Agomelatine vs L-Tetrahydropalmatine (L-THP)

Cognitive

Cognitive

Research Only

Research Only

Agomelatine acts as a high-affinity agonist at melatonergic MT1 and MT2 receptors and as an antagonist at serotonin 5-HT2C receptors. The two actions are thought to act synergistically—proposed via MT2/5-HT2C receptor heteromers with distinct Gi signaling—to resynchronize circadian rhythms and disinhibit noradrenaline and dopamine release in the frontal cortex, the proposed basis for antidepressant activity.

L-THP acts as a mixed dopamine receptor antagonist, binding D1 (Ki ~124 nM), D2 (Ki ~388 nM), and D3 receptors (Ki ~1420 nM), with additional affinity for serotonin 5-HT1A receptors (Ki ~340 nM) and alpha-1 adrenergic receptors; it also facilitates GABA-A receptor binding. In vivo microdialysis in rats indicates predominantly postsynaptic (not presynaptic) dopamine receptor antagonism underlies its effects on drug reward. L-THP modestly elevates extracellular nucleus accumbens dopamine alone but dose-dependently potentiates cocaine-induced dopamine elevation while reducing cocaine’s rewarding effects, consistent with postsynaptic antagonism.