Monoamine releasing agent
[5] A variety of different classes of drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters.
[13][14] Less selective SRAs that also stimulate the release of dopamine, such as methylenedioxymethamphetamine (MDMA), are described as more pleasant, more reliably elevating mood and increasing energy and sociability.
[16] DRAs, usually non-selective for both norepinephrine and dopamine, have psychostimulant effects, causing an increase in energy, motivation, elevated mood, and euphoria.
[18] They are used in the treatment of attention deficit hyperactivity disorder (ADHD), as appetite suppressants, wakefulness-promoting agents, to improve motivation, and are drugs of recreational use and misuse.
MRAs induce the release of the monoamine neurotransmitters serotonin, norepinephrine, and/or dopamine from monoaminergic neurons in the brain and/or periphery.
[23][24] Once in the intracellular space of the neuron, MRAs reverse the direction of the MATs, as well as of the organic cation transporter 3 (OCT3),[23][26] such that they mediate efflux of cytosolic monoamine neurotransmitters into the extracellular synaptic cleft rather than the usual reuptake.
[24][23][36][37][38] Activation of protein kinases including PKC, CaMKIIα, and others results in phosphorylation of the MATs causing them to mediate efflux instead of reuptake.
[23][24][36][34][37] A more recent study suggests that intracellular Ca2+ elevation, PKC activation, and CaMKIIα might all be dispensable for MRA-induced monoamine release, but more research is needed.
[41] The TAAR1 is a largely intracellular receptor expressed both in presynaptic and postsynaptic monoaminergic neurons and appears to be extensively co-localized with MATs in the brain.
[44][45][46][47][48][49] In addition, MRAs can still induce monoamine efflux in the absence of TAAR1 in vitro,[50][51][42] well-known MRAs like amphetamine and methamphetamine exhibit only low-potency human TAAR1 agonism[52][53][35] that is of uncertain general significance in humans,[26][54][55][56][57] many other MRAs are inactive as TAAR1 agonists in humans,[52][53][25][26][note 2] the monoamine release and behavioral effects of amphetamines are not only preserved but substantially augmented in TAAR1 knockout mice,[44][42] and the monoamine release and behavioral effects of amphetamines are strongly reduced or abolished in mice with TAAR1 overexpression.
[61][62] TAAR1 signaling also activates G protein-coupled inwardly rectifying potassium channels (GIRKs) and thereby robustly inhibits the firing rates of brain monoaminergic neurons and suppresses exocytotic monoamine release.
[63][42][46] Due to the preceding mechanisms, potent TAAR1 agonism by MRAs that possess this action may actually auto-inhibit and constrain their monoaminergic effects.
[56][26][64][49] Although induction of MAT reverse transport and consequent monoamine efflux is the leading theory of how MRAs act, an alternative and more recent theory has proposed that amphetamine, at therapeutic doses, may not actually act by inducing DAT reverse transport and dopamine efflux, but instead by augmenting exocytotic dopamine release and hence by enhancing phasic rather than tonic dopaminergic signaling.
[3][5][35] In contrast, MRAs do not depend on action potentials to induce monoamine release, and thus are able to largely bypass the negative feedback mediated by autoreceptors.
[7][76][77][78] Under this model, typical cocaine-like DRIs have been referred to with the new label of dopamine transporter (DAT) "inverse agonists" to distinguish them from conventional substrate-type DRAs.
[81][82] MAEs without concomitant potent monoamine-releasing actions, like selegiline (L-deprenyl), phenylpropylaminopentane (PPAP), and benzofuranylpropylaminopentane (BPAP), have been developed.
[5] On the other hand, many MRAs but not all also act as VMAT2 inhibitors and reversers, and hence concomitantly induce the release of vesicular monoamine neurotransmitters like dopamine into the cytoplasm.
[103][97][99] In contrast to amphetamines, monoamine reuptake inhibitors like methylphenidate lack apparent neurotoxic effects.
[96] For instance, the selective MAO-B inhibitor selegiline has been found to prevent the serotonergic neurotoxicity of MDMA in rodents.
[5] The activities of many MRAs in terms of their potencies, efficacies, and selectivities for monoamine release induction in vitro have been characterized in numerous studies in the scientific literature.
[2][71][3][5][144] These studies have been especially conducted by the research lab led by Richard B. Rothman and Michael H. Baumann at the National Institute on Drug Abuse (NIDA).
[2][71][3][144] These researchers developed an assay measuring monoamine release from rat brain synaptosomes in 1999 that has subsequently been widely employed.
[51][58][28][148][106] However, MRAs show differing and much lower potencies in this system compared to rat brain synaptosomes, and it is much less frequently employed.
