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Is it possible to regulate the functional properties of abnormally developed spinal neuronal locomotor networks using transcutaneous spinal cord stimulation? This question has been studied in twenty-eight participants (∼9 yrs) with spastic cerebral palsy, and mainly Gross Motor Function Classification System for Cerebral Palsy level III. The participants were randomly assigned to two groups. The experimental group received transcutaneous spinal cord stimulation at two spinal levels (over T11 and L1 spinous processes), combined with locomotor treadmill training, whereas the participants of the control group received locomotor treadmill training only. After spinal cord stimulation in the experimental group we found an incremental increase in knee torque whereas in the control group this effect was absent. The amplitude of hip motion increased in both groups. A decrease of co-activation of hip and muscles of the lower extremities was observed in the experimental group while in the control group co-activation decreased only in hip muscles. The results support the idea that locomotor function can be improved significantly with the combination of training and transcutaneous spinal cord stimulation than with training alone., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We analyzed the efficiency of percutaneous electrical stimulation of the spinal cord and serotonin receptor activation in rehabilitation of paralyzed patients. Four-week course of spinal cord electrical stimulation combined with mechanotherapy produced positive shifts in the status of chronically paralyzed patients. Serotonin receptor activation potentiated the effect of spinal cord stimulation and can be regarded as an additional neurorehabilitation option.

There is a growing body of evidence indicating that stimulation of metabotropic glutamate type II receptors (mGlu2/3) reduces anxiety in laboratory animals and humans. Surprisingly, it was reported that mGlu2/3 receptor antagonists have antidepressant- and anxiolytic-like activities in laboratory animal studies as well. The present study aimed to resolve this controversy by characterizing behavioral effects of a selective mGlu2/3 receptor antagonist, LY-341495, in a variety of animal models sensitive to clinically used anxiolytic and antidepressant agents. In agreement with previous reports, LY-341495 (0.3-3 mg/kg, i.p.) reduced immobility in the mouse forced swim test. LY-341495 was also effective in the marble burying test in mice, although similar effects were observed after administration of various drugs including methamphetamine. Further, LY-341495 had no effects in the elevated plus maze and stress-induced hyperthermia tests in mice, as well as on punished drinking (Geller-Seifter's test) and differential reinforcement of low rates of responding (DRL) in rats. It is concluded that behavioral profile of mGlu2/3 receptor antagonists as represented by LY-341495 is different from that of conventional anxiolytic and antidepressant drugs.

Rationale: Metabotropic glutamate 1 (mGlu1) receptor antagonists were reported to induce cognitive deficits in several animal models using aversive learning procedures., Objective: The present study aimed to further characterize behavioral effects of mGlu1 receptor antagonists using appetitively motivated tasks that evaluate working memory, timing, and impulsivity functions., Materials and Methods: Separate groups of adult male Wistar rats were trained to perform four food-reinforced operant tasks: delayed non-matching to position (DNMTP), differential reinforcement of low rates of responding 18 s (DRL 18-s), signal duration discrimination (2-s vs 8-s bisection), and tolerance to delay of reward. Before the tests, rats were pretreated with (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM; 2.5-10 mg/kg, i.p.; JNJ16567083)., Results: In DNMTP task, EMQMCM produced delay-dependent increases in performance accuracy so that, at 10 mg/kg dose level, percentage of correct lever choices was enhanced at 8- and 16-s delays. In DRL task, at all three tested doses, response rates were higher, and reinforcement rates were lower than under control conditions. In signal duration discrimination tasks, EMQMCM did not have any specific effects on temporal control. In tolerance to delay of reward, EMQMCM (5 and 10 mg/kg) facilitated choice of the lever associated with large reward at longer delay levels., Conclusions: Blockade of mGlu1 receptors improves working memory and reduces impulsive choice at the doses that have no effects on time perception but appear to facilitate impulsive action.

In contrast to conventional opioid analgesics, antagonists acting at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors are capable of suppressing pain-related phenomena in chronic pain models while having little or no effect on acute nociception. One of the few clinically used NMDA receptor antagonists, memantine, differs from prototypic antagonists with psychotomimetic activity such as phencyclidine and (+)MK-801, in showing lower receptor affinity, faster unblocking kinetics and stronger voltage-dependency. Recently, a series of novel amino-alkyl-cyclohexanes was reported to interact with NMDA receptors in a manner similar to that of memantine. The present study aimed to evaluate the effects of these compounds as well as (+)MK-801 and memantine in two rat models of chronic pain and the rotarod test. Unlike (+)MK-801 and memantine, most of the tested compounds were inactive against tactile allodynia induced by sciatic nerve ligation. On the other hand, all tested drugs were found to inhibit formalin-induced grooming behavior-a model of chronic pain induction. In agreement with previous reports on the effects of NMDA receptor antagonists in similar assays, the late phase seemed to be inhibited to a greater extent than the early phase. For all tested compounds, inhibition of formalin-induced behaviors occurred at dose levels that were also producing significant motor deficits (rotarod test). These results confirm low efficacy of acute administration of NMDA receptor antagonists in the models of established pain states. Thus, studies on the prevention and management of chronic pain should focus on preemptive or long-term administration of NMDA receptor antagonists.

Antagonists acting at N-methyl-D-aspartate (NMDA) receptors have been demonstrated repeatedly to attenuate the expression of drug and alcohol withdrawal syndromes. The present study aimed to evaluate the effects of NMDA receptor blockade on the expression of behavioural signs of caffeine withdrawal syndrome, assessed using the social interaction paradigm. Adult male Swiss mice were treated with increasing doses of caffeine (40-100 mg/kg, i.p., twice daily) for 8 days. Twenty-four hours after the last injection of caffeine, there were significant increases in duration and frequency of defensive behaviours, as well as decreased locomotor activity. These changes faded within 72 hours. Pretreatment with a single dose of caffeine (1 mg/kg; 24 h after the end of repeated caffeine administration and 30 min prior to the test) completely reversed these withdrawal-related changes. Separate groups of mice were treated i.p. with different doses of memantine (1, 3 or 10 mg/kg) or neramexane (MRZ 2/579; 1, 3 or 10 mg/kg) 24 h after the last caffeine injection. Both compounds dose-dependently reduced the expression of defensive behaviours while increasing motor activity. These data suggest that NMDA receptor blockade may counteract the acute behavioural effects of caffeine withdrawal.

The 'deprivation effect' (DE) phenomenon is expressed as an increase in the level of free choice consumption of drugs, alcohol, or saccharin following a period of forced abstinence in humans and in several species of laboratory animals. The DE may reflect relapse-like drinking and be relevant for modeling addictive behaviors. In humans, drug or alcohol abstinence is commonly associated with the increased physical and sexual abuse. The present study aimed to study whether aggressive and sexual behaviors are affected by the conditions known to result in the DE. Adult male Wistar rats had unlimited free choice access to water and saccharin-containing solution (0.1%, w/v). After the preference for saccharin was established, animals underwent repeated 7-day-long episodes of saccharin deprivation. It was found that (i) aggressive and sexual behaviors were facilitated after 7 days of saccharin deprivation, and (ii) DE was significantly reduced in animals that were allowed to interact with the nonaggressive male or receptive female conspecifics during the last day of deprivation exposure. These results suggest that the saccharin deprivation exposures may facilitate aggressive and sexual behaviors. Alternative behavioral strategy may serve as a mechanism of coping with the deprivation state.

In humans and laboratory animals, drug withdrawal often is associated with depression-like behaviors. In the present study, rats had unlimited free-choice access to water and a saccharin-containing solution before being subjected to repeated episodes of saccharin deprivation. Saccharin deprivation (1) reduced immobility time in the forced swim test, (2) increased reinforcement rate in rats trained to lever-press under the differential reinforcement of a low-rate (72-sec) schedule of food reinforcement, and (3) lowered intracranial self-stimulation thresholds in a discrete-trial current titration procedure. Taken together, these findings suggest that deprivation from a nondrug reinforcer, saccharin, is not associated with depression-like behaviors. In contrast, saccharin-deprived rats demonstrated improved performance in the behavioral paradigms used here., ((c) 2003 APA, all rights reserved)

Sensitization to the rate-decreasing effects of opioid antagonists induced by acute pretreatment with opioid agonists has been suggested to reflect initial changes in opioid systems that underlie physical dependence. Glutamate receptors are implicated in the development and expression of opioid dependence, and antagonists acting at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors have been shown repeatedly to attenuate the severity of opioid withdrawal. The present study evaluated the ability of a competitive NMDA receptor antagonist, D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid), to affect morphine-induced sensitization to naloxone in rats trained to lever-press on a multiple-trial, fixed-ratio 10 schedule of food reinforcement. D-CPPene (0.3-3 mg/kg) was administered either 4 h or 30 min prior to the test session. Morphine (10 mg/kg) or its vehicle was administered 4 h before naloxone challenge (0.3-3 mg/kg). D-CPPene failed to prevent morphine-induced potentiation of the naloxone-produced decrement in operant performance. Thus, these results suggest that agonist-induced sensitization to behavioral effects of opioid antagonists may be insensitive to NMDA receptor blockade.

There is a considerable body of evidence indicating that stimuli associated with drug administration may become conditioned and evoke drug-like effects. The purpose of this study was to evaluate the ability of morphine-paired stimuli to affect an expression of morphine withdrawal-facilitated aggression. Individually housed aggressive adult mice were subjected to the repeated subcutaneous administration of morphine (twice a day, 8 days, increasing doses 10-80 mg/kg). Morphine treatment cessation facilitated an aggressive behaviour of animals during the second day of withdrawal. Subcutaneous but not intraperitoneal injection of saline attenuated the aggressive behaviour in morphine-withdrawn mice. These results suggest that the site of drug injection may serve as a conditioned stimulus.

Acute pretreatment with opioid receptor agonists potentiates behavioral effects of opioid antagonists. This phenomenon was suggested to serve as an acute model of opioid dependence. Since antagonists acting at N-methyl-D-aspartate (NMDA) receptors were repeatedly shown to attenuate development, maintenance, and expression of opioid dependence, the present study evaluated the effects of competitive NMDA receptor antagonist, D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid), and low-affinity channel blocker, 1-amino-3,5-dimethyl adamantane hydrochloride (memantine), on establishment of naloxone-conditioned place aversion in mice that were pre-exposed to morphine. Morphine (20 mg/kg) pretreatment significantly potentiated the ability of naloxone (0.01-0.3 mg/kg) to produce place aversion. The place aversion produced by naloxone (0.1 mg/kg) was attenuated by D-CPPene (1 and 3 mg/kg but not 0.1 or 0.3 mg/kg) when it was administered 3.5 h after morphine (0.5 h prior to conditioning trial with naloxone) but not 0.5 h prior to morphine. Memantine (1-10 mg/kg) had no effect under any treatment condition (0.5 h prior to morphine, simultaneously with morphine, 2 or 3.5 h after morphine). Thus, the ability of NMDA receptor antagonist to affect development and/or expression of morphine dependence may not be a good predictor of their effects on establishment of morphine-potentiated naloxone-conditioned place aversion.

Rationale: Opioid withdrawal is known to facilitate aggressive behavior in laboratory rodents. Aggression develops as the somatic signs disappear and thus may reflect protracted withdrawal-related behavioral alterations. Antagonists acting at the NMDA receptor are known to attenuate the expression of morphine withdrawal syndrome in laboratory animals., Objective: The present study aimed to evaluate the effects of low-affinity NMDA receptor channel blockers (memantine and MRZ 2/579) on aggression facilitated by morphine withdrawal in mice., Methods: Significant increases in aggressive behavior were observed 48 h after repeated morphine administration (8 days, b.i.d., 10-80 mg/kg, s.c.) was discontinued. Separate groups of mice were treated intraperitoneally with vehicles or different doses of memantine (1, 3, 10 or 30 mg/kg) or MRZ 2/579 (1, 3 or 10 mg/kg) 48 h after the last morphine injection., Results: Both compounds dose-dependently reduced the expression of aggressive behavior while having no significant effect upon the intensity of non-aggressive social contacts. Memantine significantly diminished the occurrence of all recorded components of aggressive behavior (attacks/bites, threats, tail rattling) while MRZ 2/579 affected mainly the appetitive events of aggressive bursts (threats, tail rattling). For both compounds, anti-aggressive effects occurred at dose levels that did not produce motor impairment in the Rotarod test., Conclusions: Taken together with the evidence on the lack of selective anti-aggressive effects of these drugs in morphine-naive mice, attenuation of the aggression observed in the present study may be due to specific interaction with morphine withdrawal-triggered processes.

The behavior of individuals and their responses to external stimuli are controlled by the microsocial environment, which for most mammals is associated with dominant-subordinate relationships. Physiological and behavioral differences between dominant and subordinate individuals may be 'primary' (genetically determined) or 'secondary' (due to position in the group's hierarchical structure). A series of experiments was conducted to investigate the physiological (pain response threshold), immunological (thymus, spleen weights, primary immune response), and behavioral (motor activity, behavior in a shuttle box test) characteristics of dominant and subordinate individuals in groups of three laboratory mice formed on the basis of linear hierarchy. Assessment of the effects of group conditions was made using a conditioned reflex location preference test. The results showed: 1) there are no statistically significant differences in physiological and behavioral (except for motor activity) parameters between dominant and subordinate mice; 2) co-housing of dominant and subordinate individuals in groups with stable hierarchical relationships was not aversive for them.

Current perspectives on clinical use of N-methyl-D-aspartate (NMDA) receptor antagonists infer acute and repeated administration schedules for management of different pathological states. Development of tolerance and cross-tolerance between different antagonists may significantly affect their clinical effectiveness. Since ethanol was repeatedly demonstrated to act as NMDA receptor antagonist, ethanol use may also have its impact on the effects of NMDA receptor ligands. Using the rotarod test in mice, the present study evaluated development of tolerance and cross-tolerance between ethanol (3.2 g/kg, p.o.), competitive NMDA receptor antagonist, D-CPPene (5.6 mg/kg, i.p.), and low-affinity NMDA receptor channel blocker, memantine (30 mg/kg, i.p.), that were administered for seven days once a day after the daily rotarod training session. Acute tests with ethanol (0.3, 1, 1.7, 3.2 g/kg), D-CPPene (0.3, 1, 3, 5.6 mg/kg) and memantine (1, 3, 10, 30 mg/kg) revealed that (a) each of these drugs dose-dependently disrupted rotarod performance in drug-naive mice; (b) in ethanol- and D-CPPene-treated mice, tolerance was observed to ethanol and D-CPPene but not to memantine; moreover, effects of memantine were even more pronounced in D-CPPene-treated subjects; and (c) repeated memantine administration decreased acute motor impairing effects of ethanol, D-CPPene and memantine. Thus, the history of ethanol use or abuse may influence pharmacological activity of NMDA receptor antagonists and this effect is dependent on type of the NMDA receptor antagonist applied.

Mice were subjected to two successive treatment protocols: first with NMDA receptor channel blockers (14 days, once a day) and second with morphine (5 mg/kg, 8 days, once a day). Treatment with the higher doses of dizocilpine (1 mg/kg), memantine (30 mg/kg), and MRZ 2/576 (30 mg/kg) upon discontinuation revealed only minor behavioral abnormalities attributable to the state of withdrawal. Following repeated administration of low-dose morphine, tolerance to morphine analgesia developed in mice preexposed to dizocilpine (1 mg/kg but not 0.3 mg/kg) but not memantine (10 and 30 mg/kg), MRZ 2/579 (10 and 30 mg/kg), or saline. There were no signs of morphine dependence in any treatment group. Overall, the present study found only minor effects of the subchronic administration of high doses of NMDA receptor channel blockers, suggesting that clinical use of NMDA receptor channel blockers such as memantine will not be accompanied by increased propensity to induction of morphine tolerance and dependence.

The present study assessed the ability of voltage-sensitive calcium channel (VSCC) blockers to affect the behavioral effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine, in male Wistar rats. Dizocilpine produced dose-dependent increases in locomotor activity. Nimodipine, verapamil, and flunarizine suppressed dizocilpine-facilitated vertical activity, while horizontal activity was attenuated by verapamil and nimodipine but not flunarizine. Repeated dizocilpine injections resulted in the development of sensitization to its locomotor stimulating properties. Development of sensitization was not context specific, and was observed following repeated exposures to 0.1 but not 0.056 or 0.3 mg/kg of dizocilpine. Nimodipine retarded the development of sensitization to dizocilpine's stimulating effects on horizontal activity, while verapamil suppressed sensitization to the vertical stimulating effects of dizocilpine. Flunarizine had no significant effects on sensitization to dizocilpine's locomotor stimulating properties. In rats trained to discriminate between injections of 0.056 mg/kg of dizocilpine and vehicle, none of the tested VSCC blockers was able to completely antagonize the discriminative stimulus properties of dizocilpine. Nimodipine, when administered in combination with the training dose of dizocilpine, modestly decreased the dizocilpine-lever selection. Dizocilpine dose dependently decreased the self-determined stimulation threshold implanted in rats with electrodes into the ventral tegmental area. Nimodipine exhibited some tendency to block the facilitating effects of dizocilpine, while verapamil and flunarizine had no effects. In summary, in the present experiments VSCC blockers exerted only modest interactions with the behavioral effects of dizocilpine, and it is unlikely that VSCC blockers have remarkable potential as adjunct treatment aimed at correcting the negative side effects of NMDA receptor antagonists (e.g., dizocilpine).

Behaviour of individuals and their responses to external stimuli are controlled by the micro-social environment in which most mammals are subject to dominant-subordinate relations. Physiological (pain sensitivity, immunological data: thymus and spleen weight, first immunological response) and behavioural (locomotor activity, shuttle-box behaviour) signs were studied in dominant and subordinate male mice of linear hierarchy groups. No significant difference was found between both groups of sings in both groups of the animals. Housing of dominant with subordinate mice seems not to be aversive for both types of the animals.

Distribution of specific 3H-flunitrazepam and 3H-beta-carboline-3-carboxylate binding sites in the brain regions of aggressive and timid-defensive mice was investigated before and after subchronic injection of diazepam (5 mg/kg). The absence of differences between the affinity and concentration of 3H-flunitrazepam binding sites in diencephalon and brain cortex in aggressive and defensive mice may be explained by general benzodiazepine receptor reaction on isolation and agonistic interaction stress. Significant predominance of 3H-beta-carboline-3-carboxylate binding sites in the brain cortex, as compared to the concentration of 3H-flunitrazepam binding sites suggests the presence of specific binding sites for beta-carbolines, which have specific distribution in the brain.