Krivsky Julie A, Stoffel Erin C, Sumner Jean E, Inman Bryce C, Craft Rebecca M
Department of Psychology, Washington State University, Pullman, Washington 99164-4820, USA.
Behav Pharmacol. 2006 May;17(3):259-70. doi: 10.1097/00008877-200605000-00007.
Previous studies have produced mixed results about the role of the ventral tegmental area, periaqueductal gray and parabrachial nucleus in morphine discriminations, perhaps owing to the considerably different methodologies used. The purpose of the present study was to compare the roles of these three brain areas using the same food-reinforced discrimination protocol, to determine whether the schedule of reinforcement influenced maximal substitution produced by site-specific morphine administration and to determine whether the time course of substitution differed by site of morphine administration. Rats were trained to discriminate 3.0 mg/kg subcutaneous morphine from saline under variable interval 15-s or fixed ratio 10 schedules of food reinforcement. Rats were then implanted with one cannula aimed at the lateral ventricle (intracerebroventricular) and one aimed at the ventral tegmental area, periaqueductal gray or parabrachial nucleus. Morphine discrimination curves were obtained by subcutaneous, intracerebroventricular and intrasite routes. When administered subcutaneously, morphine was equipotent in variable interval-trained and fixed ratio-trained rats, although it was more potent in fixed ratio-trained females than fixed ratio-trained males. When administered intracerebroventricularly, morphine (0.3-10 microg) engendered a maximum average of 63% drug-appropriate responding in both variable interval-trained and fixed ratio-trained rats; females showed significantly greater drug-appropriate responding than males, again under the fixed ratio but not under the variable interval schedule. In variable interval-trained rats, intrasite infusions of morphine (0.3-10 microg) produced maximal drug-appropriate responding of approximately 57% (ventral tegmental area), 56% (periaqueductal gray) and 41% (parabrachial nucleus); mean maximal substitution was slightly (< or = 17%) greater in fixed ratio-trained rats. When injected into the ventral tegmental area or periaqueductal gray, but not the parabrachial nucleus, naloxone methiodide (2 microg) significantly decreased drug-appropriate responding following 3.0 mg/kg subcutaneous morphine, in both variable interval-trained and fixed ratio-trained rats. The time course of the discriminative stimulus effects of morphine differed among the three brain sites: intraventral tegmental area morphine produced peak drug-appropriate responding by 15 min after injection, whereas the discriminative stimulus effects of intraperiaqueductal gray and intraparabrachial nucleus morphine peaked at approximately 60 min after injection. Taken together, these results indicate that ventral tegmental area, periaqueductal gray and parabrachial nucleus each play a role in the ability of morphine to function as a discriminative stimulus, regardless of the sex of the subject or the schedule under which the subjects are responding. Ventral tegmental area and periaqueductal gray, however, appear to be more critical than parabrachial nucleus in mediating the discriminative effects of systemic morphine in rats responding under a food reinforcement procedure. The pretreatment time and, to a lesser extent, the schedule of reinforcement are additional variables that should be considered when comparing the relative roles of different brain areas in drug discrimination.
以往的研究对于腹侧被盖区、导水管周围灰质和臂旁核在吗啡辨别中的作用得出了不一致的结果，这可能是由于所使用的方法有很大差异。本研究的目的是使用相同的食物强化辨别方案来比较这三个脑区的作用，确定强化程序是否会影响特定部位注射吗啡所产生的最大替代反应，并确定替代反应的时间进程是否因吗啡注射部位而异。大鼠在可变间隔15秒或固定比率10的食物强化程序下接受训练，以区分皮下注射3.0mg/kg吗啡和生理盐水。然后给大鼠植入一根指向侧脑室（脑室内）的套管和一根指向腹侧被盖区、导水管周围灰质或臂旁核的套管。通过皮下、脑室内和部位内途径获得吗啡辨别曲线。皮下注射时，吗啡在可变间隔训练和固定比率训练的大鼠中效力相当，尽管在固定比率训练的雌性大鼠中比固定比率训练的雄性大鼠效力更强。脑室内注射时，吗啡（0.3 - 10微克）在可变间隔训练和固定比率训练的大鼠中平均产生的最大药物相关反应均为63%；在固定比率程序下，雌性大鼠的药物相关反应明显大于雄性大鼠，而在可变间隔程序下则不然。在可变间隔训练的大鼠中，部位内注射吗啡（0.3 - 10微克）产生的最大药物相关反应约为57%（腹侧被盖区）、56%（导水管周围灰质）和41%（臂旁核）；在固定比率训练的大鼠中，平均最大替代反应略高（≤17%）。当注射到腹侧被盖区或导水管周围灰质而非臂旁核时，甲硫氨酸纳洛酮（2微克）在可变间隔训练和固定比率训练的大鼠中，均能显著降低皮下注射3.0mg/kg吗啡后的药物相关反应。吗啡辨别刺激效应的时间进程在三个脑区有所不同：腹侧被盖区内注射吗啡后15分钟产生最大药物相关反应峰值，而导水管周围灰质和臂旁核内注射吗啡的辨别刺激效应在注射后约60分钟达到峰值。综上所述，这些结果表明，无论实验对象的性别或反应程序如何，腹侧被盖区、导水管周围灰质和臂旁核在吗啡作为辨别刺激发挥作用的能力中均发挥作用。然而，在介导食物强化程序下反应的大鼠中，系统注射吗啡的辨别效应时，腹侧被盖区和导水管周围灰质似乎比臂旁核更为关键。预处理时间以及在较小程度上强化程序是在比较不同脑区在药物辨别中的相对作用时应考虑的额外变量。
