Psychology Department, University of Florida, 114 Psychology Building, 945 Center Drive, Gainesville, FL, 32611-2250, USA.
Center for Addiction Research and Education (CARE), University of Florida, Gainesville, FL, USA.
Psychopharmacology (Berl). 2020 Jan;237(1):115-125. doi: 10.1007/s00213-019-05351-8. Epub 2019 Aug 24.
Cocaine use disorder (CUD) remains difficult to treat with no FDA-approved medications to reduce relapse. Antagonism of metabotropic glutamate receptor 5 (mGlu5) has been demonstrated to decrease cocaine-seeking but may also further compromise cognitive function in long-term cocaine users.
Here we assessed the effect of repeated administration of negative or positive allosteric modulators (NAM or PAM) of mGlu5 on both cognitive performance and (context+cue)-primed cocaine-seeking after prolonged abstinence (≥ 45 days).
Adult male Sprague-Dawley rats underwent 6 days of short-access (1 h/day) and 12 days of long-access (6 h/day) cocaine self-administration. Rats were then trained and tested in a delayed match-to-sample (DMS) task to establish baseline working memory performance over a 5-day block of testing. Next, rats received daily systemic administration of the mGlu5 NAM 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP; 3 mg/kg), the mGlu5 PAM 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB; 30 mg/kg) or vehicle prior to DMS testing during a block of 5 days, followed by a 5-day washout DMS testing block.
MTEP and CDPPB decreased drug-seeking in response to cocaine-associated cues after prolonged abstinence. However, repeated treatment with MTEP impaired working memory, while CDPPB had no effects on performance.
These results emphasize the relevance of evaluating cognitive function within the context of investigating pharmacotherapies to treat CUD. Further research is needed to determine how two mechanistically different pharmacological compounds can exert the same behavioral effects to reduce cocaine-seeking.
目前尚无经美国食品药品监督管理局（FDA）批准的药物可用于减少可卡因使用障碍（CUD）的复发，因此可卡因使用障碍的治疗仍然具有挑战性。已有研究证实，代谢型谷氨酸受体 5（mGlu5）拮抗剂可减少可卡因觅药行为，但也可能进一步损害长期可卡因使用者的认知功能。
本研究评估了重复给予 mGlu5 负变构调节剂（NAM）或正变构调节剂（PAM）对长期戒断（≥45 天）后认知表现和（情境+线索）引发可卡因觅药的影响。
成年雄性 Sprague-Dawley 大鼠接受 6 天的短程（1 小时/天）和 12 天的长程（6 小时/天）可卡因自我给药。然后，大鼠在延迟匹配样本（DMS）任务中接受训练和测试，以在 5 天的测试块中建立基线工作记忆表现。接下来，大鼠在 DMS 测试前每天接受系统给予 mGlu5 NAM 3-((2-甲基-1,3-噻唑-4-基)乙炔基)吡啶盐酸盐（MTEP；3mg/kg）、mGlu5 PAM 3-氰基-N-(1,3-二苯基-1H-吡唑-5-基)苯甲酰胺（CDPPB；30mg/kg）或载体，在 5 天的测试块中进行 DMS 测试，然后进行 5 天的洗脱 DMS 测试块。
MTEP 和 CDPPB 可减少长期戒断后可卡因相关线索引发的觅药行为。然而，重复给予 MTEP 会损害工作记忆，而 CDPPB 对表现没有影响。
这些结果强调了在研究治疗可卡因使用障碍的药物治疗时，在评估认知功能的背景下进行研究的相关性。需要进一步研究以确定两种具有不同机制的药理学化合物如何产生相同的行为效应来减少可卡因觅药。
