While reviewing some literature on cocaine, I came across this:
Blunted response to cocaine in the Flinders hypercholinergic animal model of depression.
Fagergren P, Overstreet DH, Goiny M, Hurd YL.
The Flinders sensitive line (FSL) rat is a proposed genetic hypercholinergic animal model of human depression. [...]
http://www.ncbi.nlm....pubmed/15857718
I haven't seriously explored the idea of hypercholinergic depression, but the title is interesting.
Anyway, what I think has not been sufficiently discussed in this thread is the need for balance between different subsystems of the CNS. Neither the cholinergic, the dopaminergic or any other subsystem exists in a vacuum, but is interconnected with variois others systems in both directions.
Especially those like myself afflicted with ADHD may be particularly interested in optimising the catecholamine innervation of the prefrontal cortex, as this region of the brain is the primary location of working memory, which is important in attentional, organisational and executive functions. For example, the working memory will not work well if dopamine D1- or alpha1-adrenergic receptors are overstimulated, and it seems logical to hypothesise that a certain noradrenaline to dopamine ratio is optimal and that deviation from this ideal will be more or less detrimental. The alpha2-adrenergic receptor may be less sensitive to overstimulation and is therefore an attractive target for pharmacological intervention, especially considering the availability of clinically tested alpha2-adrenergic agonists. Guanfacine is the most well researched option, but guanabenz seems an interesting alternative, whereas clonidine is associated with considerable sedative effects. Meanwhile, those who use the alpha2-adrenergic antagonists yohimbine, mirtazapine and/or mianserin should be wary of possible detrimental effects on working memory. My own aversive exprience with mirtazapine suggests thats those with ADHD may be more vulnerable to such adverse effects.
It seems sensible also to begin by fixing the subsystem that is most dysfunctional. Personally, I've experienced the most robust and indisputable benefits from dopaminergic intervention with stimulants. Such benefits include greater eloquence (verbal fluidity?), motivation, working memory and motor coordination, some of which others seems to experience readily with piracetam (or other racetams). Meanwhile, my experience with the racetams have yielded at best subtle benefits so far, but I may not have been consistent enough in my dosing thereof. While huperzine A seemed to have a definite effect on my memory, I wasn't certain enough that I liked it in order to use it daily. Memantine has occasionally produced a strong stimulant-like experience that surpasses methylphenidate, but is subject to rapid tolerance. Amantadine was mostly without effect, but may have been a triggering factor for a hypomanic episode, which in almost every respect surpasses any experience I've had with drugs, supplements or herbs; notably, however, it did not relieve anhedonia - a mission briefly accomplished only by pramipexole. Sulpiride deserves mention as a particularly powerfully activating and motivational drug, but as usual, the effects were lost within weeks and have never fully returned; furthermore cross-tolerance to the related amisulpride seemed complete. Apart from some temporary mild nausea and somnolence, all my experience with opiates so far has been positive, and of particular interest here may be the beneficial effects from buprenorhpine on working memory and motivation, as well as its apparent synergism with stimulants. I didn't note a working memory benefit from codeine (metabolically activated by conversion to morphine) but it deserves mention for the accidental and unique "high" that resulted from an attempt to treat cough with two different cough medicines; the experience may further involve an interaction with other drugs or foods I had ingested, because I've not been able to reproduce it after several attempts. I would not describe it as euphoria or pleasure, but rather a sense of complete freedom from fears and anxieties combined with feelings of warmth and relaxation, and while I wouldn't describe it as my happiest moment ever, I'm inclined to say it was the most comfortable.experience to date. Moreover, there was little if any of the enthusiasm and hypermotivation observed in hypomania, and which stimulants at their best, can only begin to approximate, but there was also none of the apathy that characterises depression. Furthermore, while any boost in self-confidence wasn't as distinct as with stimulants, the total anxiolysis may be functionally equivalent and certainly has a nicer feel to it. Finally, the capacity to enjoy life was not restored as clearly as from the anti-anhedonic effect of pramipexole, but on the other hand, the codeine experience seemed closer to satisfaction. These experiences combined suggests to me approximately what life ought to be like in the absence of disorder and dysfunction. Not all of the experiences could possibly co-exist at any given time, but it's not unreasonable to suggest that they should all be normal parts of a heathy life. After all, its obvious that the neurophysiological infrastructure is intact and capable of producing these experiences, but it seems as though some of the facilites have remained unused for decades only waiting to be put into operation my some impulse that seems to come only from drugs, or from some random sequence of events, as in the case of hypomania.
Seriously, though, I don't believe it's logically sound to deduce that because the effects of cocaine excitotoxicity and possible piracetam excitotoxicity are not the same, that some of the negative effects people experience from piracetam are not excitotoxic in origin. What you're talking about with cocaine, when it becomes "less effective" and then you have to take more, could be explained by "tolerance" through various mechanisms. It may not be due to excitotoxicity at all, but rather excitotoxicity may just be an undesirable side-effect of cocaine over-use. Are you saying the excitotoxic effect of cocaine causes simple tolerance?
This is probably not the best place to expound on the topic of tolerance to cocaine and similar stimulants, but it's a major research interest of mine, arising from both curiosity and practical needs.
Cocaine inhibits the reuptake of the three monoamine neurotransmitters dopamine (DA), serotonin and noradrenaline (norepinephrine) and blocks voltage-gated sodium channels, and also acts as an agonist at the sigma-receptor, but this is only an abbreviated list of its pharmacological actions. Its pharmacology becomes even more complex when its active metabolites are taken into account - especially if the drug is taken with alcohol. In the case of the mixture sold as "cocaine" on the street, one ought also to consider the other ingredients, which in a best case scenario will include at least several other natural coca alkaloids, some of which are known to be pharmacologically active. However, attempts to treat cocaine as anything more complex than a selective dopamine reuptake inhibitor (DRI) are usually reserved to serious researchers and enthusiasts of cocaine trivia. Fortunately, the simplified DRI model seems a surprisingly accurate approximation for the purpose of understanding many of cocaine's properties, because the same properties can be observed in other less complex or less researched DRIs, including (but not limited to) methylphenidate (Ritalin), amineptine, and 2-DPMP (diphenylmethylpiperidine or desoxypipradrol), the last of which is mentioned only for its special roles in the production of this text and as a backbone in my current regimen. To cut it short, given my current understanding of this complex matter, tolerance develops as a result of prolonged elevation of synaptic DA concentratiions secondary to the drug's inhibition of the DA reuptake transporter protein (DAT) of dopaminergic nerve terminals, which in turn induces an upregulation of dynorphin synthesis via a DA D1 receptor-dependent mechanism. Dynorphin is an opioid peptide which serves as the major endogenous ligand for the kappa-opioid receptor (KOR). Activation of the KOR triggers a chain of events, which among other possible consequences, results in a downregulation of DA receptor density and hence reduced opportunity to trigger the responses mediated by the receptors in question. At least some studies furthermore suggest a KOR-mediated downregulation of .DAT, which would diminish the relative influence of the DRI on synaptic DA concentrations. Presynaptic DA autoreceptors also trigger negative feedback mechanisms that reduce neuronal firing rate and possibly a downregulation of tyrosine hydroxylase - the rate-limiting step in catecholamine synthesis.
The model of cocaine tolerance depicted above is likely to be incomplete, but seems to be supported by experimental evidence, including the attenuation of drug consumption observed in rats treated with KOR antagonists such as norbinaltorphimine and JDTic, as well as my own prematurely terminated experiments with buprenorphine (BUP), which strongly suggested not only prolonged, but enhanced, response to methylphenidate. It should be noted however, that BUP has other actions beyond KOR antagonism that presumably contributed to the effects observed. BUP is the only clinically available KOR antagonist, but to be honest, I'd much rather resume my work in elucidating the role of KORs in mental illness and stimulant tolerance using more selective and longer lasting tools such as the aforementioned norbinaltorphimine or JDTic.
Unfortunately, my last review of chemical suppliers turned up only sources that charge hundreds of dollars for trace amounts of these substances, which was out of my budget. The same was true in the case of other chemical tools required in my investigations of targets other than the KOR, including the delta opioid, the serotonin 5-HT2C, the beta3-adrenergic, and the dopamine D1 receptors, respectively. Meanwhile, several cannabinoid-receptor (CBR) agonists have been advertised to me at more acceptable prices and in reasonable quantities; I mention this for the benefit of other potential investigators, because the CBRs currently have low priority in my research, due of course to their memory-impairing and appetite-stimulating actions, although naturally the analgesic properties seem exciting. Several "research" stimulants were also offered, and while stimulants certainly are of major interest to me, the items offered seemed merely to be minor chemical variations for the purposes of circumventing the latest ban on predecessor substances that proved too popular for various drug-warriors' tastes, and as long as more trusted alternatives remain available, I have no need for yet another potentially neurotoxic noradrenaline+dopamine reuptake inhibitor. However, I would be most interested if someone were to offer potent and selective DRIs. Combined serotonergic and dopaminergic or triple monoaminergic RIs, respectively, may be of interest as well, if the dopaminergic component predominates. Currently, I'm not particularly optimistic about the prospect of having my requirements for research supplies met at a price reasonable for an independent, small scale and primarily non-profit investigator, since currently, all known research matierial suppliers appear to focus on the recreational user market, on big universities funded by huge government grants, or on pharmaceutical companies with unlimited resources.
LongeCity
