Rolipram, fos-protein and addiction

[Deleted member 170540]

The compound rolipram is an experimental substance that acts by inhibiting the phosphodiesterase 4 enzyme (nothing mystical about it, caffeine inhibits PDE too but has different subtype selectivity). Wikipedia says that it has antidepressant, antipsychotic and nootropic effects...

I also found this article where the possibility of rolipram blocking opioid dependence and withdrawal is investigated:

http://www.ncbi.nlm.nih.gov/pubmed/11163637

A selective phosphodiesterase IV inhibitor, rolipram blocks both withdrawal behavioral manifestations, and c-Fos protein expression in morphine dependent mice.

Abstract

We investigated the effect of rolipram, a selective phosphodiesterase IV inhibitor, on morphine dependence in mice. The withdrawal manifestations were significantly reduced in mice that were treated with rolipram in combination with morphine repeatedly, compared to the mice treated with morphine and saline. Immunohistochemical study of c-Fos protein revealed a significant increase in the protein expression, 1 h after naloxone induced withdrawal manifestations. A combination of rolipram and morphine treatment for 5 days prevented the increase of c-Fos protein expression. Acute rolipram treatment prior to the naloxone challenge had no effect. Repeated treatment with rolipram itself had no effect either on behavior, or on c-Fos protein expression. These results suggest that chronic rolipram treatment in combination with morphine in mice will abolish the development of morphine dependence and the expression of c-Fos protein induced by naloxone challenge.

The overexpression of fos-protein is observed in various conditions of substance dependence, including opioid and nicotine addiction. Rolipram seems to block the formation of dependence by inhibiting the fos-protein expression...

I couldn't find any info on roliprams effect on tolerance development, though... Does someone know more about this?

Just thought this was interesting... Looks like a useful compound.

 

[Epsilon Alpha]

Fos proteins in general have a ton to to with behavioral sensitization, and some fuzzy links to what could be considered tolerance. Can't find the study I wanted to post regarding self administration, but its pretty ill defined link from what I've seen.

But, keep up the good work!

 

[Deleted member 170540]

I looked for info about other PDE-4 inhibitors, and found for instance that the compound ibudilast is one and has effects on opioid tolerance... Wikipedia says: "Ibudilast crosses the blood-brain barrier and suppresses glial cell activation. This activity has been shown to make ibudilast useful in the treatment of neuropathic pain and it not only enhances analgesia produced by opioid drugs, but also reduces the development of tolerance."

There was also a reference to the article at http://www.ncbi.nlm.nih.gov/pubmed/17594181 , where in the end of the abstract it is said that "Preclinical data indicate that ibudilast crosses the blood-brain barrier, is well tolerated, is active on oral administration, reduces glial activation and attenuates pain symptoms in diverse rat models of neuropathic pain. In addition, it enhances acute morphine analgesia and attenuates morphine tolerance and withdrawal."

Another thing I found was that the alkaloid mesembrine (from herb Kanna, sceletium tortuosum) is also a PDE-4 inhibitor, but there have been no experiments on its effects on opioid tolerance/withdrawal... This is quite interesting because the herb Sceletium is probably legally available in most places (unlike the above mentioned synthetics), and someone who wants to be a guinea pig could try using it to reverse opioid tolerance.

 

[acetylcholine]

I think fos is generally used as a marker to show brain activity due to an agent of interest (in this case Rolipram). This is opposed to the suggestion that fos modulation itself has a direct role in the change in behavior.

Interesting, though.