How do Benzodiazepines induce Rewarding (Euphoric) effects?

Question

Benzodiazepines are a class of drugs that serve as positive allosteric modulators of the GABA_A receptor by binding to their own "site" on the aforementioned receptor. By doing this they produce euphoria and a wide range of effects characteristic of Central Nervous System (CNS) depression (e.g. anxiolysis, sedation, amnesia, mental confusion, muscle relaxant effects).

I know that an interaction with the mesolimbic dopamine ("reward") pathway would have to come in somewhere but where? I also know that GABAergic neurons downregulate activity in the mesolimbic dopamine pathway and that this is how opioids and cannabinoids induce euphoria -- they inhibit the release of GABA from presynaptic neurons in the mesolimbic dopamine pathway. I just find that this would be confusing in the case of benzodiazepines since they increase GABA activity, presumably also in the mesolimbic dopamine pathway thus producing dysphoria and not euphoria.

I just would like to know how they manage to induce euphoria in full (what they do to increase activity in the mesolimbic dopamine pathway that thus leads to euphoria)

Please cite journal articles to substantiate your claims.

Answer 1

Okay, I read the question wrong.

Benzodiazepines do not bind to GABA_A receptors universally. Thus the presumption that it inhibits the mesolimbic dopamine pathway may be wrong. They may not interact directly with said pathway at all.

Many subtypes for the GABA_A receptor exist. The receptor consists of 5 subunits. The following subunits are known to exist: α1-6, β1-3 and γ1-3. The most common combination has two α, two β and one γ. You find ones with distinct compositions at distinct locations in the brain. All have two bindingsites for GABA, but only a subset has an additional binding site for benzodiazepines.

The benzodiazepine binding site is at the interface of an α and a γ subunit, so receptors without this structure will show no affinity for benzodiazepines. Additionally the α subunit must contain a histidine residue, which is only true for α1, α2, α3 and α5. That is paraphrased from wikipedia, where you can find the sources as well.

I still think you need to consider the idea that benzodiazepines may not interact directly with the dopaminergic reward pathway, like opiates and cocaine does. I attribute the euphoria to be an indirect effect, resulting from the muscle relaxation (which will feel like you had a good massage), and the calmness of the mind.