Bản mẫu:Dược lực học amphetamin

Dược lực học amphetamin trong neuron dopamin

thông qua AADC

Ảnh có văn bản/hình ảnh chứa liên kết tới bài viết khác

Amphetamin đi vào neuron trước synap qua màng tế bào hoặc DAT (chất vận chuyển dopamin).^[1] Khi ở bên trong, amphetamin liên kết với TAAR1 (trace amine-associated receptor 1) hoặc vào túi synap nhờ vào VMAT2 (vesicular monoamine transporter 2).^[1]^[2] Khi amphetamin vào trong túi synap thông qua VMAT2, nó làm vỡ bóng do gradient của pH, làm giải phóng dopamin vào bào tương nhờ có VMAT2.^[2]^[3] Khi amphetamine gắn với TAAR1, nó làm giảm tần số phát điện thế hoạt động của neuron dopamin nhờ vào kênh GIRK (một loại kênh kali), hoạt hóa protein kinase A (PKA) và protein kinase C (PKC). Các protein này phosphoryl hóa DAT.^[1]^[4]^[5] Phân tử DAT đã được PKA phosphoryl hóa chui vào neuron trước synap theo hình thức nhập bào và ngừng vận chuyển.^[1] Phân tử DAT đã được PKC phosphoryl hóa có thể có cơ chế ngược lại hoặc giống với cơ chế phân tử DAT đã được PKA phosphoryl hóa.^[1] Amphetamin làm tăng nồng độ calci nội bào, một hiệu ứng có liên quan đến quá trình phosphoryl hóa DAT thông qua con đường phụ thuộc CAMKIIα, làm dopamin thoát ra ngoài.^[6]^[7]

Tham khảo

^ ^a ^b ^c ^d ^e Miller GM (tháng 1 năm 2011). “The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity”. J. Neurochem. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468.
^ ^a ^b Eiden LE, Weihe E (tháng 1 năm 2011). “VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse”. Ann. N. Y. Acad. Sci. 1216 (1): 86–98. Bibcode:2011NYASA1216...86E. doi:10.1111/j.1749-6632.2010.05906.x. PMC 4183197. PMID 21272013. VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC). ... AMPH release of DA from synapses requires both an action at VMAT2 to release DA to the cytoplasm and a concerted release of DA from the cytoplasm via "reverse transport" through DAT.
^ Sulzer D, Cragg SJ, Rice ME (tháng 8 năm 2016). “Striatal dopamine neurotransmission: regulation of release and uptake”. Basal Ganglia. 6 (3): 123–148. doi:10.1016/j.baga.2016.02.001. PMC 4850498. PMID 27141430. Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle. ... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.
^ Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB (tháng 7 năm 2011). “Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons”. Front. Syst. Neurosci. 5: 56. doi:10.3389/fnsys.2011.00056. PMC 3131148. PMID 21772817. Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.
^ “TAAR1”. GenAtlas. University of Paris. 28 tháng 1 năm 2012. Truy cập ngày 29 tháng 5 năm 2014. • tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)
^ Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (tháng 7 năm 2014). “Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons”. Neuron. 83 (2): 404–416. doi:10.1016/j.neuron.2014.05.043. PMC 4159050. PMID 25033183. AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012). ... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate. ... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH
^ Vaughan RA, Foster JD (tháng 9 năm 2013). “Mechanisms of dopamine transporter regulation in normal and disease states”. Trends Pharmacol. Sci. 34 (9): 489–496. doi:10.1016/j.tips.2013.07.005. PMC 3831354. PMID 23968642. AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].

[Miller-1] Miller GM (tháng 1 năm 2011). “The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity”. J. Neurochem. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468.

[E_Weihe-2] Eiden LE, Weihe E (tháng 1 năm 2011). “VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse”. Ann. N. Y. Acad. Sci. 1216 (1): 86–98. Bibcode:2011NYASA1216...86E. doi:10.1111/j.1749-6632.2010.05906.x. PMC 4183197. PMID 21272013. VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC). ... AMPH release of DA from synapses requires both an action at VMAT2 to release DA to the cytoplasm and a concerted release of DA from the cytoplasm via "reverse transport" through DAT.

[Amphetamine_VMAT2_pH_gradient-3] Sulzer D, Cragg SJ, Rice ME (tháng 8 năm 2016). “Striatal dopamine neurotransmission: regulation of release and uptake”. Basal Ganglia. 6 (3): 123–148. doi:10.1016/j.baga.2016.02.001. PMC 4850498. PMID 27141430. Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle. ... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.

[GIRK-4] Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB (tháng 7 năm 2011). “Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons”. Front. Syst. Neurosci. 5: 56. doi:10.3389/fnsys.2011.00056. PMC 3131148. PMID 21772817. Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.

[Genatlas_TAAR1-5] “TAAR1”. GenAtlas. University of Paris. 28 tháng 1 năm 2012. Truy cập ngày 29 tháng 5 năm 2014. • tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)

[EAAT3-6] Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (tháng 7 năm 2014). “Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons”. Neuron. 83 (2): 404–416. doi:10.1016/j.neuron.2014.05.043. PMC 4159050. PMID 25033183. AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012). ... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate. ... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH

[DAT_regulation_review-7] Vaughan RA, Foster JD (tháng 9 năm 2013). “Mechanisms of dopamine transporter regulation in normal and disease states”. Trends Pharmacol. Sci. 34 (9): 489–496. doi:10.1016/j.tips.2013.07.005. PMC 3831354. PMID 23968642. AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].

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