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diphenhydramine sensitization of dextroamphetamine via H and M4 receptors?

D

d1nach

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Oct 12, 2016
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Hello, I seem to find when I take 5 25 mg diphenhydramine with 55 mg of amphetamine xr (dph 75 mg + 50 mg 4 hours later. Amph 30 +25 mg 4 Hours Later) seems to increase the effects when the amphetamine kicks in even if most of the dph is gone.



I read that antagonism of the muscarinic acetylcholinergic receptor (mACh) M4 increases dopamine activity in the striatium

And

Blockade of histamine receptors incrwases amphetamine conditioned placepreference

And

Sodium channel blockade can cause a supersensitivity Of The D 2 receptor

And

Muscarinic antagonissm directly stimulates activity in the nucleus accumbens .

I was wondefing what you guys thought or if anyone had some papers on this area .
 
"During sensorimotor learning, the arrival of a conditioned stimulus reporting a reward evokes a pause response in the firing of the tonically active cholinergic interneurons in targeted areas of the striatum, whereas the same stimulus triggers an increase in the firing frequency of the dopaminergic neurons in the substantia nigra pars compacta. The pause response of the cholinergic interneurons begins with an initial depolarizing phase followed by a pause in spike firing and ensuing rebound excitation. The timing of the pause phase coincides well with the surge in dopaminergic firing, indicating that a dramatic rise in dopamine (DA) release occurs while nicotinic receptors remain unbound by acetylcholine. The pause response begins with dopamine D5 receptor-dependent synaptic plasticity in the cholinergic neurons and an increased GABAergic IPSP, which is followed by a long pause in firing through D2 and D5 receptor-dependent modulation of ion channels. Inactivation of muscarinic receptors on the projection neurons eventually yields endocannabinoid-mediated, dopamine-dependent long-term depression in the medium spiny projection neurons. Breakdown of acetylcholine-dopamine balance hampers proper functioning of the cortico-basal ganglia-thalamocortical loop circuits. In Parkinson's disease, dopamine depletion blocks autoinhibition of acetylcholine release through muscarinic autoreceptors, leading to excessive acetylcholine release which eventually prunes spines of the indirect-pathway projection neurons of the striatum and thus interrupts information transfer from motor command centers in the cerebral cortex." (Geriatr Gerontol Int. 2010 Jul;10 Suppl 1:S148-57. doi: 10.1111/j.1447-0594.2010.00588)

Wow, can you explain this ? Ths more i read it the more confused i get lol
So
Are they saying muscarinic cholinergic autoreceptors on interneurons interact to inhibit dopamine in motor areas so antagonizing them could indirectly increase dopamine in motor areas. Hence like why benadyrl and scopolamind could reverse pilocarpine or nicotine induced hand tremor
 
They might be more concerned with more chronic effects concerning spine pruning, but it appears they're saying that dopamine normally facilitates inhibition of acetylcholine through muscarinic auto receptors, and at the top of the abstract you can see they say that a rise in dopamine occurs when the nicotinic receptors are unbound. So maybe muscarinic autoreceptor blockade leads to less nicotinic receptor activation and that leads to increased dopamine and better communication through those movement disorder related circuits.
 
Thats what confused me i thought nicotinic receptors increase dopamine???
 
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