Cleva Richard M, Watterson Lucas R, Johnson Meagan A, Olive M Foster
Interdisciplinary Graduate Program in Neuroscience, Arizona State University Tempe, AZ, USA.
Front Pharmacol. 2012 Jan 6;2:93. doi: 10.3389/fphar.2011.00093. eCollection 2012.
Pharmacological manipulation of the type 5 metabotropic glutamate (mGlu5) receptor alters various addiction related behaviors such as drug self-administration and the extinction and reinstatement of drug-seeking behavior. However, the effects of pharmacological modulation of mGlu5 receptors on brain reward function have not been widely investigated. We examined the effects of acute administration of positive and negative allosteric modulators (PAMs and NAMs, respectively) on brain reward function by assessing thresholds for intracranial self-stimulation (ICSS). In addition, when acute effects were observed, we examined changes in ICSS thresholds following repeated administration. Male Sprague-Dawley rats were implanted with bipolar electrodes into the medial forebrain bundle and trained to respond for ICSS, followed by assessment of effects of mGlu5 ligands on ICSS thresholds using a discrete trials current-intensity threshold determination procedure. Acute administration of the selective mGlu5 NAMs MTEP (0, 0.3, 1, or 3 mg/kg) and fenobam (0, 3, 10, or 30 mg/kg) dose-dependently increased ICSS thresholds (∼70% at the highest dose tested), suggesting a deficit in brain reward function. Acute administration of the mGlu5 PAMs CDPPB (0, 10, 30, and 60 mg/kg) or ADX47273 (0, 10, 30, and 60 mg/kg) was without effect at any dose tested. When administered once daily for five consecutive days, the development of tolerance to the ability of threshold-elevating doses of MTEP and fenobam to increase ICSS thresholds was observed. We conclude that mGlu5 PAMs and NAMs differentially affect brain reward function, and that tolerance to the ability of mGlu5 NAMs to reduce brain reward function develops with repeated administration. These brain reward deficits should be taken into consideration when interpreting acute effects of mGlu5 NAMs on drug self-administration, and repeated administration of these ligands may be an effective method to reduce these deficits.
对5型代谢型谷氨酸（mGlu5）受体进行药理调控会改变各种与成瘾相关的行为，如药物自我给药以及觅药行为的消退和恢复。然而，mGlu5受体的药理调节对脑奖赏功能的影响尚未得到广泛研究。我们通过评估颅内自我刺激（ICSS）阈值，研究了急性给予正性和负性变构调节剂（分别为PAMs和NAMs）对脑奖赏功能的影响。此外，当观察到急性效应时，我们还研究了重复给药后ICSS阈值的变化。将雄性Sprague-Dawley大鼠双侧电极植入内侧前脑束，并训练其对ICSS做出反应，随后使用离散试验电流强度阈值测定程序评估mGlu5配体对ICSS阈值的影响。急性给予选择性mGlu5 NAMs MTEP（0、0.3、1或3mg/kg）和非诺班（0、3、10或30mg/kg）剂量依赖性地提高了ICSS阈值（在测试的最高剂量下约提高70%），表明脑奖赏功能存在缺陷。急性给予mGlu5 PAMs CDPPB（0、10、30和60mg/kg）或ADX47273（0、10、30和60mg/kg）在任何测试剂量下均无效果。当连续五天每天给药一次时，观察到对阈值升高剂量的MTEP和非诺班提高ICSS阈值的能力产生了耐受性。我们得出结论，mGlu5 PAMs和NAMs对脑奖赏功能有不同影响，并且对mGlu5 NAMs降低脑奖赏功能的能力的耐受性会随着重复给药而产生。在解释mGlu5 NAMs对药物自我给药的急性效应时，应考虑这些脑奖赏缺陷，并且重复给予这些配体可能是减少这些缺陷的有效方法。
