Now I'm Confused..so I come here...? about Reverse Tolerance

[Jabberwocky]

Hello

I've been reading about incentive salience theories of drug addiction and now I've branched out and it seems like some neuropsychologists are very loose with the term 'reverse tolerance'. They seem to use it in a widely disparate fashion...for instance, I thought some reserve the concept for the possibility of a drug that in its administration requires less in the future for equal intensity (although am I incorrect and is this too 'cutting edge' a use for the concept?). Others will use it for the process of upregulation (or replacing missing monoamines) that comes about from abstaining from the drug.

The latter use is very uninteresting to me...in my view, 'reverse tolerance' and 'reversing the effects of tolerance' (from amphetamine or something) are QUITE different concepts.

I'm interested whether there are any new (or old hehe) drugs that cause reverse tolerance in the first sense: that a use of the drug will require less in the future to bring about same effects. This would require long-term biochemical changes (enzymatic pathways maybe?) or something similar, correct?

can you help a conceptually confused philosopher make sense of your concepts?

 

[theWorldWithin]

Cannabis is said to have a reverse tolerance but only to a degree and depending on the strings selected. Also I feel LSD has a reverse tolerance with smaller amounts taking trippers further on subsequent administrations. But it is also only withing reason, you will hit a lower limit sooner rather than later.

 

[Nagelfar]

I always thought of 'reverse tolerance' as synonymous with 'sensitization', where an effect of a drug, for good or ill, has greater impact with each subsequent use. (the local anesthetic effects of cocaine on the heart, for example)

 

[The Monkey Mantra]

GP, I'd imagine dopaminergic pathways were originally associated with motion more than anything else. In bacteria, there's a flagella that makes the bug spin around, and another that makes it go forward. Bacteria spin, spin, spin, and go forward, in kinda random directions. But if they pick up a molecule of, say, glucose, the glucose actually fits into a receptor or changes a signalling mechanism that STOPS the spinning and lets the "go forward" happen instead. This way, the bug is preferentially seeking out directions where there's more glucose, bouncing around like a pinball between random "hits" into glucose.

Dopaminergic pathways, which are associated with locomotor activities, probably evolved in a similar way, to make very simple critters (think flatworms) go toward good stuff when they find it. The sensitization allows the creature to require less and less stimulation to head toward the good stuff so they don't just flop around after they get it. They really fuckin' speed on toward it, getting more and more focused in that direction as they pick up more food. I mean, they're blind as shit, so they're relying on sensors and that dopamine pathway to guide their motion. In humans, we have a consciousness that perceives it as "want", but if you ever watch someone stand over a bowl of chips at a party and eat the whole goddamn thing, you can see that sometimes your "want", which involves the VTA to NAc pathway, which then goes to the OFC (orbitofrontal cortex) to be "gated" (as in, prioritizing your attention), starts to really warp the gating toward that one thing and actually prunes back the OFC connections to other activities (does anyone see a connection to addiction here?) and just lets the dopamine shit take over. Like, the decision making process becomes less and less involved and there's just a direct connection from the reward system to motor activity. That's what Chris Evans, the addiction neuroscientist guy down at UCLA told me, but he didn't actually explain the neurobiology - that's all just my guesswork.

 

[Limpet_Chicken]

Salvia Divinorum is said to build a 'reverse tolerance', requiring less of the plant to produce effects with more use.

I wonder though, if it could be more that the user learns to more effectively manipulate (or be manipulated BY, of course you don't 'do' salvia, she does YOU) the headspace induced by it, becoming more 'psychically' sensitive, rather than a direct physiochemical interaction.

 

[pallidamors]

I've heard nitrous oxide fits the first definition you mentioned, although with experience I wouldn't say this is so.

 

[The Monkey Mantra]

Limpet Chicken, I agree. I learned how to get "deeper" into, say, a mushroom trip, by combining it with skills and the ability to totally relax because of the familiarity. Like, when you say, "Fuck the visuals, fuck the body high, it's all meaningless..." and you enter that weird, loving, hellish ego-burning void.

 

[Jabberwocky]

MM, I really love the connection between attention and addiction. Brilliant. I had not honestly thought of the role of attention in addiction (but it so OBVIOUSLY has a major role!)

 

[Jabberwocky]

Salvia Divinorum is said to build a 'reverse tolerance', requiring less of the plant to produce effects with more use.

I wonder though, if it could be more that the user learns to more effectively manipulate (or be manipulated BY, of course you don't 'do' salvia, she does YOU) the headspace induced by it, becoming more 'psychically' sensitive, rather than a direct physiochemical interaction.

is the latter explanation not sensitization? Some scientists seem to use the terms interchangeably (thats one of my primary questions here, SHOULD we use these interchangeably or do they mean different things if even slightly?)

 

[Limpet_Chicken]

Well it is 'sensitization' in my book, of a kind, but more of a kind of familiarity breeding better ability to navigate the space, rather than an actual sensitization at the neurochemical level.

A sort of 'turn right, flash green and get swallowed by the 3'rd alien vines on the left.......oh and watch for those clowns this time...

Thats not to discount it, I would love to know how it does it, salvinorin and its friends seem to have'wierd case' plastered all over them in, I just find it odd that a potent agonist at a receptor would induce upregulation, although I cannot exclude something like a conformational change in receptor shape that could exist in a long lasting agonist-bound sensitised state, I know it happens with (allosteric) antagonists/negative modulators, with desensitization.

What is the molecular architecture of the K receptor like? with regards to the binding sites available, is salvinorin selective for K1/K2 or not?

Y'all got me curious now, good job I'm not completely feline.

 

[5-HT2]

Simply put, sensitization is an increase in the response to a stimulus after repeated experience of the stimulus.

As for MM's speculations about neural mechanisms, let me first clear up a few ambiguities. The OFC projects to the NAc and has reciprocal connections with the VTA, but the NAc does not project directly to any cortical area. Also, the OFC is more on the sensory side of things in the prefrontal cortex than the motor side. Evidence from multiple laboratories strongly suggests that it calculates the expected value of outcomes based on the stimuli that predict them. Visceromotor and affective motor functions are subserved by other cortical areas, such as anterior cingulate (ACC), medial precentral, and anterior insular cortices. Neuroimaging studies have demonstrated a decrease in OFC and ACC activation and dopamine receptor availability in addiction.

 

[The Monkey Mantra]

^^^ Right-o about the decrease in OFC activation in addicts. Does the . And yeah, the OFC sends inhibitory signals back to the mesolimbic pathway. Can you clear up what you mean by reciprocal connections? I know it sends efferents (is it efferents and not afferents in this case? you *receive* afferents, right?) back to the NAc, but I don't know much more other than it helps regulate the perceived incentive salience/reward of an activity. I'm with you on the calculating expected outcomes deal. Can you help me understand the role of the ACC?

You have to forgive me for my speculations. I know they're kinda bogus/they just plain suck. I'm a biochem undergrad with absolutely NO training in any of this, so what I know is self-taught. If you ever feel generous enough to give me a little reward system overview, I'd be sooo happy!

 

[Tsukasa]

Salvia divinorum definately and maybe Nitrous oxide

 

[5-HT2]

^^^ Right-o about the decrease in OFC activation in addicts. Does the . And yeah, the OFC sends inhibitory signals back to the mesolimbic pathway.

What part of it? I don't believe I'm aware of this literature, unless you are talking about feedforward activation of striatal interneurons; AFAIK, OFC is generally thought to provide excitatory input to the principal neurons in the mesolimbic pathway.

Can you clear up what you mean by reciprocal connections? I know it sends efferents (is it efferents and not afferents in this case? you *receive* afferents, right?) back to the NAc

Correct, it is efferents. Reciprocal connectivity means that the two regions both send and receive inputs from each other.

but I don't know much more other than it helps regulate the perceived incentive salience/reward of an activity. I'm with you on the calculating expected outcomes deal. Can you help me understand the role of the ACC?

Not much is known about the role ACC plays in addiction. More generally, it is involved in action selection and seems to integrate the animal's reinforcement history to update action-outcome contingencies.

 

[The Monkey Mantra]

^^



And let me check on that thing about the OFC. I'm gonna defer to you on this one, but I'll look at my books. I'm teaching this stuff to myself, so I get it all mixed up sometimes.

 

[The Monkey Mantra]

To 5-HT2 regarding PFC

To 5-HT2:

Here's a study about the PFC inhibiting DA activity in the NAc:

NSFW:

Titre du document / Document title
Stimulation of prefrontal cortex at physiologically relevant frequencies inhibits dopamine release in the nucleus accumbens
Auteur(s) / Author(s)
JACKSON Mark E. (1) ; FROST Adam S. (1) ; MOGHADDAM Bita (1) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) Department of Psychiatry, Yale University School of Medicine, VA Medical Center, West Haven, Connecticut, ETATS-UNIS
Résumé / Abstract
The prefrontal cortex (PFC) is thought to provide an excitatory influence on the output of mesoaccumbens dopamine neurons. The evidence for this influence primarily arises from findings in the rat that chemical or high-intensity and high-frequency (60-200 Hz) electrical stimulations of PFC increase burst activity of midbrain dopamine neurons, and augment terminal release of dopamine in the nucleus accumbens. However, PFC neurons in animals that are engaged in PFC-dependent cognitive tasks increase their firing frequency from a baseline of 1-3 Hz to 7-10 Hz, suggesting that the commonly used high-frequency stimulation parameters of the PFC may not be relevant to the behavioral states that are associated with PFC activation. We investigated the influence of PFC activation at lower physiologically relevant frequencies on the release of dopamine in the nucleus accumbens. Using rapid (5-min) microdialysis measures of extracellular dopamine in the nucleus accumbens, we found that although PFC stimulation at 60 Hz produces the expected increases in accumbal dopamine release, the same amplitude of PFC stimulation at 10 Hz significantly decreased these levels. These results indicate that activation of PFC, at frequencies that are associated with increased cognitive demand on this region, inhibits the mesoaccumbens dopamine system.
Revue / Journal Title
Journal of neurochemistry ISSN 0022-3042 CODEN JONRA9
Source / Source
2001, vol. 78, no4, pp. 920-923 (24 ref.)