Antidrug effects of GTS201 dipeptide, an imitation of the second bird BDNF, in morphine-addicted rats

BACKGROUND: The V.V. Zakusov Research Institute of Pharmacology developed hybrid digital sensors for the first, second, and fourth BDNF patches (GSB-214, GTSB-201, and GSB-106, respectively). When tested in vitro, on an oxidative stress model, in the culture of hippocampal neurons NT-22, the compound GTS201 (hexamethylenediamide bis-hexanoyl-seryl-lys), a simulator of the 2^nd series of BDNF, activates the TrkB spy receptor and MAPK/Erk kinase pathway but does not affect the PI3K/Akt signature pathway and has neuroprotective activity similar to BDNF.

AIM: To study the effect of GTS-201 dipeptide on the behavior of laboratory white rats during the formation of their dependency state and morphine withdrawal syndrome.

MATERIALS AND METHODS: Morphine dependence in rats was developed due to administration of morphine in a doses escalation manner ranging from 10 to 20 mg/kg twice daily at 8-h intervals for 5 days. GTS-201 was given in 1- or 5-mg/kg doses for once in 30 minutes before morphine on the 5^th day of the experiment or daily (in one of the groups) for 5 days in the morning 30 minutes before morphine administration. On the 5^th day of the experiment, animals were tested for the presence of specific signs of morphine withdrawal syndrome in an “open field” for 5 minutes. Four experimental groups were formed: group 1 “morphine hr. + naloxone” (“active control” group); group 2 “morphine hr. + GTS-201 (1) + naloxone”; group 3 “morphine hr. + GTS-201 (5) + naloxone”; and group 4 “morphine hr. + GTS-201 (1 × 5) + naloxone.” Designations: hr. — morphine administration within 5 days; (1) and (5) — doses of substances in mg/kg, (1 × 5) — chronic administration of the peptide for 5 days.

RESULTS: When studying the effect of GTS-201 dipeptide on behavioral, somatic, and neurological markers of animal behavior after morphine withdrawal, significant changes in the severity of individual signs of withdrawal syndrome were noted. Manifestations of diarrhea were significantly decreased in all groups of animals injected with the peptide. In animals from group 3, “morphine hr. + GTS201 (5) + naloxone showed the maximum effect: diarrhea was decreased by 71.0% (p < 0.001), convulsions were decreased by 83.3 % (p < 0.05), running was decreased by 71.4% (p < 0.01), and vocalization was decreased by 62.5% (p < 0.05). GTS-201, administered at a dose of 1 mg/kg once, eliminated the appearance of escape attempts in group 2, but the peptide at the same dose completely blocked convulsive reactions in rats in group 4. Despite significant changes in individual indicators, the total index (of morphine withdrawal syndrome for groups chronically injected with morphine) did not change statistically significantly compared with group 1 of “active control.” In the control group, its value in points was 7.3 ± 0.36 (100%), whereas in groups 2–4, it ranged from 6.2 (84.9%) to 6.5 (89.0%; p > 0.05).

CONCLUSIONS: It is assumed that the antiaddictive dipeptide activity of GTS-201 is mediated by activation of these receptors and markers/the Erk-kinase signaling pathway, which does not exclude the involvement of opioid receptor mechanisms in the implementation of the observed behavioral phenomena.