio 1 sessions, maximum of 20 infusions) or 24-hour extended access (ExA) to cocaine for 10 days (4 trials/hour). Motivation for cocaine was assessed after a 14-day abstinence period with a progressive-ratio schedule. Once responding stabilized, the effects of intra-accumbens infusion of the D1-receptor antagonist, SCH-23390 (0, .3, 1.0, 3.0 µg), were examined.
Motivation for cocaine was markedly higher after abstinence from ExA versus ShA self-administration in intact males and females, indicating the development of an addicted phenotype in these groups. Motivation for cocaine was also higher than ShA control subjects in OVX+E but not OVX+Veh females after ExA self-administration, confirming the categorization of these groups as vulnerable versus resistant. After ExA self-administration, intact males and females and OVX+E but not OVX+Veh females were less sensitive to the effects of D1-receptor antagonism as compared with their ShA counterparts.
These results suggest that the role of D1-receptor signaling, although critical in "nonaddicted" stages, becomes diminished once addiction has developed.
尽管有大量证据表明伏隔核中的多巴胺D1受体信号传导在成瘾早期对可卡因的动机形成中起作用，但关于其在成瘾发展后的作用知之甚少。在此，我们研究了其在完整雄性和雌性大鼠以及对成瘾表型有抵抗力或易感性的雌性大鼠成瘾表型发展中的作用。
对完整雄性、雌性以及去卵巢（OVX）且有或无雌二醇的雌性大鼠（易感性，OVX+E；抗性，OVX+Veh）给予短期接触（ShA）（三个固定比率1疗程，最多20次输注）或24小时延长接触（ExA）可卡因，持续10天（每小时4次试验）。在14天的禁欲期后，采用累进比率程序评估对可卡因的动机。一旦反应稳定，检查伏隔核内注射D1受体拮抗剂SCH-23390（0、0.3、1.0、3.0μg）的效果。
在完整雄性和雌性大鼠中，与ShA自我给药相比，ExA自我给药后禁欲期对可卡因的动机明显更高，表明这些组中出现了成瘾表型。ExA自我给药后，OVX+E雌性大鼠对可卡因的动机也高于ShA对照组，但OVX+Veh雌性大鼠则不然，这证实了将这些组分类为易感性与抗性。ExA自我给药后，与ShA组相比，完整雄性和雌性大鼠以及OVX+E雌性大鼠对D1受体拮抗作用的敏感性降低，但OVX+Veh雌性大鼠则不然。
这些结果表明，D1受体信号传导的作用虽然在“未成瘾”阶段至关重要，但一旦成瘾发展，其作用就会减弱。
