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This paper is concerned with the displacement of the end effector of a manipulator, when subjected to an externally applied force system, which arises because of the flexibility of the actuator drives. General results are developed for the end effector infinitesimal stiffnesses (and compliances) in terms of the actuator infinitesimal stiffnesses (and compliances) for serial and parallel manipulators. It is shown that these quantities are dependent upon the instantaneous force system applied to the end effector, so that the relationship between the applied force system and the resulting displacement is non-linear, even for a given manipulator configuration. These results are of interest for a number of reasons. For example, the accuracy of a manipulator is directly related to its stiffness, and knowledge of the stiffnesses (or compliances) can be used to develop means of simultaneously controlling the force and displacement for a partially constrained end effector. Examples are provided to demonstrate the application of the general results to specific manipulator mechanisms, including both serial and parallel types.

The authors have been studying the fundamental mechanics of legged vehicles with the aim of establishing generic principles for their mechanical design. The approach to date has been to consider overall machine design and leg mechanism design separately. In leg design there is inevitably a trade-off between workspace (reach) and leg weight for given loading conditions. To understand this trade-off, the effects of leg geometry on both kinematic workspace and leg weight must be investigated. Leg weight is largely a function of the hip and knee design torques; the former is determined by the overall machine design which has been discussed elsewhere. This paper considers the effect of leg geometry on the total design torque that the knee must support through both its structure and the knee actuator. The actuator design torque is also considered. The leg geometry varied includes link lengths and knee twist angles. The necessary mathematical analyses are developed and data presented showing the relationship between knee or actuator torque and leg geometry.

The effects of body geometry on walking machine performance have been investigated, and a body design procedure proposed. The relationships between static workspace, body-geometry and installed joint torques have been derived. A body design procedure that uses this data is then described, and two design examples discussed. The procedure results in a body geometry which minimises the installed joint torques, and hence the machine weight, for the desired workspace area.

Several new, non-benzodiazepine hypnotic drugs have recently been marketed (zopiclone, zolpidem) or are in development (zaleplon, SX 3228). These compounds act at benzodiazepine (BZ) (omega) receptors but have mechanisms of action which are not identical to those of benzodiazepines; in particular, zolpidem, zaleplon and SX 3228 have been reported to have selectivity for the BZ1 (omega 1) receptor subtype. In the present study the effects of the four hypnotic drugs were investigated in rats trained to discriminate ethanol (1 g/kg). Comparisons were made with pentobarbital and the benzodiazepines, lorazepam and midazolam. The two benzodiazepines and the barbiturate produced dose-related substitution for ethanol. In contrast, zolpidem, zaleplon, SX 3228 and zopiclone gave rise to only partial (maximum effect 50-67%) substitution, even at doses which greatly reduced rates of lever pressing. The limited ethanol-like effects of zolpidem, zaleplon and SX 3228 may be related to the more selective mechanism of action of these compounds. It is not clear why the effects of zopiclone differed from those of the benzodiazepines.

A machine's weight is directly related to the strength of the installed joint actuators, and it is reasonable to assume that minimizing the installed joint torques will minimize the machine weight. Unfortunately, the workspace area will also reduce with the installed joint torques; thus there must be a compromise between weight (joint strength) and workspace. Methods are presented to generate the set of static workspaces corresponding to a range of installed joint torques. In this way the relationship between the workspace area and installed joint torque can be established. A numerical example is presented which shows that a small reduction in the workspace area can lead to a substantial reduction in installed joint torque and hence machine weight.

The first stage in developing a task planning language for redundant manipulators is that of constructing an algorithm to produce a schedule of joint displacements for the specified task. This algorithm may be based upon the use of an inverse infinitesimal kinematic analysis for the majority of the path with a finite inverse analysis used to provide an initial joint configuration and periodically to correct for any joint errors that may have accumulated. Here, it is assumed that there is complete correlation and coherence of solutions between these analyses, otherwise problems, such as a lack of repeatability may occur. This may be accomplished by modelling the manipulator as an elastic system which permits the development of a task planning method by using analyses which are all mutually coherent. In this paper, the method is developed and demonstrated using a redundant manipulator that simultaneously avoids obstables, singularities and joint motion limitations. The task planning method and associated analyses are applicable to the general serial redundant manipulator with an arbitrary degree of redundancy.

In this paper methods are presented for analysing the kinematics of walking machines using vector and screw algebra. Firstly, displacement analysis is covered; this includes methods for deriving the position vector of any joint in any leg, and for calculating the active joint displacements in any leg. Secondly, velocity analysis is covered which tackles the problem of calculating active joint velocities given the velocity, position and orientation of the body and the positions of the feet. Numerical examples are given to demonstrate the application of these methods.

SummaryThis paper addresses the kinematic workspaces of a walking machine and their graphical representation. The workspaces for walking machines are denned and the methods for investigating various workspaces are presented; the kinematic workspace constraints are established; the displacement is analysed; an algorithm for investigation of kinematic workspaces is presented; and the position and orientation kinematic workspaces are analysed and graphically represented for an example walking machine design.

A parallel mechanism is one whose links and joints form two or more serially connected chains which join the fixed base and the end effector The mechanism of a multi-legged walking machine can be considered as a parallel mechanism whose base is not fixed and whose configuration changes during different phases of its gait. This paper presents methods for analysing the mechanics of parallel mechanisms and walking machines using vector and screw algebra Firstly, displacement analysis is covered; this includes general methods for deriving the position vector of any joint in any leg and for calculating the active joint displacements in any leg. Secondly, velocity analysis is covered which tackles the problem of calculating active joint velocities given the velocity, position and the orientation of the body and the positions of the feet. Thirdly, the static analysis of these classes of mechanisms using the principle of virtual work and screw algebra is given. Expressions are derived for the actuator forces and torques required to balance a given end effector (or body) wrench and, in the case of a walking machine, the ground reactions at the feet. Numerical examples are given to demonstrate the application of these methods.

Rats can be trained to discriminate benzodiazepines (BZ) from vehicle and there is considerable evidence that the stimulus effects of these drugs are mediated by activity atω (BZ) modulatory sites of the GABAA receptor complex. A number of recent studies, however, have indicated that differences may exist between the discriminative stimulus effects of benzodiazepines and those of certain non-benzodiazepine ligands for theω (BZ) receptors (e.g. zolpidem, abecarnil). As it is known that several subtypes ofω (BZ) sites are found in the central nervous system, and that drugs such as zolpidem have selectivity for certain subtypes, it is possible that differential stimulus effects may be associated with receptor selectivity. In the present study, correlations were calculated between the potencies of nine compounds with affinity forω receptors (diazepam, lorazepam, triazolam, clonazepam, alprazolam, zopiclone, suriclone, CL 218, 872 and zolpidem) to substitute for chlordiazepoxide in rats trained to discriminate a dose (5 mg/kg) of this benzodiazepine and the ability of the same compounds to inhibit the binding of [3H]-flumazenil from different structures in the rat central nervous system in vivo. The correlations obtained were: cerebellum 0.46, cortex 0.39, striatum 0.78 (P

SUMMARYThis paper, as an extension of an earlier paper, presents a geometrical representation and theoretical foundation of robot grasping that is affected by friction and by the magnitudes of normal contact forces. Grasp analysis and synthesis are based on the concepts of constraint cone (region), restraint cone and freedom cone in the force screw-space and location screw-space. In fact, the freedom cone is the aggregate of all the screws repelling and reciprocal to the grasp geometry (denoted by the restraint cone). Moreover, the constraint cone and the constraint region describe the effect of friction and the influence of the amplitudes of normal forces. The conditions of equilibrium grasp, stable grasp, form closure, force closure, and relative form closure are derived from the geometrical representation, and approaches are suggested for the design of adaptable fixtures, and for automatic grasp planning. It is shown that relative form closure is of great significance for frictional grasp, since it is possible to generate enough internal forces in the subspace spanned by the contacts and consequently produce corresponding friction forces in the reciprocal subspace.

This article presents a meaningful, practical, and theoretically sound solution that solves the problem of grasping a rigid object with a hand that has redundant (>6) grasping contacts. This is accomplished by introducing compliance at each contact point in such a way as to provide the engineer with the capabilities of object manipulation via controlled forces at the contact points. This method of solution is adapted straight-away to compute the static forces generated in the legs of a redundant in-parallel manipulator that equilibrates a wrench applied to the moving/platform or end-effector. In a way similar to the redundant grasping problem, this is accomplished by introducing the knowledge of the compliances that exist in the legs. The solution thus obtained stems from physical parameters that model the in-parallel manipulator. The in-depth study of the duality between the statics of in-parallel manipulators and the kinematics of serial manipulators reveals a meaningful, practical, and theoretically sound solution for the inverse kinematics of a redundant serial manipulator. This is accomplished by incorporating the knowledge of the compliances that exist or are desired to exist in the joints of the manipulator. (For instance, the torsional compliance in revolute joints or the linear compliance in prismatic joints.) Such information provides a physically meaningful model of the serial manipulator that in turn yields a physically meaningful set of joint increments for a given end-effector twist. © 1992 John Wiley & Sons, Inc.

Previous studies have shown that discriminative stimulus control established with the 5HT1A receptor agonist, 8-OH-DPAT, generalizes to other 5HT1A agonists and partial agonists but also to the alpha 2-adrenoceptor antagonist, yohimbine. On the basis of these results it has been proposed that the 8-OH-DPAT cue may be produced by activity at more than one receptor. In the present study rats were trained to discriminate a dose of 8-OH-DPAT (0.05 mg/kg, SC) from saline. Substitution tests showed dose-dependent generalisation with the 5HT1A compounds, buspirone, ipsapirone, MDL 72832 and MDL 73005EF, the alpha 2-adrenoceptor antagonists, yohimbine and idazoxan, and BMY 14802, which is usually described as a sigma ligand. The buspirone metabolite 1-pyrimidinyl piperazine (1-PP) which possesses mainly alpha 2-adrenoceptor antagonist properties produced only partial generalisation which was not dose related. Receptor binding studies showed that all the compounds which substituted for 8-OH-DPAT displaced [3H]-8-OH-DPAT binding to rat hippocampal membranes. Furthermore, there were statistically significant positive correlations between drug affinity for 5HT1A sites and their ED50 values for both substitution for 8-OH-DPAT and potency to decrease response rates. These results are consistent with the view that the 8-OH-DPAT cue, like the ability of the compounds tested to decrease rates of responding, is largely mediated by activity at 5HT1A receptors.

The object of this paper is to develop a procedure that will allow the establishment of necessary and sufficient point contacts on a rigid body to ensure that the body has any desired state of instantaneous motion or restraint. The screw space and its sub-spaces are employed; these are vector spaces but not Euclidean spaces. The states of restraint and instantaneous motion of a body restrained by a system of screws of point contacts are specified by reciprocal sub-spaces of the screw space. This leads to a synthesis procedure for restraint of a rigid body by means of point contacts. The existence and uniqueness of the synthesis solution are discussed, and necessary and sufficient conditions for a realizable surface of a kinematic pair are given. Finally, two quality measures for a feasible set of screws are defined. One represents the uniformity of the distribution of internal forces while the other indicates the restraint's ability to resist external forces.

Recent studies have shown that several compounds known to act as competitive or non-competitive antagonists of NMDA receptors can disrupt learning in rodents. The present study was carried out to investigate the effects of a range of NMDA antagonists, acting at several sites in the NMDA receptor complex, on the acquisition of learned fear in mice. Dose-related disruptions of learning were produced by the non-competitive antagonists phencyclidine, dizocilpine, dextromethorphan and (+) and (-)N-allylnormetazocine. The (+) enantiomer of N-allylnormetazocine was approximately twice as potent as the (-) enantiomer. The competitive NMDA receptor antagonist, CGS 19755, also blocked the acquisition of learned fear as did the non-specific glutamate antagonist riluzole. In contrast, the anti-ischaemic drugs ifenprodil and SL 82.0715, which probably act as NMDA antagonists through an effect on the polyamine site, had no effect on learning up to doses which substantially reduced locomotion. The sigma receptor ligand DTG was also inactive. These results confirm that both competitive and non-competitive NMDA antagonists disrupt learning but indicate that the extent to which such an effect is observed may depend on the site at which the compounds act within the receptor complex. Activity at sigma receptors is unrelated to the effect on learning.

The restricted localization of dopamine (DA) D3 receptors in the rat cerebellum lobule 9/10 appears to provide a method for investigating the in vivo selectivity of dopaminergic compounds for the D3 receptor subtype. Sprague-Dawley rats implanted with a cannula aimed at lobule 9/10 were microinjected with DA receptor ligands and immediately placed into activity chambers to record their spontaneous locomotor activity for short term (0 to 20 min) and delayed (20 to 40 min) effects. The DA D2/D3 receptor agonists quinelorane (0.1 to 2.5 microg) and 7-OH-DPAT (0.1 to 10 microg) decreased locomotor activity in the first 20 min post-microinjection. In contrast, the DAD1, receptor agonist 6-Br-APB (0.1 to 10 microg) did not affect locomotor activity during this time period, but markedly increased locomotion between 20 and 40 min at the highest dose tested. The DA receptor antagonists haloperidol and raclopride (1 to 10 microg) were also found to reduce locomotor activity. Furthermore, quinelorane and 7-OH-DPAT, but not haloperidol, when microinjected into lobules 1/2 or 6/7 (where no DA D3 receptors have been detected) decreased locomotor scores. These results show that both DA receptor agonists and antagonists decrease locomotor activity when microinjected into lobule 9/10 of the cerebellum. Additionally, DA receptor agonists can reduce spontaneous locomotion when microinjected outside of lobule 9/10. This would suggest that, at least for quinelorane and 7-OH-DPAT, the locomotor decreasing effects following microinjection into cerebellar lobule 9/10 may not be mediated by activity at DA D3 receptors, and that this behavioural assay is unlikely to provide a means for studying the in vivo pharmacology of the DA D3 receptor.

The GABA(A) receptor complex contains a number of binding sites at which a variety of psychotropic drugs, including benzodiazepines, barbiturates, and some neurosteroids, act to potentiate or inhibit the effect of the transmitter. Many studies have reported that these drugs can produce discriminative stimulus actions, but the cueing effects of compounds acting at different sites to enhance the effects of GABA are not identical. The discriminative stimulus effects of benzodiazepines have been analyzed in detail, and there is also a great deal of information available on the effects of nonbenzodiazepine compounds acting at BZ(omega) recognition sites, which form part of the GABA(A) receptor complex. Of particular interest are compounds with selectivity for the BZ1(omega1) receptor subtype including zolpidem, zaleplon, and CI 218,872. BZ1(omega1)-selective drugs substitute for the discriminative stimulus produced by chlordiazepoxide only partially and at sedative doses. This is consistent with the view that sedative effects of BZ(omega) receptor agonists are mediated by the BZ1(omega1) receptor subtype, whereas the discriminative stimulus produced by chlordiazepoxide may be produced by activity at the BZ2(omega2) subtype. Analysis of this hypothesis is complicated by the variety of levels of intrinsic activity shown by different drugs.

The present series of experiments compared the behavioral effects of the novel non-peptide CRF antagonist CP-154,526 with those of diazepam and the 5-HT1A receptor partial agonist buspirone in classical animal models of anxiety including conflict tests (punished lever pressing and punished drinking tests in rats) and exploratory models (elevated plus-maze test in rats, light/dark choice and free-exploration tests in mice), and a recently developed mouse defense test battery (MDTB) which has been validated for the screening of anxiolytic drugs. Results from both conflict procedures showed that diazepam (2.5-10 mg/kg, i.p.) produced clear anxiolytic-like effects, whereas buspirone (2.5 mg/kg, i.p.) displayed anticonflict activity in the punished drinking test only. CP-154,526 (0.6-20 mg/kg) was devoid of significant activity in both procedures. In the elevated plus-maze, diazepam (2 mg/kg, i.p.) produced significant effects on traditional (i.e. spatio-temporal) and ethologically derived (i.e. risk assessment and directed exploration) indices of anxiety. Buspirone (1-4 mg/kg, i.p.) reduced risk assessment activities only, and CP-154,526 (0.6-20 mg/kg, i.p.) did not modify the indices of anxiety in the elevated plus-maze. In the light/dark test, diazepam (2.5-5 mg/kg, i.p.) and CP-154,526 (10-40 mg/kg, i.p.) affected all behavioral indices of anxiety, while buspirone reduced risk assessment activities at the highest doses only (10 and 15 mg/kg, i.p.). In the free-exploration test, diazepam (1 mg/kg, i.p.) reduced avoidance responses towards novelty, as indicated by the increase in exploratory activity in a novel compartment and the decrease in risk assessment. CP-154,526 failed to affect the former behavior and weakly reduced the latter (5 and 20 mg/kg, i.p.). Buspirone (1.25-5 mg/kg, i.p.) was inactive in this test. Finally, in the MDTB, diazepam (0.5-3 mg/kg, i.p.) attenuated all defensive reactions of mice confronted with a rat stimulus (i.e. flight, risk assessment and defensive attack) or with a situation associated with this threat (i.e. contextual defense). Buspirone (1.25-5 mg/kg, i.p.) reduced defensive attack and contextual defense, while CP-154,526 (5-20 mg/kg, i.p.) affected all defensive behaviors, with the exception of one risk assessment measure. The finding that CP-154,526 displayed positive effects in mice but not in rats may be due to increased sensitivity to environmental stress of the strains used (i.e. BALB/c, Swiss) and/or to the fact that animals were exposed to unavoidable stress stimuli which may lead to a significant activation of the CRF system. Although in mice the anxiety-reducing potential of CP-154,526 is superior to that of the atypical anxiolytic buspirone, it is smaller in terms of the magnitude of the effects and the number of indices of anxiety affected than that of diazepam.

The ability of tiapride, a selective D2/D3 dopamine receptor antagonist, to exert discriminative stimulus control of responding was investigated by training rats to discriminate this drug (30 mg/kg) from saline in a two-lever, food-reinforcement procedure. Acquisition of tiapride discrimination required a relatively lengthy training period (mean of 76 sessions) but stable performance was maintained throughout the 18- month study. The dose of tiapride eliciting 50% tiapride-lever choice (ED50) was 2.2 mg/kg. After determination of the dose-effect curve with tiapride, substitution tests with several dopamine antagonists and other reference compounds were performed. All dopamine antagonists, including amisulpride (ED50 4 mg/kg), sulpiride (18 mg/kg), sultopride (1.5 mg/kg), clebopride (0.13 mg/kg), raclopride (0.16 mg/kg), metoclopramide (1.4 mg/kg), remoxipride (4.8 mg/kg), pimozide (2.7 mg/kg), thioridazine (3.4 mg/kg), olanzapine (0.97 mg/kg), chlorpromazine (1.9 mg/kg), risperidone (0.22 mg/kg) and haloperidol (0.14 mg/kg), except clozapine (10 mg/kg), produced dose-dependent substitution for tiapride. Tiapride-like stimulus effects were observed at doses that decreased response rates. However, ED50 values for substitution by tiapride, amisulpride, sulpiride, sultopride, pimozide, clebopride and thioridazine were lower than ED50 values for decreasing responding. Additional studies were conducted to evaluate the ability of direct and indirect dopamine agonists to attenuate the tiapride discriminative stimulus. Pretreatment with d-amphetamine and nomifensine antagonized the discriminative stimulus effects of tiapride. Quinpirole, 7-OH-DPAT, bromocriptine and apomorphine partially blocked the stimulus effects of tiapride whereas SKF 38393 did not affect the discrimination. These results from substitution and antagonism tests indicated that the discriminative effects of tiapride are mediated by activity at D2/D3 dopamine receptors.

Amisulpride, a benzamide derivative, is an antipsychotic drug with a pharmacological profile distinct from that of classical neuroleptics such as haloperidol and from that of another benzamide, remoxipride. In mice, amisulpride antagonized hypothermia induced by apomorphine, quinpirole or (+/-) 7-hydroxy-2-(di-n-propylamino)-tetralin, an effect involving D2/D3 receptors, at similar doses (ED50 approximately 2 mg/kg i.p.), which were much lower than doses that blocked apomorphine-induced climbing, an effect involving postsynaptic D2 and D1 receptor activation (ED50 = 21 mg/kg i.p.). Much higher doses (ED50 = 54 mg/kg i.p.) of amisulpride were needed to block grooming behavior observed after a short period in water, a D1 receptor-mediated behavior. In rats, amisulpride preferentially inhibited effects produced by low doses of apomorphine (hypomotility and yawning), related to stimulation of presynaptic D2/D3 dopamine autoreceptors (ED50 = 0.3 and 0.19 mg/kg i.p.). By contrast, amisulpride antagonized apomorphine-induced hypermotility, a postsynaptic dopamine receptor-mediated effect, at a much higher dose (ED50 = 30 mg/kg i.p.). Amisulpride (100 mg/kg i.p.) only partially inhibited apomorphine-induced stereotypies (gnawing) and had no effect on stereotypies induced by d-amphetamine. However, d-amphetamine-induced hyperactivity was antagonized by doses of amisulpride as low as 3 mg/kg i.p., which may indicate selectivity of this drug for limbic dopaminergic mechanisms. In addition, in contrast to haloperidol or remoxipride, which produced catalepsy at doses 2 or 3 times higher than those that antagonized stereotypies induced by apomorphine, amisulpride did not induce catalepsy up to a dose of 100 mg/kg i.p., which occupies 80% of striatal D2 receptors. This pharmacological profile of amisulpride, characterized by a preferential blockade of effects involving presynaptic mechanisms and limbic structures, may explain the clinical efficacy of this drug against both negative and positive symptoms of schizophrenia and its low propensity to produce extrapyramidal side effects.

This chapter discusses intelligent gripping systems. The gripping system is composed of a new system of theories and methodologies, a novel fingertip sensor system, and a versatile user-oriented computer package. The new system of theories has shown great advantage in grasping arbitrary objects. The implementation of the gripping system has been carried out by a series of experiments on the grasping of practical objects.

Within-session decrements in instrumental responding are a characteristic effect of certain neuroleptic drugs including haloperidol and pimozide. There is little consensus, however, as to whether these effects can best be explained as motivational or motor deficits. A number of recently developed drugs have been described as atypical antipsychotics and are claimed to produce fewer motor side effects than more traditional neuroleptics. Little work has been done to investigate whether such atypical agents also give rise to within-session response decrements. The present experiment used the operant responding of rats to study the effects of a range of antipsychotic drugs. Rats were trained to lever press for food during daily sessions (FR10 schedule) and responding was recorded during each 3-min period of the 15-min sessions. Dose-related decreases in overall response rates were produced by all the drugs studied; ED50 values were: haloperidol 0.17 mg/kg, risperidone 0.18 mg/kg, setoperone 0.23 mg/kg, remoxipride 1.2 mg/kg, sertindole 4.8 mg/kg, thioridazine 7.6 mg/kg, clozapine 8.9 mg/kg, amisulpride 34 mg/kg, sulpiride 74 mg/kg. The presence of within-session response decrements was confirmed for haloperidol and demonstrated with remoxipride, but similar effects were not observed with clozapine, thioridazine, risperidone, sertindole, setoperone, sulpiride and amisulpride. As a number of these drugs were known to have high affinity for 5HT2 receptors, the effects of the 5HT2 antagonist ritanserin (1 and 10 mg/kg) were studied alone and in combination with haloperidol. Ritanserin had no effect on response rates, and did not antagonize but rather potentiated the effect of haloperidol.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpidem in an imidazopyridine derivative which binds selectively to the omega 1 (BZ1) receptor subtype. It is active in some, but not all, behavioural tests sensitive to benzodiazepine anxiolytics and has clinical anti-anxiety effects. However, in a previous study, it was shown that alpidem did not substitute for chlordiazepoxide in rats trained to discriminate this benzodiazepine. The present experiments were carried out to investigate the discriminative stimulus properties of alpidem in greater detail. In the first experiment rats learned to discriminate a dose of 10 mg/kg alpidem from saline. Acquisition of the discrimination was long and performance unstable. Chlordiazepoxide, clorazepate and zolpidem substituted only partially for alpidem but the effects of the training dose of alpidem were blocked by 10 mg/kg flumazenil. The second experiment established stimulus control more rapidly to a dose of 30 mg/kg alpidem. Alpidem induced dose-related stimulus control, and dose-related and complete substitution for alpidem was produced by zolpidem, abecarnil, CL 218,872, triazolam and suriclone. Partial substitution occurred with chlordiazepoxide, clorazepate and pentobarbital. In most cases, high levels of substitution were produced only by doses which greatly reduced response rates even though the training dose of alpidem produced only modest decreases in rates. Ethanol, buspirone and bretazenil produced very little substitution for alpidem and both flumazenil and bretazenil antagonised the effects of alpidem. In two further experiments alpidem was found to substitute for the stimulus produced by zolpidem (2 mg/kg) but not for that produced by ethanol (1.5 g/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Zolpidem is a new, short-acting hypnotic of imidazopyridine structure which binds selectively to a subpopulation of receptors involved in the action of benzodiazepines [omega 1 (BZ1) sites of the gamma-aminobutyric acidA receptors]. The present study investigated whether tolerance and physical dependence develop after repeated treatment with zolpidem as is observed with benzodiazepines. Mice were given zolpidem or the benzodiazepine midazolam (2 x 30 mg/kg, p.o.) for 10 consecutive days. Tolerance to central depressant effects (evaluated by recording spontaneous locomotor activity) and to anticonvulsant effects (measured against pentylenetetrazole-, electroshock- and isoniazid-induced convulsions) was assessed 42 hr after the last administration. A decrease in the latency to isoniazid-induced convulsions was taken as an index of physical dependence and was evaluated 3, 6, 14, 24, 42 and 67 hr after the end of chronic drug treatment. Repeated treatment with midazolam produced tolerance to its sedative and anticonvulsant activities as indicated by shifts of the dose-response curves by a factor of 3 to 5. Fourteen hr after discontinuation of treatment, spontaneous withdrawal was observed and lasted 3 days. When flumazenil was given 3 or 6 hr after the final midazolam injection, precipitated withdrawal was observed. In contrast, after repeated treatment with zolpidem, there was no change in its ability to produce sedative and anticonvulsant effects. Moreover, neither spontaneous nor flumazenil-induced precipitated withdrawal was observed in zolpidem-treated mice.

This paper describes a mechanism which generates straight-line motion segments and which is especially appropriate for use as the basis for a walking wheel in various kinds of vehicles. The straight-line motion capability, with multiple legs in the wheel, is exploited to ensure that the height of the wheel centre above ground is maintained constant. Thus, the wheel can be used on hard surfaces as well as on soft surfaces, with a suitable foot attached to the leg to ensure that an appropriate level of ground pressure is maintained.

Buspirone has been reported to have effects on punished responding in rats which are considerably smaller and less reliable than those produced by benzodiazepines. A recent study, however, found that buspirone and ipsapirone increased operant responding suppressed by a stimulus which preceded unavoidable shock, suggesting that conditioned emotional response protocols may be more sensitive than punishment procedures. This hypothesis was not supported by the results of the present study. The food-reinforced lever pressing of rats was maintained by a multiple VI schedule with punished and unpunished components. The experimental parameters were similar to those used in the previous conditioned emotional response study. The benzodiazepines, chlordiazepoxide and clorazepate, as well as buspirone (at one dose) and ipsapirone (at several doses), increased rates of punished responding. The 5-hydroxytryptamine-1A receptor ligands 8-hydroxy-2-(di-n-propylamino)tetralin and MDL 73005EF did not reliably produce similar effects, although increased rates of punished responding were seen in some animals. Haloperidol, imipramine and idazoxan did not increase punished response rates. Although the increases in punished responding produced by buspirone were smaller than those produced by chlordiazepoxide and clorazepate, the effect of ipsapirone was quantitatively similar to that of the benzodiazepines.

There have been a number of important recent developments in the search for novel drugs for treating anxiety disorders, which have implications for the development and validation of animal models. It has been proposed that anxiolytic activity may be shown by compounds acting at serotonin receptors (5HT1A, 5HT2, 5HT3) and at excitatory amino acid receptors, as well as by ω (BZ) receptor ligands which differ structurally from benzodiazepines. The behavioural effects of such compounds, however, often show differences from those of the benzodiazepines and barbiturates. Future psychopharmacological research will need to develop and refine animal models in the light of new information from the clinic.

The novel anxiolytic drug buspirone and its analogues, gepirone and ipsapirone, have behavioral effects that differ substantially from those of other anxiolytics such as benzodiazepines and barbiturates. In particular, buspirone does not consistently produce large increases in rates of responding suppressed by punishment in rodents or primates. To study the effects of buspirone and other compounds on suppressed operant responding in rats, two procedures were used. In the first, food-reinforced responding was suppressed during a stimulus associated with response-produced electric shocks (punishment). Chlordiazepoxide produced large increases in rates of punished responding, but neither buspirone nor ipsapirone gave rise to a similar effect. In a second experiment, food-reinforced responding was suppressed during a stimulus that terminated with an unavoidable shock (conditioned emotional response). Chlorodiazepoxide and clorazepate increased suppressed response rates at low doses and decreased nonsuppressed responding at higher doses, giving rise to dose-related increases in suppression ratios. The effects of buspirone, gepirone and ipsapirone were similar to those of the benzodiazepines with ipsapirone producing particularly marked increases in responding during the pre-shock stimulus. 8-Hydroxy-2-(di-n-propylamino)tetralin did not consistently give rise to the same effect. In addition, similar effects were not produced by haloperidol, imipramine, morphine or idazoxan. Haloperidol and morphine decreased nonsuppressed responding without changing rates of suppressed responding or suppression ratios. Imipramine decreased rates of both nonsuppressed and suppressed responding and idazoxan decreased suppression ratios. The conditioned emotional response procedure may be more sensitive for assessing the behavioral effects of buspirone and similar anxiolytic drugs in rats than are punishment procedures.(ABSTRACT TRUNCATED AT 250 WORDS)

The lever-pressing behaviour of three rats was maintained by a schedule in which food reinforcement was obtained by any response which was emitted at least 15 s after the previous response (DRL 15s). When performance on this schedule had stabilised, the animals were presented intermittently with 1-min periods of a white noise stimulus, the termination of which was accompanied by the delivery of a mild electric footshock. This procedure let to reliable increases in response rates furing the stimulus although responding at other times continued to be appropriate to the DRL 15-s schedule. Administration of the benzodiazepine chlordiazepoxide (1, 3, 10, 17 and 30 mg/kg) and of ripazepam (1, 3, 10, 30 and 56 mg/kg), a non-benzodiazepine reported to have anxiolytic properties, increased response rates on the DRL baseline while decreasing the acceleration of responding produced by the preshock stimulus. Baseline response rates were also increased by d-amphetamine (0.25, 0.5, 1.0 and 2.0 mg/kg) and at the higher doses this drug completely abolished the accelerated responding during the preshock stimulus. Although the effects of chlordiazepoxide and ripazepam are consistent with the suggestion that these drugs may attenuate the behavioural effects of aversive stimuli, in this experiment the behavioural effects of d-amphetamine were similar in many respects.

Rats pressed a lever and obtained food pellets on a schedule of differential reinforcement of low rate (DRL) which required that responses were spaced at least 15 sec apart in order for them to produce reinforcement. When responding had stabilised at slow and steady rates the effects of d-amphetamine and chlordiazepoxide were assessed. Low doses of both drugs increased response rates while higher doses decreased them. Reinforcement frequency showed a dose related decrease after both drugs. When interresponse times (IRTs) were analysed it was found that both drugs shifted the peak of the distribution towards shorter IRTs but that chlordiazepoxide also produced a specific increase in the percentage of responses after very short IRTs (bursts). When IRTs were divided into those following a reinforced response (hit) and those following a non-reinforced response (miss) it was found that bursts normally followed only misses and chlordiazepoxide consistently increased the number of bursts following misses only. Amphetamine did not affect bursts in any consistent way.

The effects of six opiate antagonists (naloxone, naltrexone, diprenorphine, Mr 1452, Mr 2266, and WIN 44,441) were studied on the food intake of food-deprived rats. The potencies of these agents in standard tests of opiate antagonism were also measured. With the exception of WIN 44,441, all opiate antagonists reduced food consumption. However, all the active drugs had similar potencies in producing this effect whereas they had very different potencies in antagonizing the effects of opiates in vivo and in vitro. Furthermore, the anorectic action of the opiate antagonists differed in several respects from the effects produced by fenfluramine and diethylpropion. These results are consistent with a role for endogenous opioids in the control of appetite but suggest that the mechanisms involved may differ from those concerned in other opioid functions and from those mediating the actions of other anorectic drugs.

Rats were exposed to a multiple variable-interval schedule of food or electrical stimulation of the lateral hypothalamus. When stable behavioral baselines had developed, the effects of several doses of chlordiazepoxide (2.5, 5, 10, and 20 mg/kg) and of d-amphetamine (.25, .5, and 1 mg/kg) were assessed. Chlordiazepoxide was found to have similar effects on responding maintained by both reinforcers, low doses increasing response rates and the highest dose reducing them. This drug also increased the duration of brain stimulation, which was under the control of the rats. The effects of d-amphetamine, in contrast, were different in the two schedule components. Responding maintained by brain stimulation was substantially increased by d-amphetamine which, however, produced either only small increases or even decreases in response rates maintained by food. The different effects of d-amphetamine in the two schedule components could not be explained in terms of differences in baseline response rates. It is therefore concluded that in some circumstances the actions of d-amphetamine are dependent on the reinforcing event maintaining behavior.

This paper presents the analysis of restraint of a rigid body in contact with any arrangement of point contacts having known frictional properties. A necessary condition for the solution of this problem is that the elastic properties of the contacts are also known. The relationship between externally applied loads and contact forces in the presence of limiting friction is established, as is the means for evaluating the resulting bodily motion, with or without slip at the contacts. An example is given to illustrate the application of the theoretical basis to a device such as a robot gripper that relies on friction for restraint.

Summmy.-Laboratory techniques for assessing the behavioral effects of anxiolytic drugs often involve the use of a punishing procedure and rats or other species as subjects. Some aspects of conventional experimental designs, however, make difficult interpretation of the drugs' effects. The present experiment made use of a modified punishment with rats, which was designed to reduce interpretative difficulties. Both food and shock presentations were scheduled at similar, though indepeqdent, variable intervals. Chlordiazepoxide and amobarbital were found to produce dose-related decreases in the suppression of responding produced by punishment. Techniques of punishment have been widely used for investigating the effects of psychoactive drugs and have proved useful for predicting the clinical potency of potential anxiolytics (Cook & Davidson, 1973; Houser, 1978). The most widely studied of such procedures was first described by Geller and Seifter ( 1960). Rats are trained to press a lever to obtain food or water reinforcement which is made available according to a variable-interval schedule. Then a signal, which often lasts for 3 min., is presented at regular intervals, e.g., once each 15 min. During these signalled periods, the schedule is changed so that each response now produces a reinforcer but also produces an electric shock. Relatively low rates cif responding are usually observed during the signal, the actual rate being dependent upon the parameters of the shock used (Geller, e; al., 1962). A number of experimenters have shown that benzodiazepines, barbiturates, and other drugs which have been used clinically as anxiolytics can increase the low rates of punished responding maintained by this procedure (Blum, 1970; Geller, et al., 1962). This facilitation of punished responding has proved to be one of the most replicable phenomena in behavioral pharmacology. There are, however, several aspects of the Geller-Seifter procedure which make such results difficult to interpret. (a) The schedule of food presentation is changed during the periods of punished responding, and so comparisons becween punished and unpunished levels of responding are not possible within any session. (b) The use of a continuous reinforcement schedule of food and of shock delivery involves a direct association between food or water reinforcement and shock, (c) Any

Rats were trained to discriminate phencyclidine (PCP) from saline at doses of 2 and 4 mg/kg, using a two-lever food reinforced operant technique. +/- N-allylnormetazocine (+/- SKF 10047), +5-methyl-10,11-dihydro-5H-dibenzo[A,D]cyclohepten-5,10-imine MK 801), 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) and ifenprodil, which have been shown to antagonise the effects of N-methyl-D-aspartate (NMDA), were tested for their ability to give rise to PCP-appropriate responding. In rats trained at both doses of PCP, +/- SKF 10047 (2-12 mg/kg) and MK 801 (0.0125-0.2 mg/kg) produced dose-related responding on the lever associated with PCP injection. The relative potency of these two compounds was the same in the two groups of animals, but their absolute potencies to produce a PCP-like discriminative stimulus were dependent on the training dose of PCP. In contrast, neither the competitive NMDA antagonist CPP (4-20 mg/kg) nor the non-competitive antagonist ifenprodil (2-12 mg/kg) produced PCP-appropriate responding and ifenprodil (4 mg/kg) neither potentiated nor antagonised PCP. These findings are discussed in the light of the hypothesis that the behavioural effects of PCP are mediated via a reduction of neurotransmission at the NMDA-subtype of glutamate receptors.

The lever pressing of five adult, female gerbils was maintained on fixed-interval schedules with interval values of 20, 60, and 180 sec. Performance was characterized by a pause after reinforcement followed by either an acceleration of responding or a constant response rate until the next reinforcer was obtained. Overall response rates and response rates calculated to exclude postreinforcement pauses (running rates) varied unsystematically with changes in the fixed-interval parameter, higher response rates tending to occur with shorter intervals. The average postreinforcement pause durations, however, were systematically related to the interval value, pause durations increasing with increases in the interval size. Gerbils thus show patterns of fixed-interval responding similar to those of other species and appear to be convenient subjects for use in studies of operant behavior.

Rats pressed a lever on either a variable interval or a fixed ratio schedule of food reinforcement. Both schedules maintained similar high overall rates of responding. A dose of 20 mg/kg of chlordiazepoxide depressed response rates on both schedules. However, the effects of lower doses (2.5, 5 mg/kg) were schedule-dependent, overall Vi response rates being increased but overall Fr response rates showing no such increase.

Previous studies of the benzodiazepine antagonist CGS 8216 have reported that this compound may enhance the punishment-induced suppression of behaviour. In order to investigate this phenomenon further, water-deprived rats were trained to drink from a water spout during a multiple schedule with shocked and unshocked components. During the shocked components a very mild electric footshock was presented after every 20th lick. The shock slightly reduced the rate of licking during these components below that which occurred during periods without shock, although this effect decreased during the experiment. CGS 8216 (0.3-10 mg/kg) produced a dose-related reduction in licking during both schedule components. The overall volumes of water consumed were reduced by CGS 8216 as was the number of licks during the first, unshocked schedule component, before shock was applied, showing that the effect on unshocked licking was not due to a generalisation of suppression between periods with or without shock. In contrast to CGS 8216, a dose of 10 mg/kg pentylenetetrazol selectively reduced shocked licking. In a second group of rats which drank under identical conditions but without shock, CGS 8216 again reduced water intake. These results show that CGS 8216 can reduce water intake in rats regardless of whether drinking results in shock presentation.

Intermittent delivery of food pellets induces high levels of adjunctive drinking in rats, a pattern of behaviour which some have suggested is due to emotional arousal. In this experiment, however, chronic administration of a dose of chlordiazepoxide, a minor tranquillizer, did not prevent the development of adjunctive drinking after food pellets delivered at 1-min intervals. Indeed, the drug was found slightly to enhance the development of drinking, an effect assumed to be due to the drug's ability to facilitate the performance of several patterns of responding. When chlordiazepoxide was withdrawn a disruption in the pattern of adjunctive drinking was observed.

It is shown that six-speed gear trains with the minimum number of gears, i.e. eight gears, can be divided into categories which are suitable for overdrive ratios or speed reduction ratios. One gear train from each category is examined and its characteristics and design limits discussed. A technique for computing solutions is outlined and a few typical solutions are given.