Latrepirdine (Dimebon), a potent 5-HT₇ receptor antagonist, modulates stress-mediated behaviors in rodents

First, determine the likely molecular target of latrepirdine. Second, using stress-mediated rodent behavioral models, determine which clinical neuropsychiatric symptoms are possibly improved by latrepirdine. Third, establish whether latrepirdine possesses properties suitable for chronic treatment of neuropsychiatric symptoms related to stress.

Characterization of the potency of latrepirdine was performed by both displacement binding with labeled LSD and inhibition of stimulated adenylyl cyclase activity using membranes from human 5-HT₇ cDNA receptor-transfected cells. Microdialysis: Samples of interstitial fluid from brain was collected using microdialysis probes and blood was obtained through a jugular cannulation. Behavioral models: Stress-related models included the elevated plus maze with either a yohimbine or CCK-4 challenge, the resident intruder aggression task, open field test, marble burying, latency to REM sleep, forced swim test and the open space swim test.

Binding and adenylyl cyclase activity aligned and indicated that affinity of latrepirdine for 5-HT₇ receptors was approximately 10 nM. Free brain levels of latrepirdine at effective doses in all models were consistently at the 10 nM level. Latrepirdine was effective after repeat dosing, reversible after stopping dosing, and demonstrated good brain penetration.

Latrepirdine, possibly by blocking 5-HT₇ receptors in the locus coeruleus, regulates anxiety, aggressive and compulsive behaviors in rodents. These effects may account for the neuropsychiatric effects detected in the clinic. Latrepirdine has properties that suggest it would be a useful drug for the chronic treatment of stress-induced and anxiety-related symptoms.