the presynaptic neuron into the synaptic cleft via reverse transport at . Norepinephrine Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine. Based upon neuronal expression, amphetamine is thought to affect norepinephrine analogously to dopamine. In other words, amphetamine induces TAAR1-mediated efflux and reuptake inhibition at phosphorylated , competitive NET reuptake inhibition, and norepinephrine release from . Serotonin Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine. Amphetamine affects serotonin via and, like norepinephrine, is thought to phosphorylate via . Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor. Other neurotransmitters, peptides, hormones, and enzymes Acute amphetamine administration in humans increases endogenous opioid release in several brain structures in the reward system. Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase in the striatum following exposure to amphetamine. This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of EAAT3, a glutamate reuptake transporter, in dopamine neurons. Amphetamine also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through . Acute amphetamine administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating the hypothalamic–pituitary–adrenal axis. In December 2017, the first study assessing the interaction between amphetamine and human carbonic anhydrase enzymes was published; of the eleven carbonic anhydrase enzymes it examined, it found that amphetamine potently activates seven, four of which are highly expressed in the human brain, with low nanomolar through low micromolar activating effects. Based upon preclinical research, cerebral carbonic anhydrase activation has cognition-enhancing effects; but, based upon the clinical use of carbonic anhydrase inhibitors, carbonic anhydrase activation in other tissues may be associated with adverse effects, such as ocular activation exacerbating glaucoma. Pharmacokinetics The oral bioavailability of amphetamine varies with gastrointestinal pH; it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine. Amphetamine is a weak base with a pKa of 9.9; consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium. Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed. Approximately of amphetamine circulating in the bloodstream is bound to plasma proteins. Following absorption, amphetamine readily distributes into