Memantine,amantadine, and L-deprenyl potentiate the action of L-DOPA in monoamine-depleted rats

Summary Some treatments used for Parkinson's disease attenuate locomotor depression in rats treated with reserpine and -methyl-p-tyrosine. In the present study memantine (2.5, 5.0mg/kg), amantadine (10, 20mg/kg) (both uncompetitive NMDA antagonists), and L-deprenyl (1.0, 5.0 mg/kg; MAO-B inhibitor) were tested for possible synergistic interactions with the dopamine agonists: bromocriptine (2.5, 5.0mg/kg) and L-DOPA (50, 100mg/kg, + benserazide, 100 mg/kg). At higher doses, memantine (10 mg/kg), amantadine (40 mg/kg), bromocriptine (5 and 10mg/kg) and L-DOPA (100, 200mg/kg) but not L-deprenyl (up to 10 mg/kg) produced a pronounced increase in locomotor activity when given alone. The combination of memantine, amantadine and L-deprenyl with bromocriptine did not result in synergism of action and, at best, an additive effect was seen. On the other hand the combination of these agents with L-DOPA produced a pronounced synergistic effect. Hence, the clinical observation that coadministration of L-DOPA with either memantine or amantadine results in enhancement of their action is also reflected in an animal model of Parkinson's disease. Such a combination therapy should allow the use of lower doses of both drugs which may reduce the occurrence of side effects and may also be predicted to have additional benefits related to the neuroprotective properties of memantine, amantadine, and L-deprenyl.     

Adaptive fusimotor reflex control in the decerebrate cat

The effect of electrical stimulation of cutaneous afferents in the superficial peroneal nerve on the locomotor discharges of single medial gastrocnemius gamma-motoneurones has been investigated in a decerebrate cat preparation. Units were classified as static (n=9) or dynamic (n=7) indirectly on the basis of their resting and locomotor discharge characteristics. Brief trains of stimulation, at 2 and 3xthreshold (T), were applied at rest and during locomotion. Responses were assessed by calculating the change in mean rate during the 100 ms after stimulus onset compared with a control period. At rest, static and dynamic gamma-motoneurones showed opposite responses. Static neurones were excited while inhibition was dominant with dynamic neurones. Effects were always present at 2T. During locomotion, inhibitory responses occurred with both types of gamma-motoneurone and excitation was not apparent. The inhibition of static neurones was maximum during (four units) or between (five units) EMG bursts and minimum in the opposite phase of EMG activity. For dynamic neurones, inhibition was not related to locomotor phase. Generally (six of seven units), the inhibition of dynamic gamma-motoneurones was reduced throughout the step cycle, including phases in which background discharge rates were comparable to resting levels. Latencies of response were measured from peristimulus time histograms. Subtraction of peripheral conduction times gave estimated central delays of locomotor inhibition for static (2.4+/-0.2 ms, n=6; mean+/-S.E.M.) and dynamic (2.2+/-0.2 ms, n=7) gamma-motoneurones that were not significantly different (P>0. 1) and are consistent with spinal oligosynaptic pathways. We conclude that low threshold skin afferents from the foot dorsum are capable of influencing both types of gamma-motoneurone during walking through short latency spinal inhibitory pathways. Further, a highly specific (reciprocal) control of the reflex responses of static and dynamic gamma-efferents occurs that is dependent upon behavioural context. The results are discussed in relation to cutaneous effects on gamma-motoneurones which are suggested to form an adaptive control system.     

An in vitro functionally mature mouse spinal cord preparation for the study of spinal motor networks

An in vitro isolated whole spinal cord preparation has been developed in ‘motor functionally mature' mice; that is mice of developmental maturity sufficient to weight-bear and walk. In balb/c mice this stage occurs at around postnatal day 10 (P10). Administration of strychnine elicited synchronous activity bilaterally in lumbar ventral roots. Rhythmic alternating locomotor-like activity could be produced by application of a combination of serotonin (5-HT), N-methyl- -aspartate (NMDA), and dopamine in animals up to P12. Using a live cell–dead cell assay, it is demonstrated that there are primarily viable cells throughout the lumbar spinal cord. The viability of descending pathways was demonstrated with stimulation of the mid-thoracic white matter tracts. In addition, polysynaptic segmental reflexes could be elicited. Although usually absent in whole cord preparations, monosynaptic reflexes could invariably be elicited following longitudinal midline hemisection, leading to the possible explanation that there might be an active crossed pathway producing presynaptic inhibition of primary afferent terminals. The data demonstrate that this functionally mature spinal cord preparation can be used for the study of spinal cord physiology including locomotion.     

Effects of early handling on amphetamine-induced locomotor activation and conditioned place preference in the adult rat

  Rationale: Altered hormonal stress responsiveness has been implicated in psychostimulant responsivity, and early handling represents a mild environmental manipulation which alters the hormonal profile following stress exposure. Objective: The present experiments examined whether early handling in rats would alter locomotor effects of amphetamine, as well as cross-sensitization of locomotor responsiveness after chronic stress. Conditioned place preference (CPP) for amphetamine was also measured. Methods: Handling consisted of daily 15-min isolation periods from days 1–12 postnatally. Novelty- and amphetamine (0, 1.5 mg/kg)-induced locomotion were examined using circular corridors in adult rats that were either restrained repeatedly over 8 days or not disturbed prior to testing. The effects of handling on amphetamine (0, 1, 2, 5 mg/kg) conditioned place preference (CPP) were also examined following 3 days of drug-compartment pairings. Results: Early handling produced a more rapid post-stress recovery in corticosterone levels. Handled animals also exhibited a significant attenuation in amphetamine-induced CPP compared to non-handled controls. Locomotor responsiveness to novelty and amphetamine was not altered by early handling. Although no cross-sensitization was observed, evidence for stress sensitization was seen, but was unaffected by early handling. Conclusions: Handled animals showed an attenuated CPP for amphetamine, data suggesting that sensitivity to the reward value of drugs of abuse in adulthood may be susceptible to relatively minor environmental manipulations early in life. This effect of handling on CPP does not seem to reflect differences in locomotor sensitivity to amphetamine. Received: 5 August 1998 / Final version: 2 November 1998     

Does crossing over repeated treatment with the dopamine reuptake inhibitors cocaine and BTCP modify their effects on cocaine-induced locomotion?

Because the dopamine reuptake inhibitors cocaine and BTCP produce different behavioral effects after repeated administration, we studied whether they could alter each other’s effects by examining the effects of crossing over repeated treatment with cocaine and BTCP on cocaine-induced locomotion. Male C57BL/6 mice were treated repeatedly with cocaine or BTCP during a first phase (days 1–3) and 3 days later, treated repeatedly with the same or the other compound during a second phase (days 7–9), after which they were administered one of several doses of cocaine on the next day. Locomotor activity was assessed after every daily treatment. The results show that 1) cocaine induced sensitization to its locomotor effects, 2) cocaine-induced sensitization was not altered by subsequent repeated treatment with BTCP, 3) initial repeated treatment with BTCP induced apparent cross-tolerance to cocaine, and 4) the initial effects of repeated BTCP were not markedly altered by subsequent repeated treatment with cocaine. The results indicate that the initial effects produced by repeated cocaine or BTCP are enduring and relatively difficult to alter by crossing over repeated treatment with the other compound. Thus, sensitization to the locomotor effects of cocaine in mice appeared to be attenuated by prior repeated treatment with BTCP but not reversed when followed by repeated treatment with BTCP. Received: 11 January 1998/Final version: 17 September 1998     

Feeding stimulated by very low doses of d-amphetamine administered systemically or by microinjection into the striatum

The effects of d-amphetamine over a wide range of doses (0.125–4.0 mg/kg IP) on rat unconditioned behaviour were examined in the presence of food and water (experiment 1), in their absence (experiment 2) and after microinjection (2.0 g in 0.5 l) directly into the striatum (experiment 3). In experiment 1 very low doses (0.125 and 0.25 mg/kg) stimulated the intake of food, but not water, and higher doses produced locomotor hyperactivity, rearing, stereotyped sniffing and anorexia. In experiment 2 all doses, including very low doses (0.125 and 0.25 mg/kg), significantly potentiated locomotor activity. In experiment 3, microinjection into the corpus striatum elicited substantial feeding, but not drinking, locomotor activity or stereotyped behaviour. The results suggest that a single graded facilitative mechanism underlies the effects on food intake and other behavioural effects of amphetamine, as implied by a general hypothesis of amphetamine action proposed in the literature, and that these effects may to a large extent by mediated by forebrain dopamine systems.     

Analysis of gait symmetry during over-ground walking in children with autism spectrum disorder

Gait symmetry is utilized as an indicator of neurologic function. Healthy gait often exhibits minimal asymmetries, while pathological gait exhibits exaggerated asymmetries. The purpose of this study was to examine symmetry of mechanical gait parameters during over-ground walking in children with Autism Spectrum Disorder (ASD). Kinematic and kinetic data were obtained from 10 children (aged 5–12 years) with ASD. The Model Statistic procedure (α = 0.05) was used to compare gait related parameters between limbs. Analysis revealed children with ASD exhibit significant lower extremity joint position and ground reaction force asymmetries throughout the gait cycle. The observed asymmetries were unique for each subject. These data do not support previous research relative to gait symmetry in children with ASD. Many individuals with ASD do not receive physical therapy interventions, however, precision medicine based interventions emphasizing lower extremity asymmetries may improve gait function and improve performance during activities of daily living.     

The gearing function of running shoe longitudinal bending stiffness

The purpose of the present study was to investigate whether altered longitudinal bending stiffness (LBS) levels of the midsole of a running shoe lead to a systematic change in lower extremity joint lever arms of the ground reaction force (GRF). Joint moments and GRF lever arms in the sagittal plane were determined from 19 male subjects running at 3.5 m/s using inverse dynamics procedures. LBS was manipulated using carbon fiber insoles of 1.9 mm and 3.2 mm thickness. Increasing LBS led to a significant shift of joint lever arms to a more anterior position. Effects were more pronounced at distal joints. Ankle joint moments were not significantly increased in the presence of higher GRF lever arms when averaged over all subjects. Still, two individual strategies (1: increase ankle joint moments while keeping push-off times almost constant, 2: decrease ankle joint moments and increase push-off times) could be identified in response to increased ankle joint lever arms that might reflect individual differences between subjects with respect to strength capacities or anthropometric characteristics. The results of the present study indicate that LBS systematically influences GRF lever arms of lower extremity joints during the push-off phase in running. Further, individual responses to altered LBS levels could be identified that could aid in finding optimum LBS values for a given individual.     

Acquiring visual information for locomotion by older adults: A systematic review

Developments in technology have facilitated quantitative examination of gaze behavior in relation to locomotion. The objective of this systematic review is to provide a critical evaluation of available evidence and to explore the role of gaze behavior among older adults during different forms of locomotion. Database searches were conducted to identify research papers that met the inclusion criteria of (1) study variables that included direct measurement of gaze and at least one form of locomotion, (2) participants who were older adults aged 60 years and above, and (3) reporting original research. Twenty-five papers related to walking on a straight path and turning (n = 4), stair navigation (n = 3), target negotiation and obstacle circumvention (n = 13) and perturbation-evoked sudden loss of balance (n = 5) were identified for the final quality assessment. The reviewed articles were found to have acceptable quality, with scores ranging from 47.06% to 94.12%. Overall, the current literature suggests that differences in gaze behavior during locomotion appear to change in late adulthood, especially with respect to transfer of gaze to and from a target, saccade-step latency, fixation durations on targets and viewing patterns. These changes appear to be particularly pronounced for older adults with high risk of falling and impaired executive functioning.     

The relationship between the anteroposterior and mediolateral margins of stability in able-bodied human walking

BackgroundControl of dynamic balance in human walking is essential to remain stable and can be parameterized by the margins of stability. While frontal and sagittal plane margins of stability are often studied in parallel, they may covary, where increased stability in one plane could lead to decreased stability in the other. Hypothetically, this negative covariation may lead to critically low lateral stability during step lengthening.Research questionIs there a relationship between frontal and sagittal plane margins of stability in able-bodied humans, during normal walking and imposed step lengthening?MethodsFifteen able-bodied adults walked on an instrumented treadmill in a normal walking and a step lengthening condition. During step lengthening, stepping targets were projected onto the treadmill in front of the participant to impose longer step lengths. Covariation between frontal and sagittal plane margins of stability was assessed with linear mixed-effects models for normal walking and step lengthening separately.ResultsWe found a negative covariation between frontal and sagittal plane margins of stability during normal walking, but not during step lengthening.SignificanceThese results indicate that while a decrease in anterior instability may lead to a decrease in lateral stability during normal walking, able-bodied humans can prevent lateral instability due to this covariation in critical situations, such as step lengthening. These findings improve our understanding of adaptive dynamic balance control during walking in able-bodied humans and may be utilized in further research on gait stability in pathological and aging populations.