Tolerance to an antagonist?

[Fornax55]

How does this work? Couldn't find anything in the search. I know (or I'm currently under the impression) that receptor downregulation is a huge factor in the development of tolerance. Antagonists, with repeated use, tend to upregulate receptor density. So what mechanism is responsible for the development of tolerance to antagonistic substances, such as DXM or CBD?

Furthermore, are any antagonistic substances known to cause dependency and withdrawal?

 

[Cotcha Yankinov]

Some antagonists work by causing downstream excitation.

As an example, DXM (or rather its major metabolite DXO) works primarily by blocking NMDA receptors. NMDA receptors are excitatory receptors that turn on neurons, which then release transmitters.

NMDA receptors are highly expressed on inhibitory interneurons like GABA neurons, where they turn on GABA interneurons, increasing GABA release and resulting in inhibition of downstream cells, for example serotonin releasing cells. When DXM blocks the excitatory NMDA receptor expressed on the GABA neuron, it turns off the GABA neuron, resulting in decreased release of the inhibitory GABA transmitter, which then leads to decreased inhibition of the serotonin cell (which expresses GABA receptors) thus resulting in more serotonin release.

As the serotonin cell releases more serotonin that goes on to bind to downstream serotonin receptors, this contributes to the effects of DXM but with time the serotonin receptors can downregulate and thus we have tolerance to the effects of an antagonist.

Clear as mud? Any questions are welcome,
CY

 

[Coolwhip]

Tolerance is much more multi-facted and complicated than simple down regulation; which in and of itself is wholly misunderstood and oversimplified, receptor "downregulation" generally refers to a whole hose of intra and extra cellular changes which occur in response to drug binding. But more importantly there are many downstream and upstream mechanisms which your body uses to maintain equilibrium in response to drug use, spanning multiple receptor/circuit systems throughout the brain and body.

 

[Fornax55]

Hm, alright. That's about the best answer I could hope for - "it's more complicated than you think."

Thanks for the well written answers and more food for thought

 

[Coolwhip]

In the context of your questions, like you said, Cotcha's answer is the best you could hope for. Yes, antagonists can behave in the way you are asking about, but generally only when they lead to activation of other circuits downstream, in effect creating agonism of other systems. In the case of antagonists that don't have such profound effects, e.g. naltrexone, you won't see such affects but there is evidence that it can lead to hypersensitivity of opioid receptors that would become apparent the next time you took an agonist, but this effect would fade almost immediately. There are also serotonin antagonists that can lead to increased/decreased levels of dopamine/norepinephrine, or presynaptic dopamine antagonists which can raise levels of dopamine. The serotonin antagonists surely have some sort of rebound effect, but I wouldn't say they cause dependency or withdrawal.

 

[Limpet_Chicken]

There are drugs like say, memantine for instance that in part, work via a mechanism like this.

Memantine, if we disregard the better known voltage-gated NMDA antagonism, is also an alpha7 neuronal nicotinic acetylcholine receptor antagonist. Agonist drugs of alpha7 NAChRs are nootropic, galantamine works partly that way in addition to its anticholinesterase effects, and with memantine (which hopefully I'll have my doc scripting me soon), initially causes a sort of brain fog and impairment of memory, partly due to alpha7 nicotinic antagonism, then a7 NAChRs are upregulated (increased expression) in response to the antagonistic effect, and after the initial down-phase in performance cognitively, one then sees the full benefit of the memantine as alpha7 nicotinic acetylcholine receptor upregulation occurs in response to the antagonism.