dopamimetic
Bluelighter
- Joined
- Mar 21, 2013
- Messages
- 2,070
Sub-anaesthetic doses of ketamine lead to changes in the expression of parvalbumin interneurons and significant changes in nitrergic and GABAergic (downregulation) systems as well as, especially after chronic dosing, upregulated NADPH oxidase and overall increase in glutamate levels in the brain.
Now, the NADPH oxidase plays a crucial role which I do not yet understand fully, but it does inactivate oxolacetate, which lowers glutamate levels, and it is a major factor in the production of superoxides, which may be responsible for the loss of parvalbumin & GABAergic neurons.
The rapid-acting antidepressant activities of ketamine have been associated with this mechanism, as well as psychotic after-effects.
But now the interesting part: Dextromethorphan is a NADPH oxidase inhibitor, active at low, sub-psychotomimetic and sub-dissociative dosages and it's not the DXO, but the actual DXM which does that. It has been studied for protective effects in Parkinson's and even to that ugly neurotoxin MPTP+ with success and a good safety profile. And DXM has a very pronounced, long-lasting antidepressant 'afterglow' that it shouldn't have if the above was true.
Also, wouldn't this mean that (besides of it's obvious, powerful adverse effects like the SNRI activity & sigma agonism) DXM would in fact make a somewhat 'safer' dissociative not inducing these long-term changes in the brain!?
Repeated application of ketamine to rats induces changes in the hippocampal expression of parvalbumin, neuronal nitric oxide synthase and cFOS similar to those found in human schizophrenia.
Loss of phenotype of parvalbumin interneurons in rat prefrontal cortex is involved in antidepressant- and propsychotic-like behaviors following acute and repeated ketamine administration.
IL-6 mediated degeneration of forebrain GABAergic interneurons and cognitive impairment in aged mice through activation of neuronal NADPH oxidase. <-- link to the inflammation model of anxiety & depression
Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase
But then again, to confuse:
Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus.
Now, the NADPH oxidase plays a crucial role which I do not yet understand fully, but it does inactivate oxolacetate, which lowers glutamate levels, and it is a major factor in the production of superoxides, which may be responsible for the loss of parvalbumin & GABAergic neurons.
The rapid-acting antidepressant activities of ketamine have been associated with this mechanism, as well as psychotic after-effects.
But now the interesting part: Dextromethorphan is a NADPH oxidase inhibitor, active at low, sub-psychotomimetic and sub-dissociative dosages and it's not the DXO, but the actual DXM which does that. It has been studied for protective effects in Parkinson's and even to that ugly neurotoxin MPTP+ with success and a good safety profile. And DXM has a very pronounced, long-lasting antidepressant 'afterglow' that it shouldn't have if the above was true.
Also, wouldn't this mean that (besides of it's obvious, powerful adverse effects like the SNRI activity & sigma agonism) DXM would in fact make a somewhat 'safer' dissociative not inducing these long-term changes in the brain!?
Repeated application of ketamine to rats induces changes in the hippocampal expression of parvalbumin, neuronal nitric oxide synthase and cFOS similar to those found in human schizophrenia.
Loss of phenotype of parvalbumin interneurons in rat prefrontal cortex is involved in antidepressant- and propsychotic-like behaviors following acute and repeated ketamine administration.
IL-6 mediated degeneration of forebrain GABAergic interneurons and cognitive impairment in aged mice through activation of neuronal NADPH oxidase. <-- link to the inflammation model of anxiety & depression
Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase
But then again, to confuse:
Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus.