I have read that amisulpride in low doses (<50mg) blocks preferentially presynaptic D2 autoreceptors thereby increasing dopamine in synaptic cleft and dopamine neurotransmission. Can other benzamides, like tiapride, sulpiride, metoclopramide also work in low doses like antidepressants? What other drugs block these D2 autoreceptors? Thanks
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Benzamide antipsychotics
- Thread starter coriolis
- Start date
The short answer is no.
The long answer is new evidence actually shows that it is amisulprides antagonism of the 5-HT7 receptor which produces its antidepressant effects.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821721/
"Amisulpride displayed a U-shaped dose-response effect in 5-HT7+/+ mice (Figure 4) in both the TST and the FST, though the effective dose of amisulpride was different in the two depression models. In 5-HT7+/+ mice the immobility time was significantly reduced at 1 mg/kg in TST and 0.1 mg/kg in FST, which is consistent with the expected antidepressant effect of the drug. On the other hand, amisulpride in doses less than 10 mg/kg in TST and less than 1 mg/kg in FST did not affect immobility in 5-HT7−/− mice (i.e., exerted no antidepressant efficacy). At 10 mg/kg of amisulpride in TST and 1 mg/kg in FST, the immobility response was significantly increased in 5-HT7−/− mice to the level of 5-HT7+/+ mice, likely due to extra-pyramidal actions at these higher doses. Similarly, the clear antidepressant effect disappears at higher doses (3 and 10 mg/kg in TST and .3 and 1 mg/kg in FST) in 5-HT7+/+ mice. This low dose antidepressant effect of amisulpride is consistent with the clinical literature"
If confusing, it says that Amisulpride showed no anti-depressant effect in 5-HT7 Knockout mice at any dose, and in non-KO mice the AD effect dissappears at high doses. And at high doses it causes 5HT-7 KO mice to score the same as wild type mice(higher time, worse score). Likely because the AD effect of 5-HT7 antagonism is extinguished by DA antagonism at higher doses.
The long answer is new evidence actually shows that it is amisulprides antagonism of the 5-HT7 receptor which produces its antidepressant effects.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821721/
"Amisulpride displayed a U-shaped dose-response effect in 5-HT7+/+ mice (Figure 4) in both the TST and the FST, though the effective dose of amisulpride was different in the two depression models. In 5-HT7+/+ mice the immobility time was significantly reduced at 1 mg/kg in TST and 0.1 mg/kg in FST, which is consistent with the expected antidepressant effect of the drug. On the other hand, amisulpride in doses less than 10 mg/kg in TST and less than 1 mg/kg in FST did not affect immobility in 5-HT7−/− mice (i.e., exerted no antidepressant efficacy). At 10 mg/kg of amisulpride in TST and 1 mg/kg in FST, the immobility response was significantly increased in 5-HT7−/− mice to the level of 5-HT7+/+ mice, likely due to extra-pyramidal actions at these higher doses. Similarly, the clear antidepressant effect disappears at higher doses (3 and 10 mg/kg in TST and .3 and 1 mg/kg in FST) in 5-HT7+/+ mice. This low dose antidepressant effect of amisulpride is consistent with the clinical literature"
If confusing, it says that Amisulpride showed no anti-depressant effect in 5-HT7 Knockout mice at any dose, and in non-KO mice the AD effect dissappears at high doses. And at high doses it causes 5HT-7 KO mice to score the same as wild type mice(higher time, worse score). Likely because the AD effect of 5-HT7 antagonism is extinguished by DA antagonism at higher doses.
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I've read several times that the effects of sulpiride are very similar to amisulpride, although it's rather likely that those two would share the same interaction with 5-HT7 receptors. However I doubt it'd be feasible to come up a general rule for all molecules in that class; like the previous poster mentioned, these drugs are fairly "dirty" - meaning that they typically affect a wide range of different receptors - and trying to figure out what even a small structural change might do to their interaction which each and every one of those receptors would be near-impossible.
Can other benzamides, like tiapride, sulpiride, metoclopramide also work in low doses like antidepressants?
Cannot find any other; however quetiapine is a D2 antagonist (atypical anti-psychotic) that in low doses (25 mg PO qDay) acts as an antidepressant both as an additive and as a monotherapy. In fact quetiapine is the only anti-psychotic that acts as an antidepressant as a monotherapy.