I have been trying to figure out the current situation in my head anyway here's what I understand as of now, I am not a pharmacologist and I tend to find neuroscience papers a bit obtuse. So if anyone has input I'd appreciate it
AMP mode of action
Tthe most important action is that AMP and METH trigger reverse transport of the catecholamines Dopamine DA and Noepinephrine NE.
this reverse transport moves DA and NE from the synaptic storage vesicles into the cytoplasm of the cell. Further reverse transport this time involving DAT the dopamine transporter and NERT the norepinephrine transporter moves the NE and DA into the synaptic cleft where it increases the levels of these neurotransmitters.
so the sequence works like this.
Uptake into the neuron
AMP or METH are taken into the neuron by the Dopamine Transporter DAT (this is why DAT inhibitors like nomifensine block a lot of amphetamines action)
Uptake into the synaptic storage vesicles
In the neuron some/most of the AMP ends up interacting with VMAT (vesicular monoamine transporter) the transporter that hoovers catecholamines out ot the cytoplasm into the storage vesicles, AMP is taken into the storage vesicles
Causes the vesicles to dump DA and NE into the cytoplasm
Once in the vesicle it appears by one mechanism or another, to cause the vesicle to dump its contents of catecholamines into the cytoplasm, this is thought to be either through disruption of the pH of the vesicle, the weak base theory AMP is a weak base, it enters the vesicle as the freebase and is converted to the salt form inside the vesicle, this has the efffect of raising the pH of the vesicle, this pushes DA and NE out of the vesicle. DA and NE are very closely linked in this respect as NE is made from DA, indeed AMP might increase the rate of conversion of DA to NE.
or disruption of VMAT by binding to it possibly causing VMAT to transport DA and NE out of the vesicle.
Which of these two mechanisms are more important I have no idea or indeed if there isn't some other mechanism but overall AMP Increases cytoplasmic concentration of DA and NE
Causes DA and NE to flood the synapse
the increased concentration of DA and NE in the cytoplasm causes increased diffusion of DA and NE out of the neuron, but more importantly AMP somehow activates DAT probably through phosphorylation by PKC (PKC inhibitors block dopamine release by AMP), creating a form that actively reverse transports DA backwards ie into the synapse rather than out of the synapse.
net result AMP dramatically increases the concentration of DA and NE in the synapse and this much increased conentration of DA and NE modifies brain activity giving euphoria wakefullness agitation paranoia etc.
to make things more complex AMP has been shown to activate certain genes in the neuron,
It is also a weak competitive (non substrate) MAOI so it reduces the breakdown of DA and NE as well.
It is also an adrenergic agonist, a D2 agonist and so on and these may cause some of the effects in the neuron..
definately not a clean drug pharmacologically.
anyway the thing I take away from this is that as a general rule releasers are probably much more fun than reuptake inhibitors.
Cocaine is often stated to be a re-uptake inhibitor and yes primarily is but it is also a releaser, this is indicated by the mis-match between its activity as DAT inhibitor and its activity in man, methiphenidate is a much more potent DAT inhibitor but is less fun (understatement of the year).
DAT inhibitors which also inhibit VMAT, which is what GBR-12909 does?? are also pretty much a waste of time.
Simple DAT inhibitors which have long half lives and slow onset are also pretty useless for fun factor, they simply cannot raise the DA levels quickly enough or high enough with simple reuptake inhibition. When they do though they keep the DA levels elevated for a long while, causing excessive sensitisation and tolerance, followed by serious cravings but no great crash because they don't cause excessive DA and NE depletion. I am thinking about things like BTCP, and probably desoxypipradrol.
I think a few more things will become clearer as I think this over..
v
AMP mode of action
Tthe most important action is that AMP and METH trigger reverse transport of the catecholamines Dopamine DA and Noepinephrine NE.
this reverse transport moves DA and NE from the synaptic storage vesicles into the cytoplasm of the cell. Further reverse transport this time involving DAT the dopamine transporter and NERT the norepinephrine transporter moves the NE and DA into the synaptic cleft where it increases the levels of these neurotransmitters.
so the sequence works like this.
Uptake into the neuron
AMP or METH are taken into the neuron by the Dopamine Transporter DAT (this is why DAT inhibitors like nomifensine block a lot of amphetamines action)
Uptake into the synaptic storage vesicles
In the neuron some/most of the AMP ends up interacting with VMAT (vesicular monoamine transporter) the transporter that hoovers catecholamines out ot the cytoplasm into the storage vesicles, AMP is taken into the storage vesicles
Causes the vesicles to dump DA and NE into the cytoplasm
Once in the vesicle it appears by one mechanism or another, to cause the vesicle to dump its contents of catecholamines into the cytoplasm, this is thought to be either through disruption of the pH of the vesicle, the weak base theory AMP is a weak base, it enters the vesicle as the freebase and is converted to the salt form inside the vesicle, this has the efffect of raising the pH of the vesicle, this pushes DA and NE out of the vesicle. DA and NE are very closely linked in this respect as NE is made from DA, indeed AMP might increase the rate of conversion of DA to NE.
or disruption of VMAT by binding to it possibly causing VMAT to transport DA and NE out of the vesicle.
Which of these two mechanisms are more important I have no idea or indeed if there isn't some other mechanism but overall AMP Increases cytoplasmic concentration of DA and NE
Causes DA and NE to flood the synapse
the increased concentration of DA and NE in the cytoplasm causes increased diffusion of DA and NE out of the neuron, but more importantly AMP somehow activates DAT probably through phosphorylation by PKC (PKC inhibitors block dopamine release by AMP), creating a form that actively reverse transports DA backwards ie into the synapse rather than out of the synapse.
net result AMP dramatically increases the concentration of DA and NE in the synapse and this much increased conentration of DA and NE modifies brain activity giving euphoria wakefullness agitation paranoia etc.
to make things more complex AMP has been shown to activate certain genes in the neuron,
It is also a weak competitive (non substrate) MAOI so it reduces the breakdown of DA and NE as well.
It is also an adrenergic agonist, a D2 agonist and so on and these may cause some of the effects in the neuron..
definately not a clean drug pharmacologically.
anyway the thing I take away from this is that as a general rule releasers are probably much more fun than reuptake inhibitors.
Cocaine is often stated to be a re-uptake inhibitor and yes primarily is but it is also a releaser, this is indicated by the mis-match between its activity as DAT inhibitor and its activity in man, methiphenidate is a much more potent DAT inhibitor but is less fun (understatement of the year).
DAT inhibitors which also inhibit VMAT, which is what GBR-12909 does?? are also pretty much a waste of time.
Simple DAT inhibitors which have long half lives and slow onset are also pretty useless for fun factor, they simply cannot raise the DA levels quickly enough or high enough with simple reuptake inhibition. When they do though they keep the DA levels elevated for a long while, causing excessive sensitisation and tolerance, followed by serious cravings but no great crash because they don't cause excessive DA and NE depletion. I am thinking about things like BTCP, and probably desoxypipradrol.
I think a few more things will become clearer as I think this over..
v
