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P.6.c.014. ACTH4-10 analogue and Adamantane derivative Hemantane produce significant reduction of withdrawal signs in -dependent rats M.A. Konstantinopolsky ¹, L.G. Kolik ¹ V.V. Zakusov Institute of Pharmacology, ¹ Laboratory of Pharmacological Regulation of , Moscow, Russia, [email protected] Introduction :. The mechanism of -like addiction has defined connections with DA-ergic reward system as well as with glutamate and NMDA systems of the brain. At the same time, some neuropeptides, namely, CCK analogues and one of taftsin derivatives, are able to reduce the severity of withdrawal signs in morphine-dependent rats [1,2] that give as the opportunity to suggest the modulating effect of these in relation to opioid induced addiction. These facts have been considered when searching for new compounds with different action mechanisms to prevent and relieve the state of dependence. The main effects of Semax are its , neuroprotective and activity with the participation of and CCK-receptors and, possible, BDNF [3], while Hemantane and Adamantane have an well-marked antiparkinsonian activity with the involvement of glutamatergic and NMDA receptor mechanisms [4]. Aim The present study was started to investigate the effects of the adrenocorticotropic hormone fragment, ACTH4-10, geptapeptide Semax (Inst. of Mol. Genetics RAN, Moscow) in comparison with those of Hemantane (N-adamant-2-yl-hexamethyleneimine hydrochloride, V.V. Zakusov Inst. of Pharmacology, Moscow) and Amantadine hydrochloride (1-aminoadamantane hydrochloride, Sigma-Aldrich), as a reference drug, upon withdrawal syndrome (WS), tactile thresholds in “von Frey test”(Ugo Basile) and ambulation in the “open field”(OF) Methods. Incremental doses of morphine were injected i.p. to outbred male rats for 5 days followed by (Du Pont De Nemours),1mg/kg, to provoke acute WS. Semax (0.05 – 0.5 mg/kg), Hemantane (10 – 20 mg/kg), Amantadine (10 - 20 mg/kg) have been injected one fold, 45 min before the test started in the “open field” or daily, 30 min before the morphine injections; 16 behavioural, neurological and vegetative signs of WS were registered in rats, placed in OF, after that the Total Index (TI) of WS was evaluated [5]. Plantar tactile thresholds were measured via “von Frey” test (Ugo Basile) before the beginning of morphine injections and after morphine withdrawal. The BW changes were marked every second day. For statistical assay Mann-Whitney-test, one way ANOVA and were used.

Rhinorrhea and nasal bleeding Flattening pose, ptosis, tonic seizures and writhing Catalepsy Tail flick & Hot plate Tests

Morphine acute effects Signs of morphine withdrawal syndrome

«DA-related conception of addiction with Hemantane possible neuropeptides involvement . Amantadine Neuropeptides modulating effect StimulantsStimulants Semax VTA + N NH2 HCl PFC . Von Frey test (tactile GABA -- DA A way to addiction… n.accumbenc + Glut HCl sensitivity test ) + amygdala Stimulants hippocampus opiates The influence of Hemantane on behavioural cannabis indices of morphine WS in rats

modified from N. Latt et al. Addiction medicine, 2009 120

Dose, mg/kg

*** %

1 control (Met-Glu-His-Phe-Pro-Gly-Pro) 100 The influence of Semax on tacktile thresholds in 2 morph chr+ Nal 80 morphine-dependent rats after a single or chronic *** # 3 Hemanane 10+ morph *** ## chr+Nal" application 60 4 Hemantane 20+morph

chr+Nal

SUMMARY OF RESULTS

100 40

level 90 80 ##- p < 0.01 Semax, administered in a small single doses of 0.05 mg/kg eliminated 20 70

to base to #- p < 0.05

individual features and decreased TI of morphine WS by 36.4%, p < 60 (vs gr.2) 50 Total Index of morphine WS, WS, morphine of Index Total 0 0.05. Subchronic administration of morphine with Semax in same dose 40 ** 30 1 2 3 4 decreased the TI of WS by 30.0 %, p < 0.05. The higher doses of Semax 20 10 Experimental groups (0.5 mg/kg) were not effective in relation to TI of WS. The tactile 0 The base level morph chr+Nal Sемаx 1+morph Semax chr+morph

thresholds were restored significantly to the 24.7% level followed by % in thresholds Tactile chr+Nal chr + Nal The effect of Hemantane upon tactile Semax was given subchronicaly in small dose (0.05 mg/kg) to morphine- Experimental groups **-p < 0.01 thresholds in morphine-dependent rats dependent rats, comparing with “morphine + naloxone” group level of Dose, mg/kg 7.59 % (p < 0.009). Effect of Semax applied in a single i/p 80 doses upon morphine WS in rats 1 control Hemantane administered once in single doses of 10 and 20 mg / kg, 70 2 morph chr+ Nal 60 significantly reduced the severity of TI of WS, respectively by 46% and # % 100 50 3 Hemantan 10+morph , ,

33.2% and induced the decrease in severity or elimination of such signs 90 chr+Nal Dose, mg/kg 40 80 4 Hemantan 20+morph * of WS as vocalization, teeth chattering and ptosis. Amantadine did not 1 control 30 ** ** chr+Nal 70 exert statisticaly significant effect on the indices of morphine WS. 60 20 2 morph chr+Nal 50 #-p < 0.05 Moreover, it caused a number of negative side effects, namely, a 10 vs to gr2 40 **- p < 0.01 3 Semax 0.05+morph chr+Nal 0 decrease of locomotion and tactile thresholds, an additional BW drop 30 1 2 3 4 vs to gr1 Tactile thresholds base in thresholds level %to Tactile and induced the aggressive behaviour in abstinent morphine dependent 20 4 Semax 0.5+morph chr+Nal 10 Experimental groups

rats. ofmorphine WS Index Total 0 *-p< 0.05 1 2 3 4 Vs contr gr1 Experimental groups Amantadine can not eliminate the behavioral symptoms Effect of chronic Semax adminisration upon of morphine withdrawal syndrome in rats CONCLUSION 120 opiate WS in male rats Dose, mg/kg

*** *** *** % %

100

1 control

ACTH4-10 analogue, geptapeptide Semax and N- 100 , , % Dose mg/kg 80 2 morph chr+Nal

90 * WS WS

adamantane derivative Hemantane, but not Amantadine, 80 3 Amantadine10+morph 70 1 control 60 are promising preparations for correction of opioid addiction. chr+Nal 60 Amantadine had not influence on any signs of morphine 2 morphine chr+Nal 40 4 Amantadine20+morph 50 ch+Nal 40 withdrawal syndrome in rats and demonstrated additional 3 Semax chr 0.05+morph

30 WS, morphine of Index Total 20 chr+Nal ***-p < 0,001

20 Index (TI) of morphine of (TI) Index

side effects in these animals. 4 Semax chr 0.5+morph 10 . chr+Nal 0 Vs gr1 control *

Total 1 2 3 4 0 1 2 3 4 Experimental groups *- P < 0.05 Experimental groups References [1] Konstantinopolsky M.A., Chernjakova I.V., Gudasheva T.A. New cholecyctokinin-4 retro-analogue and dipeptide analogue of neurotensine as opiate dependence correctors: an experimental study. Europ.Neuropsychoparmacology, 21, (2), s168, (2011) [2 ] Konstantinopolsky M.A, Kolik L.G,. Gudasheva T.A., 2014. New peptide origin , GB-115 and , as a possible tools in treatment of opiate addiction: an experimental study. Eur.Neuropsychopharmacol., v.24, N 2, s676-s677. [3] Levitskaia NG., Vilenskiĭ DA., Sebentsova EA., Anreeva LA, Kamenskiĭ AA, Miasoedov N.F. 2010. Influence of Semax on the emotional state of white rats in the norm and against the background of -tetrapeptide action. Izv Akad Nauk Ser Biol., Mar- Apr;(2):231 -7. [4] Ivanova EA, Kapitsa IG, Val'dman EA, Voronina TA.,2015 Anti-Parkinsonian Activity of Hemantane on a Model of Hemiparkinsonian Syndrome in Rats. Bull Exp Biol Med. 159(3):380-3. [5] Konstantinopolsky M.A., Cherniakova I.V. Afobazole decreases severity of morphine withdrawal syndrome: experimental evidence,. Eksp. Klin. Farmakology, 74(10):12-6, (2011)

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OH H N NH2 HN O O O HN O OH

O O HN O HO O HN N NH2 H HO Dipeptide mimetic of BDNF GSB-106 GB-115 Ph(CH2)5CO-Gly-Trp-NH2

THE BDNF CONFORMATION