But if you took a drug that increased or decreased Ca2+/Na+/K+ what effect would it have on the brain in conjunction with the adderall? e.g: neurotoxicity. i need to understand that question as i must state if neurotoxicity or other different effects occur on an exam question, but a simple short' reply 'increased ca2+ increases neurotoxicity would do'.
Thank You.
IIRC, amphetamine increases intracellular calcium by releasing intracellular calcium stores, not increasing extracellular calcium uptake. Na+ and Ca2+ intake has no effect on amphetamine's pharmacodynamics, however, Mg2+ and especially Zn2+ do modulate amphetamine's effects in dopamine neurons. The effect by zinc on amphetamine's pharmacodynamics is not due to its role as an electrolyte; rather, it's due to its role as an allosteric modulator of the human dopamine transporter, which contains a high affinity zinc binding site.
The
neurotoxicity of amphetamine is primarily mediated through marked elevations in brain temperature (i.e., one must take a dose high enough to induce
hyperpyrexia in order for neurotoxicity to occur; hyperpyrexia is a medical emergency). High concentrations on synaptic dopamine contribute via oxidative stress from dopamine auto-oxidation (aka autoxidation) and increased ROS generation, but it is not the primary mechanism by which amphetamine induces neurotoxicity.
In contrast,
methamphetamine has a multi-modal neurotoxic mechanism which arises through hyperpyrexia, dopamine autoxidation, sigma-1 receptor activation, the inhibition of EAAT2 (NB: EAAT2 is responsible for >90% of glutamate clearance in the brain) which leads to a marked elevation of synaptic glutamate, increased ROS+RNS generation, and possibly other mechanisms. In combination, these effects cause oxidative stress, promote excitotoxicity, trigger a neuroimmune response (i.e., microglial activation), and induce apoptotic signaling cascades in neurons.
FWIW, I wrote and cited both of the sections in the linked Wikipedia pages, so I know they're accurate.