<unk>  inhibitors tend to fall into two classes; those that interact with the RES binding site and those that interact with the TBZ binding site. RES, methoxytetrabenazine, and amiodarone bind to the RES binding site. TBZ, DTBZOH, ketanserin, and lobeline bind to the TBZ binding site. Substituted amphetamines, including but not limited to methamphetamine and cocaine, are known to interact with<unk> 2. Studies indicate that both amphetamines and cocaine act to increase non-exocytotic release of dopamine in specific regions of the brain by interacting directly with<unk> 2 function. Methamphetamine<unk>  is a main target of methamphetamine. Studies indicate that substituted amphetamines including methamphetamine interact with<unk> 2 at the TBZ/DTBZOH binding site. By acting as a competitive antagonist, methamphetamine blocks the presynaptic cell's ability to use<unk>  for<unk>  packaging. Methamphetamine alters the subcellular location of<unk> 2, which affects the distribution of dopamine in the cell. Treatment with methamphetamine relocates<unk> 2 from a vesicle-enriched fraction to a location that is not continuous with synaptosomal preparations. Repeated amphetamine exposure may increase<unk> 2 mRNA in certain brain regions with little or no decline upon withdrawal from the drug. A study performed by Sonsalla et al. demonstrated that methamphetamine treatment decreases DHTBZ binding and<unk>  dopamine uptake. Another study demonstrated that multiple high doses of methamphetamine removed DTBZ binding sites from the vesicles. In addition to an interaction with the TBZ/DTBZOH binding site, some researchers propose that substituted amphetamines like methamphetamine decrease dopamine uptake because of the weak base properties of substituted amphetamines. This “Weak Base Hypothesis” proposes that amphetamine analogs enter the cell through transport and lipophilic diffusion, then diffuses through the<unk>  membrane where they accumulate in synaptic vesicles and offset the proton electrochemical gradient in the vesicle that drives<unk>  transport through<unk> . Amphetamine administration would prevent<unk>  dopamine uptake through<unk> , and explain the finding that amphetamine administration correlates with decreased dopamine release from vesicles and a neurotoxic increase in intracellular dopamine. Cocaine Unlike methamphetamine, cocaine interacts with<unk> 2 by mobilizing<unk> 2-expressing vesicles, causing a shift in<unk> 2 proteins from a plasmalemmal (synaptosomal) membrane fraction to a vesicle-enriched fraction that is not associated with the synaptosomal membrane and not retained in synaptosomal preparations. Methylphenidate is believed to interact with<unk> 2 in a similar fashion. In addition to mobilizing<unk> 2-expressing vesicles, cocaine has been shown to increase the Vmax of<unk> 2 for dopamine and increase the number of DTBZ binding sites. It has also mobilized a synapsin-dependent reserve pool of dopamine-containing synaptic vesicles, which interacts with the<unk>  trafficking cycle to increase dopamine release. Short-term exposure to cocaine increases<unk> 2 density in the prefrontal cortex and striatum of mammalian brains. This is theorized to be a defensive mechanism against the depletive effects cocaine has on cytosolic dopamine through increasing<unk>  storage capacity. Chronic cocaine use has been implicated with a reduction in<unk> 2 immunoreactivity as well as a decrease in DTBZOH binding in humans. Research suggests a decline in<unk> 2 protein through prolonged cocaine use could play an important role in the development of cocaine-induced mood disorders. MDMA MDMA is known to affect serotonergic neurons, but has been shown to inhibit synaptosomal and<unk>  uptake of serotonin and dopamine to roughly the same extent in vitro. In vivo studies indicate short-term MDMA exposure causes short-term reduction in<unk> 2 activity, which is reversed after 24 hours.
Vesicular monoamine transporter
Glutamate transporter
Neurotransmitter transporter
Norepinephrine transporter
Mechanosensitive channels
Thiamine transporter 1
Acetylcholinesterase
Cyclic nucleotide–gated ion channel