Behavioral sensitization to cocaine: cooperation between glucocorticoids and epinephrine

Rationale  Stressful life experiences facilitate responsiveness to psychostimulant drugs. While there is ample evidence that adrenal glucocorticoids mediate these effects of stress, the role of the sympatho-adrenal system in the effects of psychostimulants is poorly understood. Objectives  The present study investigated the role of the two adrenal stress hormones, corticosterone and epinephrine, in sensitization to the locomotor stimulant effects of cocaine. Materials and methods  The DBA/2 mouse strain was used, as behavioral sensitization in this strain critically depends on adrenal hormones. Animals were subjected to adrenalectomy (“ADX”, surgical removal of the adrenals) or SHAM surgery, and ADX mice were given replacement of epinephrine (5 × 10⁻³ mg/kg subcutaneously (s.c.) just prior to each drug administration), corticosterone (20%, s.c., pellet), or both. Mice were subjected to a cocaine sensitization regimen (15.0 mg/kg cocaine on nine consecutive days followed by a 7.5 mg/kg cocaine challenge after a 5-day withdrawal). Results  In agreement with our previous observations, ADX prevented initiation and expression of cocaine-induced locomotor sensitization. Whereas neither corticosterone nor epinephrine alone were sufficient to reverse the ADX effect, both hormones were necessary to fully restore initiation and retention of sensitization to levels observed in SHAM animals. Conclusions  The present findings indicate that corticosterone and epinephrine cooperate to facilitate behavioral responsiveness to cocaine. These data emphasize that in addition to the hypothalamic–pituitary–adrenal axis, the sympathetic nervous system plays a critical role in psychostimulant sensitivity.     

An analytical formulation of the law of intersegmental coordination during human locomotion

The law of intersegmental coordination is a kinematic law that describes the coordination patterns among the elevation angles of the lower limb segments during locomotion (Borghese et al. in J Physiol 494:863–879, 1996). This coordination pattern reduces the number of degrees of freedom of the lower limb to two, i.e. the elevation angles covary along a plane in angular space. The properties of the plane that constrains the time course of the elevation angles have been extensively studied, and its orientation was found to be correlated with gait velocity and energy expenditure (Bianchi et al. in J Neurophysiol 79:2155–2170, 1998). Here, we present a mathematical model that represents the rotations of the elevation angles in terms of simple oscillators with appropriate phase shifts between them. The model explains what requirements the time courses of the elevation angles must fulfill in order for the angular covariation relationship to be planar. Moreover, an analytical formulation is proposed for both the orientation of the plane and for the eccentricity of the nearly elliptical shape that is generated within this plane, in terms of the amplitudes and relative phases of the first harmonics of the segments elevation angles. The model presented here sheds some new light on the possible interactions among the Central Pattern Generators possibly underlying the control of biped locomotion. The model precisely specifies how any two segments in the limb interact, and how a change in gait velocity affects the orientation of the intersegmental coordination plane mainly through a change in phase shifts between the segments. Implications of this study with respect to neural control of locomotion and other motor activities are discussed. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.

ABILOCO: a Rasch-built 13-item questionnaire to assess locomotion ability in stroke patients

Caty GD, Arnould C, Stoquart GG, Thonnard J-L, Lejeune TM. ABILOCO: a Rasch-built 13-item questionnaire to assess locomotion ability in stroke patients.

Objective

To develop a questionnaire (ABILOCO), based on the Rasch measurement model, that can assess locomotion ability in adult stroke patients (International Classification of Functioning, Disability and Health activity domain).

Design

Prospective study and questionnaire development.

Setting

A faculty hospital.

Participants

Adult stroke patients (N=100) (age, 64±15y). The time since stroke ranged from 1 to 260 weeks.

Intervention

A preliminary questionnaire included 43 items representing a large sample of locomotion activities. This questionnaire was tested on the 100 stroke patients, and their responses were analyzed using the Rasch model (RUMM 2020 software) to select items that had an ordered rating scale and fitted a unidimensional model.

Main Outcome Measure

The ABILOCO questionnaire.

Results

The retained items resulted in a 13-item questionnaire, which includes a wide range of locomotion abilities well targeted to the sample population, leading to good reliability (R=.93). The item calibration was independent of age, sex, time since stroke, and affected side. The concurrent validity of ABILOCO was also investigated by comparing it with well-known, criterion standard scales (Functional Walking Category, Functional Ambulation Categories, item 12 of the FIM instrument evaluating walking ability) and the walking speed measured with the 10-meter walk test.

Conclusions

The ABILOCO questionnaire presents good psychometric qualities to measure locomotion ability in adult stroke patients. Its range and measurement precision make it attractive for clinical use throughout the rehabilitation process and for clinical research.     

Asymmetric leg loading during sit-to-stand, walking and quiet standing in patients after unilateral total hip replacement surgery

BACKGROUND: Asymmetric limb loading persists well after unilateral total hip replacement surgery and represents a risk of the development of osteoarthritis in the non-operated leg. Here we studied bilateral limb loading in hip arthroplasty patients for a variety of everyday activities. METHODS: Twenty-seven patients and 27 healthy age-matched control subjects participated in the study. They were asked to stand up from a chair, to stand quietly, to perform isometric maximal voluntary contractions and to walk along a 10 m path at a natural and fast speed. Two force platforms measured vertical forces under each foot during quiet standing and sit-to-stand maneuver. Temporal variables of gait were measured using footswitches. FINDINGS: In all tasks patients tended to preferentially load the non-operated limb, though the amount of asymmetry depended on the task being most prominent during standing up (inter-limb weight bearing difference exceeded 20%, independent of speed or visual conditions). In contrast, when performing maximal voluntary contractions, or during walking and quiet standing, the inter-limb difference in the maximal force production, stance/swing phase durations or weight bearing was typically less than 10%. INTERPRETATION: The results suggest that the amount of asymmetry might not be necessarily the same for different tasks. Asymmetric leg loading in patients can be critical during sit-to-stand maneuver in comparison with quiet standing and walking, and visual information seems to play only a minor role in the control of the weight-bearing ability. The proposed asymmetry indices might be clinically significant for development of post-surgical rehabilitation.     

Adenosine A2A receptor blockade prevents memory dysfunction caused by beta-amyloid peptides but not by scopolamine or MK-801

Adenosine A2A receptor antagonists alleviate memory deficits caused by aging or by administration of beta-amyloid peptides in rodents, which is in accordance with the beneficial effects of caffeine consumption (an adenosine receptor antagonist) on memory performance in aged individuals and in preventing Alzheimer's disease. We now tested if A2A receptor blockade affords a general beneficial effect in different experimental paradigms disturbing memory performance in rodents. The beta-amyloid fragment present in patients with Alzheimer's disease (Abeta1-42, 2 nmol, icv) decreased spontaneous alternation in the Y-maze after 15 days (29%) to an extent similar to the decrease of memory performance caused by scopolamine (2 mg/kg, ip) or MK-801 (0.25 mg/kg, ip) after 30 min (28% and 39%, respectively). The selective A2A receptor antagonist SCH58261 (0.05 mg/kg, ip every 24 h, starting 30 min before the noxious stimuli) prevented Abeta1-42-induced amnesia, but failed to modify scopolamine- or MK-801-induced amnesia. Similar conclusions were reached when testing another A2A receptor antagonist (KW6002, 3 mg/kg, ip). These results indicate that A2A receptors do not affect general processes of memory impairment but instead play a crucial role restricted to neurodegenerative conditions involving an insidious synaptic deterioration leading to memory dysfunction.     

Increasing the incentive salience of cocaine challenges preference for pup- over cocaine-associated stimuli during early postpartum: place preference and locomotor analyses in the lactating female rat

Rationale/Objectives Prior studies using a dual-choice conditioned place preference (CPP) procedure revealed that postpartum female rats (dams) strongly prefer chambers associated with pups over those associated with subcutaneously administered cocaine almost exclusively during early but not late postpartum (Mattson et al. 2001). The present study examines whether early postpartum dams retain strong pup-associated chamber preference when contrasted with a cocaine stimulus of greater incentive salience (intraperitoneal [IP] injections with brief conditioning sessions). Locomotor rate was measured during conditioning (stimuli-present) and test (stimulus-absent) sessions. Materials and methods A three-chambered CPP apparatus was used to compare preferences for chambers associated with IP cocaine vs age-matched pups. Unconditioned stimuli were systematically assigned to the least-preferred chamber of separate groups of dams before conditioning. Control dams verified that unconditioned stimuli were necessary for CPP and stimulus-associated locomotion. Results Compared with most late postpartum dams (60%), only 31% of early postpartum dams preferred the cocaine-associated chamber (P < 0.05). Substantially more dams preferred the pup-associated chamber during early postpartum (27%) than late postpartum (5%; P < 0.05). Locomotor sensitization emerged across cocaine-conditioning sessions in cocaine-preferring but not pup-preferring dams (P < 0.05). Locomotor rates were consistently lower in preferred vs nonpreferred chambers during test. Conclusions After increasing cocaine’s incentive salience, more early postpartum dams prefer the cocaine-associated chamber than previously reported (Mattson et al. 2001). However, pup-associated chamber preference was still higher in early vs late postpartum. Pup- and cocaine-preferring dams expressed differences in the induction phase of locomotor sensitization across cocaine conditioning but expressed similar motoric patterns in their preferred chambers at test.     

Nucleus accumbens PKA inhibition blocks acquisition but enhances expression of amphetamine-produced conditioned activity in rats

Rationale The nucleus accumbens (NAc) plays a central role in dopamine-produced reward-related learning. In previous studies, the cyclic adenosine monophosphate-dependent protein kinase (PKA) inhibitor Rp-Cyclic 3′,5′-hydrogen phosphorothioate adenosine triethylammonium salt (Rp-cAMPS) blocked the acquisition but not expression of NAc reward-related learning for natural rewards and the acquisition of psychostimulant drug conditioning.Objectives The current study assessed the role of PKA in the expression of NAc amphetamine (amph)-produced conditioning using conditioned activity (CA).Materials and methods After 5 days of habituation, a test environment was paired with bilateral NAc injections of amph (0.0 or 25.0 μg) and the PKA inhibitor Rp-cAMPS (0.0, 5.0, 10.0, or 20.0 μg) over three 60-min conditioning sessions separated by 48 h. To test for effects on expression, some groups received vehicle or amph alone before conditioning sessions and were injected with 0.0, 0.25, 5.0, or 20.0 μg of Rp-cAMPS before the single 60-min test session.Results Amph produced acute increases in locomotion and robust CA. Rp-cAMPS impaired the acquisition of amph-produced CA but not its expression; in fact, it enhanced expression.Conclusions Results show that PKA inhibition blocks the acquisition but not the expression of amph-produced conditioning.     

Collateral projections from the median raphe nucleus to the medial septum and hippocampus

It has previously been shown that the median raphe nucleus (MR) is a source of pronounced projections to the septum and hippocampus. The present study examined collateral projections from MR to the medial septum (MS) and to various regions of the hippocampus. The fluorescent retrograde tracers, Fluororuby and Fluorogold, were injected into the septum and hippocampus, respectively, and the median raphe nucleus was examined for the presence of single- and double-labeled neurons. The dorsal raphe nucleus (DR) was also examined for the presence of single- and double-labeled cells and comparisons were made with the MR. The main findings were: (1) pronounced numbers of retrogradely labeled cells (approximately 50 cells/section) were present in MR with injections in the MS or in various regions of the hippocampus; (2) approximately 8-12% of MR cells were double-labeled following paired injections in the MS-CA1, MS-CA3, and MS-dentate gyrus of the dorsal hippocampus, the lateral MS-dentate gyrus, and the MS-ventral hippocampus; (3) single- and double-labeled cells were intermingled throughout MR and present in greater numbers in the rostral than caudal MR; and (4) significantly more single- and double-labeled cells were present in MR than in DR with all combinations of injections. These findings demonstrate that MR projects strongly to the MS and hippocampus, and that a significant population of MR neurons (8-12%) sends collateral projections to both sites. It is well established that the MR nucleus serves a direct role in the desynchronization of the electroencephalographic (EEG) activity of the hippocampus-or the blockade of the hippocampal theta rhythm. The MR neurons that we have identified with collateral projections to the septum and hippocampus may be critically involved in the modulation/control of the hippocampal EEG. A role for the MR in memory associated functions of the hippocampus is discussed.     

孕期不同剂量彩色多普勒超声重复辐照对仔鼠自发活动的影响

目的 观察孕期给予不同剂量彩超重复辐照后对仔鼠自发活动的影响.方法 妊娠SD大鼠30只,随机分为对照组、重复照射10 min组、重复照射20 min组3组.在妊娠第6、12、18天分别给予0 min,10 min,20 min的(3.0 MHz,MI=1.6,Tis=1.8)超声辐照.生后90天通过开场实验观察其自发活动,评价其神经精神变化、进入开阔环境后的各种行为.结果 与对照组相比,辐射10 min,20 min组仔鼠的活动总路程、活动度、中央区时间、中央区路程以及平均运动速度均无明显差异(P>0.05).结论 孕期诊断剂量彩超重复照射对仔鼠的自发活动不产生明显影响.     

Non-coding RNA as a trigger of neuropathologic disorder phenotypes in transgenic Drosophila

At most, many protein-misfolding diseases develop as environmentally induced sporadic disorders. Recent studies indicate that the dynamic interplay between a wide repertoire of noncoding RNAs and the environment play an important role in brain development and pathogenesis of brain disorders. To elucidate this new issue, novel animal models which reproduce the most prominent disease manifestations are required. For this, transgenic Drosophila strains were constructed to express small highly structured, non-coding RNA under control of a heat shock promoter. Expression of the RNA induced formation of intracellular aggregates revealed by Thioflafin T in embryonic cell culture and Congo Red in the brain of transgenic flies. Also, this strongly perturbed the brain control of locomotion monitored by the parameters of sound production and memory retention of young 5-day-old males. This novel model demonstrates that expression of non-coding RNA alone is sufficient to trigger neuropathology.