近年來由於勁歌舞廳文化及家庭私人狂歡派對更助長了多重藥物濫用的情況。依序合併使用K它命 (ketamine)和甲基安非他命(methamphetamine)是其中一種多重藥物濫用特殊的組合。K它命是一種 N-甲基天門冬胺酸鹽受器之拮抗劑。研究指出K它命會造成立即的神經細胞計劃性死亡，和隨後的神經元受損。甲基安非他命則會造成多處(特別是紋狀體位置)多巴胺神經末梢的損傷。我在實驗中發現連續給予K它命(50 mg/kg x7)加上甲基安非他命(10 mg/kg x3)注射，會各自造成中樞麩胺酸或多巴胺神經受損。連續的K它命注射不會改變立即的體溫變化，也不影響十二小時後甲基安非他命造成的體溫升高現象。但是我發現在甲基安非他命之前給予高劑量的K它命注射，可以增強甲基安非他命造成多巴胺神經末梢的損傷, 如造成多巴胺和它的代謝物二羥基苯丙胺酸濃度下降, 多巴胺運轉子密度減少和表現較差的平衡感。相反的，K它命並不影響甲基安非他命引起的血清素神經元末梢的毒性。另一方面後處理的甲基安非他命會加強K它命對於麩胺酸神經的傷害，因為海馬回位置之麩胺酸神經內液泡表面麩胺酸運轉子數量在兩種藥物依序高劑量處理後減少為最劇，水迷宮記憶表現也為最差。我進ㄧ步證明在顱內注射谷氨酸受體拮抗劑 (CNQX)可以阻斷K它命增強甲基安非他命對於多巴胺神經的傷害。然而多巴胺D1受體拮抗劑 (SCH23390)可以廢止甲基安非他命增強K它命造成的麩胺酸神經的傷害。因此我認為K它命可以透過活化谷氨酸受體去增強甲基安非他命對於多巴胺神經的傷害，甲基安非他命則是透過活化多巴胺D1受體增強K它命對於麩胺酸神經的傷害。

A survey revealed that club-going young adults were predictive of conjunctive ketamine and methamphetamine (MA) use. Ketamine, an NMDA receptor antagonist was reported to trigger acute neuronal apoptotic death and produces late-onset excitotoxic neurodegeneration. Methamphetamine has been known to produce dopaminergic terminal degenerations in striatum. Cumulative doses of ketamine (50 mg/kg x 7) and MA (10 mg/kg x 3) specifically produced central glutamatergic and dopaminergic neuron deficits, respectively. Acute ketamine injection did not affect basal body temperature or MA-induced hyperthermia. Binge doses of ketamine pretreatment aggravated MA-induced dopaminergic terminal loss, as evidenced by drastic decreases in dopamine, 3,4-dihydroxyphenylacetic acid content levels, dopamine transporter density and poor gait balance performance. In contrast, MA-induced serotonergic depletion was not altered by such ketamine pretreatment. Methamphetamine treatment exacerbated ketamine-induced glutamatergic neuronal damages, as indicated by vesicular glutamate transporter loss in hippocampus and poor memory performance in Morris water maze. We further demonstrated that intraventricular CNQX (AMPA receptor antagonist) infusion abolished ketamine’s potentiation of MA-induced dopamine neurotoxicity, while SCH23390 (D1 receptor antagonist) treatment mitigated MA potentiation of ketamine-induced glutamatergic toxicity. We conclude that binge doses of ketamine potentiate MA-induced dopamine neurotoxicity via AMPA/kainite activation. Conjunctive use of MA aggravates ketamine-induced glutamatergic neurotoxicity via D1 receptor activation.

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