Situational specificity of drug tolerance

[malakaix]

I'm not sure if this question belongs in ADD.. feel free to move it to the appropriate forum as it does discuss theoretical ideas.

I've recently been reading a Bio-psychology book written by John P.J Pinel Chapter 15 Outline in which under Chapter 15/Drug Abuse and Reward Circuits in the Brain he mentions the study of 'Situational specificity of drug tolerance'

He begins explaining initially about a study conducted on rats by (Crowell, Hinson & Shepard Siegel, 1981)

Note: I apologize in advance to anyone who reads this entire post in regards to the length of it, but i felt it was necessary to quote certain parts of the book, because of the nature of the question/topic.

In one study, two groups of rats received 20 alcohol and 20 saline injections in an alternating sequence, one injection every other day. The only difference between the two groups was that the rats in one group received all 20 alcohol injections in a distinctive test room and the 20 saline injections in there colony room, while the rats in the other group received the alcohol in the colony room and the saline in the distinctive test room. Then the tolerance of all rats to the hypo-thermic (temperature-reducing) effects of alcohol was assessed in both environments. Tolerance was observed only when the rats were injected in the environment that had previously been paired with alcohol administration. This situational specificaty of drug tolerance has been demonstrated in many other experiments involving a variety of drugs.

So this extract sets the scene for what im trying to explain, it's further highlighted in relation to human studies involving addicts and tolerance.

The next extract is the main part of my question that i want to convey across:

[Quote="Extract from Chapter 15 'Hypothesis']

The numerous demonstrations of the situational specificity of drug tolerance led Siegel and his colleagues to propose that addicts may be particularly susceptible to the lethal effects of a drug overdose when the drug is administered in a new context. Their hypothesis is that addicts become tolerance when they repeatedly self-administer their drug in the same environments, and as a result, they begin taking larger and larger doses to counteract the diminution of drug effects. Then, when the addict administers her or his usual massive dose in an unusual situation, tolerance effects are not present to counteract the effects of the drug, and there is a greater risk of death from overdose. In support of this hypothesis, Siegel, Hinson, Krank, and McCulley (1982) found that 96% of a group of heroin-tolerant rats died following a high dose of heroin administered in a novel environment, but only 64% died following the same dose administered in there usual injection environment. Heroin kills by suppressing respiration.[/Quote]

This next extract is of the most interest, because it outlines the theory as to why this reduction is likely to occur.

[Quote="Extract from Chapter 15 'Explanation']

Of the several noteworthy theories that have been proposed to account for the situational specificity of drug tolerance (see Baker & Tiffany, 1985; Eikelbomm & Stewart, 1982; Paletta & Wagner, 1986), Siegel's theory has been most influential. Siegel views each incidence of drug administration as a Pavlovian conditioning trial in which various environmental stimuli that regularly predict the administration of the drug (e.g pubs, washrooms, needles, other addicts) are conditional stimuli, and the drug effects are unconditional stimuli. The central assumption of the theory is that conditional stimuli that predict drug administration come to elicit conditional responses opposite to the unconditional effects of the drug. Siegel has termed these hypothetical opposing conditional responses conditioned compensatory responses. The theory is that as the stimuli that repeatedly predict the effects of a drug come to elicit greater and greater conditioned compensatory responses, they increasingly counteract the unconditional effects of the drug and produce situationally specific tolerance.[/Quote]

I understand this is theoretical, but i found it rather interesting.. and thought maybe i could get a more knowledgeable opinion on the matter, other then my own interpretation of what i've read.

What do you guys think? Has anyone heard of this theory before, i researched it a bit and found a few articles mentioning it.

Or may be im just slow to catch on to what a lot of people already know

 

[any major dude]

I remember my professor going over this same theory in my physiology of behavior class several years ago. If i remember correctly, the only studies that had been done had used drugs that are toxic at relatively low plasma levels (i.e. alcohol, opiates, cocaine, etc). This led me to believe that one's body could in essence "brace itself" for ingestion of a toxin if a strong enough association develops between external stimuli and exposure to a specific chemical, but that's just a guess.

I don't think it would be much of a logical leap to assume that just as pavlov's dogs exhibited a physical response (drooling) to an enviromental stimulus (bell ring), a human could exhibit drug tolerance when presented with an external stimulus (situation or physical location).

Like I mentioned earlier, this would likely only work for the more toxic drugs, since one's body doesn't defend itself against non-toxic substances. And for a bit of anecdotal evidence, I've never experienced situational tolerance from smoking pot in my living room on a fairly regular basis.

 

[immad]

^In what way are most opiates toxic? I know meperidine is, but afaik aren't most opiates really toxic, except if you see acute respiratory depression as toxicity.

 

[any major dude]

its not really the respiratory depression i see as toxicity, but respiratory cessation

Many opiates, methadone less so, are also toxic to the liver and kidneys, but respiratory failure will probably kill you before the liver or renal failure. Additionally, if one was to overdose on something like lortab, vicodin, etc, the acetaminophen would likely kill you first...

 

[daddysgone]

its not really the respiratory depression i see as toxicity, but respiratory cessation

Many opiates, methadone less so, are also toxic to the liver and kidneys, but respiratory failure will probably kill you before the liver or renal failure. Additionally, if one was to overdose on something like lortab, vicodin, etc, the acetaminophen would likely kill you first...

this is news to me. aside from the whole acetaminophen thing which of course can destroy your liver/kidneys, but then we arent talking about opiates at all, just a substance often compounded with opiates. But in terms of opiates being toxic to the liver and kidneys at low plasma levels, this is contrary to every other report ive read regarding this issue. I was STRONGLY under the impression that at moderate doses, opioids were indeed NOT toxic to these organ systems, perhaps with the exception of methadone and some of its analogues which i seem to remember reading might be slightly neurotoxic.

So whats the deal here? To see opiates mentioned in the same sentence as alcohol when discussing liver and kidney toxicity is quite surprising to me. so am i missing something?? thanks- DG

 

[any major dude]

I think i may have mis-spoke, err, mistyped, or otherwise misrepresented what i meant to say... opiates such as morphine and heroin are toxic to your liver and kidneys, but not at low plasma levels. When metabolites of the afforementioned chemicals start to build up is when you see symptoms of opiate toxicity.

Methadone doesn't produce these metabolites, and therefore is much less toxic to your liver and kidneys, though I can't speak to its neurotoxicity.

One would have to ingest a prohibitively large quantity of drugs at once to cause liver or renal failure from one dose. And that would almost certainly kill you from respiratory depression before liver or kidney failure would. However, over long periods of taking opiates (as opiate users tend to do) the metabolites can build up to very problematic levels.

 

[daddysgone]

I think i may have mis-spoke, err, mistyped, or otherwise misrepresented what i meant to say... opiates such as morphine and heroin are toxic to your liver and kidneys, but not at low plasma levels. When metabolites of the afforementioned chemicals start to build up is when you see symptoms of opiate toxicity.

Methadone doesn't produce these metabolites, and therefore is much less toxic to your liver and kidneys, though I can't speak to its neurotoxicity.

One would have to ingest a prohibitively large quantity of drugs at once to cause liver or renal failure from one dose. And that would almost certainly kill you from respiratory depression before liver or kidney failure would. However, over long periods of taking opiates (as opiate users tend to do) the metabolites can build up to very problematic levels.

Hmmm....even this is news to me. I was under the impression the chronic opioid users had higher incidences of liver or kidney problems. You seem to be suggesting that ingesting opioids over a long period of time results in a toxic buildup of metabolites that leads to renal and liver failure. I was not at all under this impression. While almost all things can be toxic in massive doses, i was always under the impression that opioids were one of the most mild and benign substances one can take regarding toxicity in the various organs. Have i somehow been misinformed?? any other opinions???DG

 

[any major dude]

it can lead to renal or liver failure, but these problems usually come to the user's attention before they cause organ failure and death. Nonetheless, they are toxic.