NMDA受體調節劑對大鼠K他命自我給藥之影響

Abstract

K他命濫用為全球面臨之公衛議題，K他命可能經由阻斷N-甲基-D-天門冬胺酸受體(N-methyl-D-aspartate receptor, NMDA receptor)導致成癮。本研究欲釐清調節NMDA受體功能的藥物是否能降低獲取K他命的動機及尋求K他命的再犯反應，測試藥物包括肌胺酸，D-絲胺酸，和L-4-fluorophenylglycine (L-4FPG)；其中肌胺酸是甘胺酸轉運蛋白1抑制劑並且作用於 NMDA受體甘胺酸結合位點，D-絲胺酸為NMDA受體甘胺酸結合位點之內生性共同致效劑，L-4FPG是中性胺基酸轉運蛋白alanine-seine-cysteine transporter(ASCT)抑制劑，藉由抑制D-絲胺酸再回收以提高突觸間隙D-絲胺酸的濃度，因此三種測試藥物均可以調節NMDA受體的功能。本研究首先利用大鼠自我給藥系統訓練Sprague-Dawley公鼠按壓壓桿以獲得靜脈K他命輸注(0.5 mg/kg/infusion)，當訓練穩定後進行以下實驗：(1)在累進比率時程下，測試分別給予肌胺酸(30及100 mg/kg)、D-絲胺酸(30及100 mg/kg)或L-4FPG (0.3及1 mg/kg)對於K他命靜脈內自我給藥大鼠之劑量依賴反應。(2)測試在線索(cue)或K他命誘發的再犯試驗前，急性給予肌胺酸(30及100 mg/kg)、D-絲胺酸(30及100 mg/kg)或L-4FPG (1及3 mg/kg)之劑量依賴反應。(3)測試在消除階段給予肌胺酸(100 mg/kg)、D-絲胺酸(100 mg/kg)或L-4FPG (3 mg/kg)是否可以促進消去形成，並利用線索或K他命誘發的再犯試驗來測試藥物效果。結果顯示，於累進比率時程下急性前給予肌胺酸(100 mg/kg)、D-絲胺酸(100 mg/kg)或L-4FPG(1 mg/kg)皆會降低大鼠按壓壓桿的次數(lever presses)、斷點數值(breakpoint)以及所獲得的藥物輸注次數(number of infusions)，與此相同的抑制效果也存在於線索及K他命誘導再犯試驗中，不過，於誘導再犯試驗中，L-4FPG的用量須提高至3 mg/kg才有顯著差異；此外，於消除階段給予此三種藥物，只能防止線索誘發再犯反應但是不能促進消除。此三種藥物均不影響壓桿取得食物粒的實驗以及運動活性。本研究結果顯示，肌胺酸、D-絲胺酸及L-4FPG可能具有防止K他命成癮的渴藥及復發的潛力，並為未來臨床研究奠立基礎。

Ketamine abuse is a worldwide public health problem. Ketamine may cause addiction through blocking the phencyclidine (PCP) binding site of N-methyl-D-aspartate (NMDA) receptors. The present study examined whether the drugs with NMDA receptors-modulation ability could attenuate the motivation and reinstatement of ketamine-seeking behavior. Sarcosine is a glycine transporter 1 inhibitor and works on the glycine binding site of NMDA receptor. D-serine is an endogenous NMDA receptor co-agonist at the glycine binding site. L-4-fluorophenylglycine (L-4FPG) is a neutral amino acid transporter ASCT (Alanine/Serine/Cysteine-preferring Transporter) inhibitor by blocking the reuptake of D-serine in the synaptic cleft. In the present study, male Sprague-Dawley rats were trained to press an active lever for self-administration (SA) of intravenous ketamine (0.5 mg/kg/infusion), and then subjected to the following three experiments. Experiment 1 is to assess the dose-dependent effects of acute treatment of sarcosine (30 and 100 mg/kg), D-serine (30 and 100 mg/kg), and L-4FPG (0.3and 1 mg/kg) on the self-administration motivation which is determined by the breakpoint according to during the progressive ratio (PR) schedule. Experiment 2 is to evaluate the acute effects of sarcosine (30 and 100 mg/kg), D-serine (30 and 100 mg/kg), and L-4FPG (1 and 3 mg/kg) on the cue-induced and ketamine priming-induced reinstatement of ketamine seeking behaviors. Experiment 3 is to examine the repeated administration of sarcosine (100 mg/kg), D-serine (100 mg/kg), and L-4FPG (3 mg/kg) during extinction on the cue-induced and ketamine priming-induced reinstatement of ketamine seeking behaviors. Our data demonstrated that sarcosine (100 mg/kg), D-serine (100 mg/kg) and L-4FPG (1 mg/kg) significantly decreased the lever presses, breakpoint and number of infusions for ketamine and attenuated the cue-induced and ketamine priming-induced ketamine seeking behavior; however, the dose of L-4FPG must be increased to 3 mg/kg to show significant difference on reinstatement. Additionally, administration of these three compounds during extinction only prevented cue-induced reinstatement of ketamine-seeking behavior but did not facilitate the extinction. These three drugs had no effect on food self-administration and locomotor activity in the present study. Our findings suggest that sarcosine, D-serine, and L-4FPG have the anti-craving and anti-relapse potential for treatment of ketamine addiction, laying the groundwork for future clinical research.