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Synaptic vesicular amine transporter Alpha-1A adrenergic receptor Alpha-2A adrenergic receptor Trace amine- associated receptor 1 Sodium- dependent noradrenaline transporter Amine oxidase [flavin- containing] A Sodium- dependent noradrenaline transporter Beta-1 adrenergic receptor Trace amine- associated receptor 1 Sodium- dependent noradrenaline transporter Synaptic vesicular amine transporter Sodium- dependent noradrenaline transporter Tyrosine 3-monooxygenase Aromatic-L- amino-acid decarboxylase Dopamine beta- hydroxylase Methamphetamine Norepinephrine Methamphetamine Methamphetamine Methamphetamine Methamphetamine Norepinephrine Norepinephrine Norepinephrine Methamphetamine Methamphetamine L-Tyrosine Sapropterin O2 L-Dopa Dihydrobiopterin H2O Dopamine CO2 Ascorbic acid O2 Dehydroascorbic acid H2O H2O O2 3,4- Dihydroxymandelaldehyde NH3 H2O2 FAD Fe2+ Pyridoxal 5'-phosphate Norepinephrine Alpha 1A Adrenergic Blood Vessel Relaxation Pathway Epinephrine B2-Adrenergic Bronchodilation Pathway Gs Signalling cascade Gq Signalling Cascade Gi Signalling Cascade Pyrroloquinoline quinone Copper Internalization Norepinephrine is mainly produced in the locus coeruleus and then stored in presynaptic vesicles In high doses methamphetamine inhibits Amine oxidase, preventing the metabolic degredation of norepinephrine, and therefore increasing the concentration of norepinephrine in the cytosol. Methamphetamine activates Trace amine-associated receptors which causes internalization of noradrenaline reuptake transporters. This prevents the reuptake of norepinephrine from the synapse. Norepinephrine accumulates in the synapse from the reversal and inhibition of noreadrenaline transporters. Methamphetamine is an agonist for Alpha 2A, 2B, and 2C adrenergic receptors, further activating them. Methamphetamine triggers the sympathetic response in the rest of the body. Increased Heart Rate Increased Breathing Rate Increased blood pressure caused by vasoconstriction Decreased appetite and digestion. Norepinephrine Presynaptic Neuron Cytosol Postsynaptic Neuron Methamphetamine enters the nerve terminal via the norepinephrine reuptake transporter or by diffusing through the membrane Methamphetamine inhibits sodium-dependent noradrenaline transporter by being a negative modulator. This prevents the reuptake of norepinephrine into the neuron from the synapse. Methamphetamine enters the synaptic vesicles through VMAT2 and inhibits VMAT2 and displaces the norepinephrine in the vesicles causing norepinephrine to spew out into the cytosol Reversal of transport Synaptic Vesicle Memory Attention The high concentration of Norepinephrine in the synapse highly activates post-synaptic adrenergic receptors which, in the brain, are responsible for memory retieval and formation as well as focusing attention The function of Trace amine-associated receptors with norepinephrine has only been observed in mRNA expression. Diffusion
SLC18A2 ADRA1A ADRA2A TAAR1 SLC6A2 MAOA SLC6A2 ADRB1 TAAR1 SLC6A2 SLC18A2 SLC6A2 TH DDC DBH Methamphetamine Norepinephrine Methamphetamine Methamphetamine Methamphetamine Methamphetamine Norepinephrine Norepinephrine Norepinephrine Methamphetamine Methamphetamine L-Tyrosine Sapropterin Oxygen L-Dopa Dihydrobiopterin Water Dopamine Carbon dioxide Ascorbic acid Oxygen Dehydroascorbic acid Water Water Oxygen 3,4- Dihydroxymandelaldehyde Ammonia Hydrogen peroxide Norepinephrine Alpha 1A Adrenergic Blood Vessel Relaxation Pathway Epinephrine B2-Adrenergic Bronchodilation Pathway Gs Signalling cascade Gq Signalling Cascade Gi Signalling Cascade