Role of noradrenergic signaling by the nucleus tractus solitarius in mediating opiate

[BilZ0r]

Role of noradrenergic signaling by the nucleus tractus solitarius in mediating opiate reward.

Olson VG, Heusner CL, Bland RJ, During MJ, Weinshenker D, Palmiter RD.

Science. 2006 Feb 17;311(5763):1017-20.

Norepinephrine (NE) is widely implicated in opiate withdrawal, but much less is known about its role in opiate-induced locomotion and reward. In mice lacking dopamine beta-hydroxylase (DBH), an enzyme critical for NE synthesis, we found that NE was necessary for morphine-induced conditioned place preference (CPP; a measure of reward) and locomotion. These deficits were rescued by systemic NE restoration. Viral restoration of DBH expression in the nucleus tractus solitarius, but not in the locus coeruleus, restored CPP for morphine. Morphine-induced locomotion was partially restored by DBH expression in either brain region. These data suggest that NE signaling by the nucleus tractus solitarius is necessary for morphine reward.

http://www.ncbi.nlm.nih.gov/entrez/..._uids=16484499&query_hl=3&itool=pubmed_docsum

One of the most complete and succinct papers I've read in a long time, worth reading for those whole like tight science. Interesting as well, for the phsiology, and also reinforces the point that the amphetamine mediated noradrenaline release is important in mediated amphetamine mediated conditioned place preference and amphetamine self-administration.

Finally, it's interesting because the drug they use when they say "These deficits were rescued by systemic NE restoration". They use dihydroxyphenylserine "Noradrenergic neurotrans-mission was restored in DBH-KO mice by administering L-3,4-dihydroxyphenylserine (DOPS), which can be converted to NE in the absence of DBH (4)." Which refers to this paper

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=9603211&dopt=Abstract

In other tissues, NE can be restored to normal levels after multiple injections of DOPS, whereas in the midbrain and cerebellum, restoration of NE is limited to 25-30% of normal. NE levels typically peak approximately 5 h after DOPS administration and are undetectable by 48 h... The elevated levels of dopamine fall modestly after injection of DOPS. S(-)-Carbidopa, which does not cross the blood-brain barrier, inhibits aromatic L-amino acid decarboxylase and effectively prevents restoration of NE by DOPS in the periphery

 

[5-HT2]

^^^Yeah, Palmiter's lab is doing some good work. Pretty straightforward approach, really goes from genes to behavior, and provides excellent leads for investigating physiological mechanism. Here is another paper from his group in the same vein:

http://www.ncbi.nlm.nih.gov/entrez/..._uids=16341013&query_hl=7&itool=pubmed_docsum

Abstract:

Dopamine has been widely implicated as a mediator of many of the behavioural responses to drugs of abuse. To test the hypothesis that dopamine is an essential mediator of various opiate-induced responses, we administered morphine to mice unable to synthesize dopamine. We found that dopamine-deficient mice are unable to mount a normal locomotor response to morphine, but a small dopamine-independent increase in locomotion remains. Dopamine-deficient mice have a rightward shift in the dose-response curve to morphine on the tail-flick test (a pain sensitivity assay), suggesting either a decreased sensitivity to the analgesic effects of morphine and/or basal hyperalgesia. In contrast, dopamine-deficient mice display a robust conditioned place preference for morphine when given either caffeine or l-dihydroxyphenylalanine (a dopamine precursor that restores dopamine throughout the brain) during the testing phases. Together, these data demonstrate that dopamine is a crucial component of morphine-induced locomotion, dopamine may contribute to morphine analgesia, but that dopamine is not required for morphine-induced reward as measured by conditioned place preference.

The combined results from the two papers are really interesting. I would have thought that NE would be required for morphine-induced locomotion, and DA for morphine induced reward, but in fact it is the other way around. However, they have yet to do the self-administration experiments with these mice, which may further illuminate things.

 

[BilZ0r]

I'm certain self-administration and CPP are going to have vastly different neuronal correlates, I mean, it seems that they do in humans.

 

[5-HT2]

^^^I agree. Can you give citations for some of the better human studies that you mention. Thanks

 

[BilZ0r]

I'm just meaning, people with self-administer drugs that aren't truely addicted...