Anxiolytic Action of Dipeptide Mimetic of the BDNF Loop 2 in Adult Animals.

We studied the anti-anxiety effect of a low-molecular-weight mimetic of the BDNF loop 2, hexamethylenediamide bis-(-N-hexanoyl-L-seryl-L-lysine) (GTS-201) in adult animals. GTS-201 at a dose of 5 mg/kg after acute intraperitoneal administration to outbred male and female rats increased the time spent in the open arms and the number of entries into the open arms in the elevated plus maze (EPM). In "highly emotional" male BALB/c mice, GTS-201 exhibited a dose-dependent anxiolytic effect in the EPM in a dose range of 0.5-2.0 mg/kg with a maximum effective dose of 1 mg/kg. These data confirm the previously revealed anti-anxiety properties of GTS-201 in inbred male and female BALB/c mice and rats and indicate the dependence of the pharmacological activity of the BDNF mimetic on animal age.

Low-Molecular-Weight Mimetic of BDNF Loop 2 Reduces Ethanol Consumption in Female Rats.

The study examined the effect of GTS-201, a low-molecular weight mimetic of brain-derived neurotrophic factor (BDNF) loop 2, on persistent alcohol craving in outbred male and female albino rats with ethanol preference score ~50% developed in the free choice paradigm between 10% ethanol and water over 24 weeks. Both single and subchronic (5 days) injections of GTS-201 in a daily dose of 5 µg/kg reduced alcohol deprivation effect in female, but not in male rats. The possibility of in vivo sex-dependent regulation of modeled alcohol craving with a low-molecular-weight dipeptide mimetic of BDNF loop 2 was demonstrated and sex-related differences in this effect were revealed.

Experimental Evaluation of Anxiolytic and Analgesic Properties of a New Linear Methoxyphenyltriazaalkane Derivative with Cardiotropic Activity.

The anxiolytic and analgesic properties of compound ALM-802, a cardiotropic linear methoxyphenyltriazaalkane derivative, combining pharmacophore elements of p-FOX inhibitors trimetazidine and ranolazine were studied in vivo. In the elevated plus-maze test, ALM-802 after acute intraperitoneal administration in doses of 1-8 mg/kg dose-dependently prevented the development of anxiety in BALB/c mice. Chronic intraperitoneal administration of ALM-802 in a dose of 2 mg/kg to alcohol-preferring rats attenuated anxiogenesis induced by ethanol withdrawal. ALM-802 demonstrated antinociceptive activity in C57BL/6 mice during thermal stimulation of nociceptors in the hot plate test and during modeling of visceral pain in the acetic acid writhing test. Thus, ALM-802 exhibits anxiolytic and analgesic properties in the dose range corresponding to its anti-ischemic and antiarrhythmic effects.

Peptide Mimetic of BDNF Loop 4 Blocks Behavioral Signs of Morphine Withdrawal Syndrome and Prevents the Increase in ΔFosB Level in the Striatum of Rats.

Activity of compound GSB-106, a low-molecular mimetic of loop 4 of the brain neurotrophic factor (BDNF), was studied in experimental morphine withdrawal syndrome simulated in outbred rats. Single and subchronic (5 intraperitoneal injections) administration of GSB-106 in a dose of 0.1 mg/kg significantly reduced the total index of morphine withdrawal syndrome by 55.2 and 45.6%, respectively. GSB-106 reduced the severity of some behavioral signs (piloerection, gnashing of teeth, wet-dog shaking, and runaway attempts), but had no effect on mechanical allodynia formed in the rats with dependence. Subchronic treatment with GSB-106 prevented the increase in the content of ΔFosB (product of early response gene) in the striatum induced by morphine withdrawal. The results confirmed the concept on the involvement of neurotrophins, specifically BDNF and its analogs, in the mechanisms associated with the formation of opiate dependence.

Selank, Peptide Analogue of Tuftsin, Protects Against Ethanol-Induced Memory Impairment by Regulating of BDNF Content in the Hippocampus and Prefrontal Cortex in Rats.

The effects of a peptide anxiolytic Selank synthesized on the basis of the endogenous peptide tuftsin on memory impairment and content of brain-derived neurotrophic factor (BDNF) in brain structures were analyzed in outbred rats receiving 10% ethanol as the only source of fluid for 30 weeks. In the object recognition test, Selank (0.3 mg/kg a day, 7 days, intraperitoneally) produced a cognitive-stimulating effect in 9 months rats not exposed to ethanol (p<0.05) and prevented the formation of ethanol-induced memory and attention disturbances (p<0.01) developing during alcohol withdrawal. In ex vivo experiments, Selank prevented ethanol-induced increase in BDNF content in the hippocampus and frontal cortex (p<0.05). These results indicate positive effects of the tuftsin analogue on age-related memory disturbances associated with chronic alcohol intoxication and confirm the involvement of the neurotrophin mechanism related to BDNF production into the effect of Selank.

Specific Features of Depolarization of the Left and Right Atria in Rats with Alcoholic Cardiomyopathy.

Using a translation model of alcoholic cardiomyopathy in rats we showed the presence of an additional abnormal excitation focus in the area of the pulmonary vein lacunae in the left atrium and enhanced heterogeneity of the atrium depolarization pattern. These changes can determine electric instability of the myocardium and induce malignant heart rhythm disturbances including, sudden cardiac death.

Non-Competitive NMDA Receptor Antagonist Hemantane Reduces Ethanol Consumption in Long-Term Alcohol Experienced Rats.

Activity of hemantane, an amino adamantane derivative, exhibiting the properties of lowaffinity non-competitive NMDA receptor antagonist, was evaluated in experimental in vivo models of alcoholism. Hemantane had no effects on the formation and manifestation of behavioral sensitization to ethanol in DBA/2 mice. Under conditions of free choice between 10% ethanol and water, hemantane (20 mg/kg/day for 14 days, intraperitoneally) significantly reduced the daily ethanol intake in random-bred male rats with formed alcohol motivation (>4 g/kg of ethanol). During modelling of withdrawal syndrome, hemantane administered intraperitoneally in doses of 5-20 mg/kg dose-dependently attenuated alcohol-deprivation effect after acute withdrawal with no effects on protracted abstinence. It was found that hemantane suppressed alcohol drinking behavior in long-term ethanol experienced rats and attenuated alcohol-seeking behavior after acute withdrawal.

Anxiolytic Properties of Trimetazidine in Experimental Models of Increased Anxiety.

Effect of trimetazidine (20 and 30 mg/kg) on elevated plus maze behavior of rodents was assessed in the genetic and pharmacological anxiety models. Single intraperitoneal injection of trimetazidine in a dose of 20 mg/kg prevented anxiety development in highly emotional male BALB/c mice and increased the time spent in open arms of the maze. In outbred male rats receiving 10% ethanol solution for 20 weeks, trimetazidine administered intraperitoneally in a dose of 20 mg/kg for 28 days abolished ethanol withdrawal-induced anxiogenesis developed against the background of 4-week alcohol deprivation: it increased the time spent in open arms, the number of entries into open arms, and total locomotor activity in the maze. Anxiolytic properties of trimetazidine were not inferior to those of the non-benzodiazepine anxiolytic Afobazole (fabomotizole) in acute and chronic administration.

Selank Inhibits Ethanol-Induced Hyperlocomotion and Manifestation of Behavioral Sensitization in DBA/2 Mice.

The effect of non-benzodiazepine anxiolytics on the ethanol-induced hyperlocomotion and behavioral sensitization was assessed in male DBA/2 mice. Selank that enhances activity of the endogenous opioid system (0.3 mg/kg, intraperitoneally), similar to the nonselective opiate receptor blocker naloxone (1.0 mg/kg, intraperitoneally), prevented the development of ethanol-induced (2.0 g/kg intraperitoneally) hyperlocomotion, in contrast to σ1-receptors agonist Afobazole (1.0 mg/kg, intraperitoneally) that did not inhibit ethanol-induced behavioral stimulation. Single dose of Selank significantly blocked manifestation of motor sensitization without affecting its formation. These findings suggest that Selank can modulate the motivational effects of ethanol.

PECULIARITIES OF THE EFFECT OF AMINOADAMANTANE DERIVATIVES ON ETHANOL-INDUCED ATAXIA. SEDATION. AND HYPERLOCOMOTION IN MICE.

The influence of two aminoadamantane derivatives representing low-affinity NMDA receptor antagonists, which show antiparkinsonian-like activity both in animal models and in patients with Parkinson's disease, have been studied in vivo on mice with acute ethanol-induced disorders. N-(adamant-2-yl) hexamethyleneimine hydrochloride (himantane) in doses of 5--20 mg/kg, i.p., dose-dependently prevented ethanol-induced ataxia in CD-I mice, sedation in C57BI/6 mice, and hyperlocomotion in DBA/2 mice. At the same time, I -aminoadamantane (amantadine) in doses of 10 - 20 mg/kg, i.p., did not attenuate acute ethanol-induced (2 g/kg, i.p.) effects. Neither himantane nor amantadine influenced the duration of ethanol narcosis (5.5 g/kg, i.p.) in CD-I mice. The obtained data showed a difference of the pharmacodynamic profile of himantane as low-affinity NMDA receptor antagonist in interaction with ethanol at doses inducing behavioral disorders.

[To the potential use of alcoholic cardiomyopathy echocardiography assessment of forming].

Chronic alcohol abuse leads not only to a significant human psychic and social degradation, but also promotes the alcoholic cardiomyopathy formation, that is one of the leading causes of high mortality of alcoholics. However, to date in clinic there are no unified approaches in the prevention and treatment of alcoholic cardiomyopathy, first of all, due to the lack of the adequate model in the experimental pharmacology, which can assess the stages of formation of alcoholic cardiomyopathy objective and in real time, and thus create the basis for the search and study the mechanisms of action of drugs for the treatment of this serious disease. Studing the possibility of echocardiography using in experiments with rats exposed to prolonged forced alcoholism is one of the approaches to solve this problem. It was shown that the significant changes of intracardiac echocardiography hemodynamics corresponding to the known from the clinic, begining to form from the 20th week of systematic consumption of alcohol by rats. At this time interval the reduction in inotropic function of the heart in alcoholized rats compared to control is observed: fraction shortening (FS) is 41.9% (40.3-42.2) and 51.3% (48.8-59.1) respectively, and ejection fraction (EF) 78.8 (77.4-79.2) and 87.5% (84.6-92.4) respectively, p = 0.0215. The dilated heart failure develops in the rats from the 24 week of regular alcohol consumption, as evidenced not only by dynamic reducing of FS and FV, but also by the dilatation ofthe heart. For example, the end-systolic size of the left ventricle in animals consuming alcohol compared with control increased more than 2 times (4.31 mm (3.80-4.41) and 2.0 mm (1.85-2.36); p = 0.0008, and the end-diastolic dimension was 5.95 mm (5.13-6.37) and 4.52 mm (3.85-4.90) respectively; p = 0.0171. Thus, the echocardiographic picture characteristic for alcoholic dilated cardiomyopathy is formed by the end of the 24th week of chronic alcoholiation.

Efficacy of peptide anxiolytic selank during modeling of withdrawal syndrome in rats with stable alcoholic motivation.

We studied the effects of selank on the development of symptoms of acute 48-h alcohol withdrawal in outbred rats drinking 10 % ethanol as the only source of fluid for 24 weeks. In alcohol-preferring animals (mean daily ethanol intake >5.0 g/kg) allowed free choice between 10 % ethanol and water, single intraperitoneal injection of selank in a dose of 0.3 mg/kg eliminated anxiety induced by ethanol withdrawal in tests elevated plus maze and social interaction tests and prevented the formation of mechanical allodynia without affecting ethanol consumption. The fi ndings suggest that selank is effective in eliminating of alcohol withdrawal symptoms in rats.

Effects of phenazepam on the behavior of C57BL/6 and BALB/c mice in the open field test after naloxone pretreatment.

We studied the effects of phenazepam (0.075 mg/kg) after pretreatment (5 minutes before) with naloxone (10 mg/kg) on open-field behavior of C57Bl/6 and BALB/c mice. In ex vivo experiments, we studied the effects of naloxone (1 and 10 mg/kg) on receptor binding of [(3)H]-flunitrazepam by membranes of brain fraction (P1+P2) of C57Bl/6 and BALB/c mice. It was shown that naloxone increased motor activity in the open field in BALB/c mice and decreased this parameter in C57Bl/6 mice. During combined treatment, naloxone potentiated the activating effects of phenazepam on the open-field behavior of BALB/c mice and slightly increased the sedative effect of this drug in C57Bl/6 mice. Naloxone stimulated reception of [(3)H]-flunitrazepam in BALB/c mice and slightly increased radioligand binding in C57Bl/6 mice. These data attest to enhanced reception in benzodiazepine site of GABAA-receptor under conditions of opioid receptor blockade, the presence of anxiolytic or sedative (depending on the phenotype of the response to emotional stress) effect of naloxone, and co-directed effects of naloxone and benzodiazepine tranquilizer on open-field behavior of C57Bl/6 and BALB/c mice.

[The role of opioid system in peculiarities of anti-anxiety effect of peptide anxiolytic selank].

Peculiarities of the anxiolytic effects of selank (heptapeptide analog of taftsin) under reduced activity of opioid system upon acute administration of naloxone have been studied in BALB/C and C57BL/6 inbred mice with high and low levels of anxiety, with passive and active emotional stress reaction phenotypes in the open field (OF) test. Selank (0.25 mg/kg, i.p.) per se exhibited anxiolytic effect in BALB/C mice by increasing the general locomotor activity, with no effects on the behavior of C57BL/6 mice in the OF test. Naloxone (1.0 mg/kg, i.p.) per se evoked swift runaway in OF peripheral areas in BALB/C mice while "freezing" the reaction in C57BL/6 mice with active response to stress under the same conditions. Pretreatment with naloxone attenuated the sensitivity to selank in BALB/C mice whereas the response to anxiolytic effects of peptide was increased in C57BL/6 mice. The data obtained reveal a new target for selank in CNS and indicate significance of the activity of enkephalin-opioid system in individual sensitivity to selank.

Naloxone effects on behavior of inbred mice with different response to emotional stress in open field test.

Effects of nonspecific opiate receptor antagonist naloxone in doses of 0.1, 0.5, 1.0, 5.0, 10.0 mg/kg on open field behavior and spontaneous motor activity were studied in male BALB/c and C57Bl/6 mice. Differently directed effects of naloxone on behavioral parameters of emotional-stress reaction in BALB/c and C57Bl/6 mice were observed. Naloxone increased motor activity in the open field test in BALB/c mice, but decreased it in C57Bl/6 mice. In the absence of stress, naloxone in the studied dose range did not affect spontaneous motor activity in C57Bl/6 mice, and significantly reduced activity in BALB/c mice in doses 0.5 and 1.0 mg/kg.