Amfetamin FAQ - Vanliga frågor och svar

Amphetamine exerts its behavioral effects by altering the use of monoamines as neuronal signals in the brain, primarily in catecholamine neurons in the reward and executive function pathways of the brain.[37][59] The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by amphetamine due to its effects on monoamine transporters.[37][59][149] The reinforcing and motivational salience-promoting effects of amphetamine are mostly due to enhanced dopaminergic activity in the mesolimbic pathway.[26] The euphoric and locomotor-stimulating effects of amphetamine are dependent upon the magnitude and speed by which it increases synaptic dopamine and norepinephrine concentrations in the striatum.[3]

Amphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines.[37][155] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits monoamine transporter function.[37][156] Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.[37][38] Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors.[37][38] Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 co-localization in the associated monoamine neurons.[37] As of 2010, co-localization of TAAR1 and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.[37]

In addition to the neuronal monoamine transporters, amphetamine also inhibits both vesicular monoamine transporters, VMAT1 and VMAT2, as well as SLC1A1, SLC22A3, and SLC22A5.[sources 13] SLC1A1 is excitatory amino acid transporter 3 (EAAT3), a glutamate transporter located in neurons, SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter.[sources 13] Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression,[10][162] a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro.[10][163][164] The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Gi/Go-coupled GPCR.[164][165] Amphetamine also inhibits monoamine oxidases at very high doses, resulting in less monoamine and trace amine metabolism and consequently higher concentrations of synaptic monoamines.[18][166] In humans, the only post-synaptic receptor at which amphetamine is known to bind is the 5-HT1A receptor, where it acts as an agonist with micromolar affinity.[167][168]

The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or neurotransmission of dopamine,[37] serotonin,[37] norepinephrine,[37] epinephrine,[149] histamine,[149] CART peptides,[10][162] endogenous opioids,[169][170][171] adrenocorticotropic hormone,[172][173] corticosteroids,[172][173] and glutamate,[153][158] which it effects through interactions with CART, 5-HT1A, EAAT3, TAAR1, VMAT1, VMAT2, and possibly other biological targets.[sources 14]

Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[174] Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.[40][174]

Dopamine
In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft.[37] Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly.[37] As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.[37] Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation.[37] Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces the reversal of dopamine transport through DAT (i.e., dopamine efflux).[37][175] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through an unidentified Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent pathway, in turn producing dopamine efflux.[155][153][154] Through direct activation of G protein-coupled inwardly-rectifying potassium channels, TAAR1 reduces the firing rate of dopamine neurons, preventing a hyper-dopaminergic state.[151][152][176]

Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.[149][150] Following amphetamine uptake at VMAT2, amphetamine induces the collapse of the vesicular pH gradient, which results in the release of dopamine molecules from synaptic vesicles into the cytosol via dopamine efflux through VMAT2.[149][150] Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at DAT.[37][149][150]

Norepinephrine
Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine.[46][59] Based upon neuronal TAAR1 mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine.[37][149][175] In other words, amphetamine induces TAAR1-mediated efflux and non-competitive reuptake inhibition at phosphorylated NET, competitive NET reuptake inhibition, and norepinephrine release from VMAT2.[37][149]

Serotonin
Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.[37][59] Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1.[37][149] Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor.[167][168]

Other neurotransmitters, peptides, and hormones
Acute amphetamine administration in humans increases endogenous opioid release in several brain structures in the reward system.[169][170][171] Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase in the striatum following exposure to amphetamine.[153] This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of EAAT3, a glutamate reuptake transporter, in dopamine neurons.[153][158] Amphetamine also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through VMAT2.[149] Acute amphetamine administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating the hypothalamic–pituitary–adrenal axis.[35][172][173]

Pharmacokinetics
The oral bioavailability of amphetamine varies with gastrointestinal pH;[144] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[9] Amphetamine is a weak base with a pKa of 9.9;[4] 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.[4][144] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[4] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[10] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.[16]

The half-life of amphetamine enantiomers differ and vary with urine pH.[4] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[4] Highly acidic urine will reduce the enantiomer half-lives to 7 hours;[16] highly alkaline urine will increase the half-lives up to 34 hours.[16] The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively.[4] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[4] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[4] When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively.[4] Following oral administration, amphetamine appears in urine within 3 hours.[16] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.[16