Pavlovian cues and overdose rate in rats

[Cyc]

I'm having a hard time believing this study and the results..

A particularly dramatic demonstration of the important role of Pavlovian conditioning to opiate tolerance was reported by Dr. Shepard Siegel and colleagues at McMaster University (Siege t al, 198x). Rats were prepared with chronic indwelling catheters that allowed for intravenous infusions of heroin. Rats were infused with heroin whenever they were in the context of a particular set of "predrug" cues, while on other occasions they were infused with saline in the presence of a different set of cues. The dose of heroin was systematically increased to mimic how heroin addicts increase their dose as tolerance develops. There was also a group of rats that did not receive any heroin during this initial phase of the study. These rats received saline infusion with both sets of cues and were desigtned to serve as drug naive controls for the final test. In the final test, all rats were given a large dose of heroin. Half of all the rats received this "overdose" with the predrug cues and half with the different set of cues. As expected, most of the drug naive control rats died from the large dose and the death rate was equal in the two sets of cues for the control rats. Among the drug experienced rats, there was a dramatic difference in the number of overdose deaths depending on where the overdose was administered. When the overdose was administered with the usual predrug cues, very few animals died- it appeared that these animals were tolerant and were able to survive. However, those drug experienced animals given the large dose without the usual predrug cues succumbed to the lethal effects at about the same rate as the naive control animals. Removing the usual predrug cues seemed to remove tolerance, as predicted by the Pavlovian conditioning model of tolerance.

Riley Hinson - 2012

Using this logic, you could take someone tolerant to heroin, shoot them up with their normal dose while they're sleeping and they would overdose at the same rate as someone who has never taken heroin in their life.

Alternatively, someone who has chronic amnesia could take a tiny dose of heroin every day and never become tolerant.

Can someone please explain to me the physiological response that these "predrug cues" exhibit in an animal, that makes them physiologically naive to drugs, simply by making them believe that they won't be taking drugs? Dog salivating to the sound of a bell I get, but this seems like a bunch of 'mind over matter' bullshit.

 

[Deleted member 170540]

Here's the full text of Siegel's article: http://people.whitman.edu/~herbrawt/classes/390/Siegel.pdf

This thing is not a new finding. A similar phenomenon was how lots of US soldiers used heroin in the Vietnam war, but were able to kick the habit surprisingly easily when they got back home (completely different environment). Their opioid dependence seem to have been 'situational-specific' to the war-zone conditions.

http://archives.drugabuse.gov/pdf/monographs/84.pdf

Unlike most civilian addicts, following treatment, these Vietnam addicts returned to an environment very different from that in which they used drugs. They also evidenced much less relapse than civilian addicts. In one report, narcotic use in the United States by returned veterans addicted in Vietnam was compared to that seen in addicts of comparable age treated at the large Federal facilities in Lexington, KY, and Fort Worth, TX (Robins et al. 1975). Those addicted in Vietnam (and returned to a very different environment) were much less likely to relapse than those addicted in the environment to which they subsequently returned. Indeed, the veterans evidenced “rates of remission unheard of among narcotics addicts treated In the United States” (Robins et al. 1975, p. 958 ). Many of Robins’ conclusions have been substantially confirmed in a more recent follow up study of a different population of returned soldiers who were addicted in Vietnam (O’Brien et al. 1980).

 

[Cyc]

So am I correct in saying that physical tolerance, or the need to take more of a drug over repeated usage to feel the same effects, has its foundation 100% in psychology, and all one needs to do to reset the effects of tolerance, both physical and subjective, is erase the memory of ever having taken the drug in the first place?

So I could hit my head on a rock tomorrow and suddenly I'd get drunk off 2 beers again like I was 14?

 

[Deleted member 170540]

This phenomenon and its neurochemical mechanism is not fully understood, AFAIK...

The Pavlovian model seems to work for alcohol tolerance, too:

http://www.springerlink.com/content/h275720431485745/

Human tolerance to alcohol: The role of Pavlovian conditioning processes

Abstract
To test the Pavlovian conditioning model of alcohol tolerance, two groups of eight male social drinkers each received five administrations of alcohol and five administrations of an equal volume of tonic each, on an alternating basis, during the initial 10-session tolerance development phase of the study. Group 1 received alcohol in a distinct environment and received tonic in a home environment. For group 2, the relationship between environmental cues and substances consumed was reversed. In a subsequent tolerance test session, both groups received alcohol in the distinct environment. When group 2 subjects were tested in this session under cues never before associated with alcohol, they were significantly more impaired on a complex cognitive task than group 1 subjects who expected alcohol; this result was in accord with the classical conditioning model of tolerance. In a final session, both groups received tonic in the distinct environment. As predicted, group 1 exhibited a compensatory enhancement in cognitive performance relative to group 2.

 

[Deleted member 170540]

^ Siegel himself did some research on opiate use by Vietnam veterans...

http://www.peele.net/lib/moa3.html

For example, Siegel (1983) applied conditioning theory to explain why the Vietnam soldier addicts who most often relapsed after their return home were those who had abused drugs or narcotics before going to Asia (Robins et al. 1974). Only these men would be exposed to familiar drug-taking environments when they returned home that set off the withdrawal that in turn required them to self-administer a narcotic (cf. O'Brien et al. 1980; Wikler 1980).

 

[Liric]

If you get into this kind of phenomenon academically you will never cease to be amazed by the extent of influence of psychological factors on bodily homeostasis. Imagine that a well-established pattern has been maintained around a drug use ritual for some time, those elements, the drugs, the sensations, actions, all form a dosing system that has developed as a whole. The environmental cues are part of the system as well, so imagine they contribute to the process of physiological readiness that develops as the brain's recognition of those cues make inroads, over time, to deeper brain behavior, including autonomic CNS regulation of breathing, heart rate, blood pressure, etc. so that part of that tolerance to the untoward effects of the dose is based on that cue recognition triggering downstream neurological events related to preserving bodily homeostasis. You grow the system up, tolerance-wise, as a whole, so when you start changing settings you may be withholding something thats deterministic of the extent to the brain/body will be running its intrinsic lets-shoot-iv-narcotics-without-od'ing program by the time you spike that vein. I can't find the study atm but its similar to how simply having an conditioned 'exercise mind-set' can burn significantly more calories and mobilize fat regardless of whether physical exercise is actually being undertaken. The fact that iv drug use is such a ritualized act with a very acute effect likely emphasizes the extent to which conditioned responses can be quickly formed and extend their influence. These kinds of acts lend themselves to highly repetitive, stereotyped events in the context of behavior (addictive behavior being an example); the same is true for arguably all other biological spheres because life is always adapting on all levels. Also it does not mean that if you are amnesic that you will not develop tolerance (it is a contributing factor, not the sole factor), but co-administration of mind-body decoupling mechanisms (ketamine?) could have very interesting implications for this kind of phenomenon. (and as I recall, does ketamine not have some applications in heroin addiction therapy?)