Role of Cholinergic and Dopamine Receptors in the Physiology of Caffeine Tolerance

NewACC

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Dear Forum Members, I found three interesting studies on reversing (or reducing) caffeine tolerance, by adding to chronic (or sub-chronic) caffeine treatment, either the dopamine agonists bromocriptine (a predominantly d2/d3 family agonist) or pergolide (a very potent d1 agonist), or scopolamine (a non-selective potent mAch receptor antagonist). Researchers are even suggesting a possible therapeutic effect of adding caffeine to dopamine agonist therapy by preventing (or markedly reducing) tolerance to the effects of both. The latest study may hint at the possibility of using caffeine with cyproheptadine, which is a similarly potent and non-selective muuscarinic acetylcholine receptor antagonist as scopolamine, and may even increase synergism in tolerance reversal along with bromocriptine or pergolide due to rather strong dopamine antagonism, that would offset the caffeine in combination with any dopamine agonist, creating a super-combination.

"We studied the synergistic effects of pergolide and bromocriptine with caffeine on turning behavior in 6-OHDA denervated rats...When caffeine was removed, tolerance to bromocriptine effects was observed for 1 day only, while no tolerance was observed to pergolide. These results suggest that caffeine could be useful in the treatment of Parkinson's disease, preferentially as an adjuvant of mixed dopaminergic agonists like pergolide"

"...In agreement with previous data, our results showed that on the first administration, both caffeine and bromocriptine injected plus saline produced a significant increase in contralateral rotational behavior as compared to saline-saline injections. However, with repeated administrations, tolerance was observed to caffeine, but not to bromocriptine. The combination of different doses of bromocriptine (0.1, 0.2, 0.4 and 0.8 mg/kg) with caffeine (40 mg/kg) significantly enhanced the effects of either drug injected with saline on rotational behavior, and no tolerance was observed with repeated treatment. The continuous co-administration of both substances was necessary to maintain elevated levels of rotational behavior, since withdrawing one or the other drug led to decreased contralateral turning. These results demonstrate that when caffeine is administered repeatedly in combination with bromocriptine, tolerance to its psychostimulant effects is not observed, suggesting that caffeine could be used as an adjunctive therapeutic agent with dopamine agonists for the treatment of Parkinson's disease."

"Continuous administration of caffeine has been shown to induce tolerance to its psychostimulant effects... we administered either caffeine (40 mg/kg) plus saline or scopolamine (5, 10 and 20 mg/kg) plus saline, as well as caffeine in combination with the various doses of scopolamine for 7 consecutive days, and measured ipsilateral and contralateral rotational behavior. The results showed that acute injections of scopolamine plus saline produced similar levels of both ipsilateral and contralateral turning, while caffeine produced more contralateral than ipsilateral turning. Tolerance to caffeine-induced contralateral turning was observed as of the second administration, while scopolamine plus saline injections did not produce significant changes in rotational behavior with repeated treatment. Scopolamine co-administered with caffeine significantly attenuated the increased contralateral turning produced by acute injections of caffeine plus saline, but significantly prevented the tolerance effects with repeated administration. These findings strongly suggest that muscarinic cholinergic processes may be involved in tolerance to caffeine-induced contralateral turning. The results are interpreted in terms of the possible interactions between dopamine, adenosine and acetylcholine neurotransmitter systems within the basal ganglia circuitry involved in motor behavior."

@haidut , @Hans , @Lokzo can you comment on this post, as well as every reader who has access to the full text of these studies, attach it to the stream below, since it would be great to see specific figures for physical activity (in this case, an indicator of tolerance)!
 

haidut

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Dear Forum Members, I found three interesting studies on reversing (or reducing) caffeine tolerance, by adding to chronic (or sub-chronic) caffeine treatment, either the dopamine agonists bromocriptine (a predominantly d2/d3 family agonist) or pergolide (a very potent d1 agonist), or scopolamine (a non-selective potent mAch receptor antagonist). Researchers are even suggesting a possible therapeutic effect of adding caffeine to dopamine agonist therapy by preventing (or markedly reducing) tolerance to the effects of both. The latest study may hint at the possibility of using caffeine with cyproheptadine, which is a similarly potent and non-selective muuscarinic acetylcholine receptor antagonist as scopolamine, and may even increase synergism in tolerance reversal along with bromocriptine or pergolide due to rather strong dopamine antagonism, that would offset the caffeine in combination with any dopamine agonist, creating a super-combination.

"We studied the synergistic effects of pergolide and bromocriptine with caffeine on turning behavior in 6-OHDA denervated rats...When caffeine was removed, tolerance to bromocriptine effects was observed for 1 day only, while no tolerance was observed to pergolide. These results suggest that caffeine could be useful in the treatment of Parkinson's disease, preferentially as an adjuvant of mixed dopaminergic agonists like pergolide"

"...In agreement with previous data, our results showed that on the first administration, both caffeine and bromocriptine injected plus saline produced a significant increase in contralateral rotational behavior as compared to saline-saline injections. However, with repeated administrations, tolerance was observed to caffeine, but not to bromocriptine. The combination of different doses of bromocriptine (0.1, 0.2, 0.4 and 0.8 mg/kg) with caffeine (40 mg/kg) significantly enhanced the effects of either drug injected with saline on rotational behavior, and no tolerance was observed with repeated treatment. The continuous co-administration of both substances was necessary to maintain elevated levels of rotational behavior, since withdrawing one or the other drug led to decreased contralateral turning. These results demonstrate that when caffeine is administered repeatedly in combination with bromocriptine, tolerance to its psychostimulant effects is not observed, suggesting that caffeine could be used as an adjunctive therapeutic agent with dopamine agonists for the treatment of Parkinson's disease."

"Continuous administration of caffeine has been shown to induce tolerance to its psychostimulant effects... we administered either caffeine (40 mg/kg) plus saline or scopolamine (5, 10 and 20 mg/kg) plus saline, as well as caffeine in combination with the various doses of scopolamine for 7 consecutive days, and measured ipsilateral and contralateral rotational behavior. The results showed that acute injections of scopolamine plus saline produced similar levels of both ipsilateral and contralateral turning, while caffeine produced more contralateral than ipsilateral turning. Tolerance to caffeine-induced contralateral turning was observed as of the second administration, while scopolamine plus saline injections did not produce significant changes in rotational behavior with repeated treatment. Scopolamine co-administered with caffeine significantly attenuated the increased contralateral turning produced by acute injections of caffeine plus saline, but significantly prevented the tolerance effects with repeated administration. These findings strongly suggest that muscarinic cholinergic processes may be involved in tolerance to caffeine-induced contralateral turning. The results are interpreted in terms of the possible interactions between dopamine, adenosine and acetylcholine neurotransmitter systems within the basal ganglia circuitry involved in motor behavior."

@haidut , @Hans , @Lokzo can you comment on this post, as well as every reader who has access to the full text of these studies, attach it to the stream below, since it would be great to see specific figures for physical activity (in this case, an indicator of tolerance)!

Very interesting, thanks for posting. There are several studies showing caffeine potentiates the effects of almost everything it is co-administered with. For that reason, it is apparently commonly added to steroid injections or taken orally by juicing bodybuilders. So, it may be that the addition of caffeine potentiated the effects of those drugs, though caffeine seems to have dopaminergic effects of its own.

The findings on the cholinergic system is interesting, as caffeine is shown by some studies to have anticholinergic effects and this is one reason Ray has been recommending it (in the form of coffee) to smokers. I guess the effects are more complex. Niacinamide may be able to mimic the effects of scopolamine since it consumes methyl groups from choline and that leaves less choline available to activat the cholinergic system. Estrogens also activate the cholinergic system and it has been shown that elevated estrogens lead to increased tolerance of drugs, alcohol, etc. So, blocking or lowering estrogen may also help, and niacinamide may be able to do that as well.
 
OP
NewACC

NewACC

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Great info re Cyproheptadine. I have always found it potentiates everything 4 days after a single dose.
Lokzo, I love your posts. Now for me the most interesting is the role of H2 histamine receptors in metabolism. No matter what anyone says, but histamine is THE MOST DISPUTE THING IN PEATING
 
OP
NewACC

NewACC

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Very interesting, thanks for posting. There are several studies showing caffeine potentiates the effects of almost everything it is co-administered with. For that reason, it is apparently commonly added to steroid injections or taken orally by juicing bodybuilders. So, it may be that the addition of caffeine potentiated the effects of those drugs, though caffeine seems to have dopaminergic effects of its own.

The findings on the cholinergic system is interesting, as caffeine is shown by some studies to have anticholinergic effects and this is one reason Ray has been recommending it (in the form of coffee) to smokers. I guess the effects are more complex. Niacinamide may be able to mimic the effects of scopolamine since it consumes methyl groups from choline and that leaves less choline available to activat the cholinergic system. Estrogens also activate the cholinergic system and it has been shown that elevated estrogens lead to increased tolerance of drugs, alcohol, etc. So, blocking or lowering estrogen may also help, and niacinamide may be able to do that as well.
@haidut , I found a bit disstressing research
Studies with bromocriptine: III. Concomitant administration of caffeine to patients with idiopathic parkinsonism - PubMed , but it is absolutely not specified in any way and absolutely does not coincide with my personal experience and the experience of members of the forum
 

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