Initiation Of Locomotion Research Articles

Hypothalamic neuronal outputs transmit sensorimotor signals at the onset of locomotor initiation

The lateral hypothalamus (LH) plays a critical role in sensory integration to organize behavior responses. However, how projection-defined LH neuronal outputs dynamically transmit sensorimotor signals to major downstream targets to organize behavior is unknown. Here, using multi-fiber photometry, we show that three major LH neuronal outputs projecting to the dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and lateral habenula (LHb) exhibit significant coherent activity in mice engaging sensory-evoked or self-initiated motor responses. Increased activity at LH axon terminals precedes movement initiation during active coping responses and the activity of serotonin neurons and dopamine neurons. The optogenetic activation of LH axon terminals in either of the DRN, VTA, or LHb was sufficient to increase motor initiation but had different effects on passive avoidance and sucrose consumption. Our findings support the complementary role of three projection-defined LH neuronal outputs in the transmission of sensorimotor signals to major downstream regions at movement onset.

Chx10+V2a interneurons in spinal motor regulation and spinal cord injury.

Chx10-expressing V2a (Chx10+V2a) spinal interneurons play a large role in the excitatory drive of motoneurons. Chemogenetic ablation studies have demonstrated the essential nature of Chx10+V2a interneurons in the regulation of locomotor initiation, maintenance, alternation, speed, and rhythmicity. The role of Chx10+V2a interneurons in locomotion and autonomic nervous system regulation is thought to be robust, but their precise role in spinal motor regulation and spinal cord injury have not been fully explored. The present paper reviews the origin, characteristics, and functional roles of Chx10+V2a interneurons with an emphasis on their involvement in the pathogenesis of spinal cord injury. The diverse functional properties of these cells have only been substantiated by and are due in large part to their integration in a variety of diverse spinal circuits. Chx10+V2a interneurons play an integral role in conferring locomotion, which integrates various corticospinal, mechanosensory, and interneuron pathways. Moreover, accumulating evidence suggests that Chx10+V2a interneurons also play an important role in rhythmic patterning maintenance, left-right alternation of central pattern generation, and locomotor pattern generation in higher order mammals, likely conferring complex locomotion. Consequently, the latest research has focused on postinjury transplantation and noninvasive stimulation of Chx10+V2a interneurons as a therapeutic strategy, particularly in spinal cord injury. Finally, we review the latest preclinical study advances in laboratory derivation and stimulation/transplantation of these cells as a strategy for the treatment of spinal cord injury. The evidence supports that the Chx10+V2a interneurons act as a new therapeutic target for spinal cord injury. Future optimization strategies should focus on the viability, maturity, and functional integration of Chx10+V2a interneurons transplanted in spinal cord injury foci.

Targeted activation of midbrain neurons restores locomotor function in mouse models of parkinsonism

The pedunculopontine nucleus (PPN) is a locomotor command area containing glutamatergic neurons that control locomotor initiation and maintenance. These motor actions are deficient in Parkinson’s disease (PD), where dopaminergic neurodegeneration alters basal ganglia activity. Being downstream of the basal ganglia, the PPN may be a suitable target for ameliorating parkinsonian motor symptoms. Here, we use in vivo cell-type specific PPN activation to restore motor function in two mouse models of parkinsonism made by acute pharmacological blockage of dopamine transmission. With a combination of chemo- and opto-genetics, we show that excitation of caudal glutamatergic PPN neurons can normalize the otherwise severe locomotor deficit in PD, whereas targeting the local GABAergic population only leads to recovery of slow locomotion. The motor rescue driven by glutamatergic PPN activation is independent of activity in nearby locomotor promoting glutamatergic Cuneiform neurons. Our observations point to caudal glutamatergic PPN neurons as a potential target for neuromodulatory restoration of locomotor function in PD.

Multiple Rhythm-Generating Circuits Act in Tandem with Pacemaker Properties to Control the Start and Speed of Locomotion

In vertebrates, specific command centers in the brain can selectively drive slow-explorative or fast-speed locomotion. However, it remains unclear how the locomotor central pattern generator (CPG) processes descending drive into coordinated locomotion. Here, we reveal, in adult zebrafish, a logic of the V2a interneuron rhythm-generating circuits involving recurrent and hierarchical connectivity that acts in tandem with pacemaker properties to provide an ignition and gear-shift mechanism to start locomotion and change speed. A comprehensive mapping of synaptic connections reveals three recurrent circuit modules engaged sequentially to increase locomotor speed. The connectivity between V2a interneurons of different modules displayed a clear asymmetry in favor of connections from faster to slower modules. The interplay between V2a interneuron pacemaker properties and their organized connectivity provides a mechanism for locomotor initiation and speed control. Thus, our results provide mechanistic insights into how the spinal CPG transforms descending drive into locomotion and align its speed with the initial intention.

Gait Ignition Failure in JNPL3 Human Tau-mutant Mice.

Cognitive impairments and motor dysfunction are commonly observed behavioral phenotypes in genetic animal models of neurodegenerative diseases. JNPL3 transgenic mice expressing human P301L-mutant tau display motor disturbances with age- and gene dose-dependent development of neurofibrillary tangles, suggesting that tau pathology causes neurodegeneration associated with motor behavioral abnormalities. Although gait ignition failure (GIF), a syndrome marked by difficulty in initiating locomotion, has been described in patients with certain forms of tauopathies, transgenic mouse models mirroring human GIF syndrome have yet to be reported. Using the open field and balance beam tests, here we discovered that JNPL3 homozygous mice exhibit a marked delay of movement initiation. The elevated plus maze excluded the possibility that hesitation to start in JNPL3 mice was caused by enhanced levels of anxiety. Considering the normal gait ignition in rTg4510 mice expressing the same mutant tau in the forebrain, GIF in JNPL3 mice seems to arise from abnormal tau deposition in the hindbrain areas involved in locomotor initiation. Accordingly, immunohistochemistry revealed highly phosphorylated paired helical filament tau in JNPL3 brainstem areas associated with gait initiation. Together, these findings demonstrate a novel behavioral phenotype of impaired gait initiation in JNPL3 mice and underscore the value of this mouse line as a tool to study the neural mechanisms and potential treatments for human GIF syndrome.

Direct and indirect pathways of the basal ganglia: opponents or collaborators?

Direct and indirect pathways of the basal ganglia: opponents or collaborators?

Regulation of dopamine release by CASK-β modulates locomotor initiation in Drosophila melanogaster.

CASK is an evolutionarily conserved scaffolding protein that has roles in many cell types. In Drosophila, loss of the entire CASK gene or just the CASK-β transcript causes a complex set of adult locomotor defects. In this study, we show that the motor initiation component of this phenotype is due to loss of CASK-β in dopaminergic neurons and can be specifically rescued by expression of CASK-β within this subset of neurons. Functional imaging demonstrates that mutation of CASK-β disrupts coupling of neuronal activity to vesicle fusion. Consistent with this, locomotor initiation can be rescued by artificially driving activity in dopaminergic neurons. The molecular mechanism underlying this role of CASK-β in dopaminergic neurons involves interaction with Hsc70-4, a molecular chaperone previously shown to regulate calcium-dependent vesicle fusion. These data suggest that there is a novel CASK-β-dependent regulatory complex in dopaminergic neurons that serves to link activity and neurotransmitter release.

Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry

Neural circuits of the basal ganglia are critical for motor planning and action selection. Two parallel basal ganglia pathways have been described, and have been proposed to exert opposing influences on motor function. According to this classical model, activation of the 'direct' pathway facilitates movement and activation of the 'indirect' pathway inhibits movement. However, more recent anatomical and functional evidence has called into question the validity of this hypothesis. Because this model has never been empirically tested, the specific function of these circuits in behaving animals remains unknown. Here we report direct activation of basal ganglia circuitry in vivo, using optogenetic control of direct- and indirect-pathway medium spiny projection neurons (MSNs), achieved through Cre-dependent viral expression of channelrhodopsin-2 in the striatum of bacterial artificial chromosome transgenic mice expressing Cre recombinase under control of regulatory elements for the dopamine D1 or D2 receptor. Bilateral excitation of indirect-pathway MSNs elicited a parkinsonian state, distinguished by increased freezing, bradykinesia and decreased locomotor initiations. In contrast, activation of direct-pathway MSNs reduced freezing and increased locomotion. In a mouse model of Parkinson's disease, direct-pathway activation completely rescued deficits in freezing, bradykinesia and locomotor initiation. Taken together, our findings establish a critical role for basal ganglia circuitry in the bidirectional regulation of motor behaviour and indicate that modulation of direct-pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits.

Effects of flufenamic acid on fictive locomotion, plateau potentials, calcium channels and NMDA receptors in the lamprey spinal cord

A Ca 2+-activated, non-selective cation current ( I CAN) has been suggested to contribute to plateau potentials in lamprey reticulospinal neurons, providing the drive for locomotor initiation. Flufenamic acid (FFA) is commonly used as a blocker of I CAN. To explore the effects of FFA on spinal locomotor pattern generation, we induced fictive locomotion in the isolated lamprey spinal cord. Bath-applied FFA (100–200 μM) caused a marked reduction of amplitude and regularity of the locomotor burst activity. We next analyzed the NMDA-induced membrane potential oscillations in single spinal neurons. The duration of depolarizing plateaus was markedly reduced when applying FFA, suggesting an involvement of I CAN. However, in experiments with intracellular injection of the Ca 2+ chelator BAPTA, and in the presence of the K Ca-channel blocker apamin, no support was found for an involvement of I CAN. We therefore explored alternative explanations of the effects of FFA. FFA reduced the size of the slow, Ca 2+-dependent afterhyperpolarization, suggesting an influence on calcium channels. FFA also reduced the NMDA component of reticulospinal EPSPs as well as NMDA-induced depolarizing responses, demonstrating an influence on NMDA receptors. These non-selective effects of FFA can account for its influence on fictive locomotion and on membrane potential oscillations and thus, a specific involvement of the I CAN current in the lamprey spinal cord is not supported.

Priming pattern determines the correlation between hippocampal theta activity and locomotor stepping elicited by stimulation in anesthetized rats

The after-effects of locomotor stimulation are a transient facilitation of locomotor initiation (the priming effect), and a transient increase in hippocampal rhythmic slow activity in the 3–6 Hz band of the theta range. The similar time course of the two effects suggests that hippocampal 3–6 Hz activity may be linked to the excitability of locomotor initiation. This study tested the hypothesis that power in the 3–6 Hz band that is present prior to stimulation would predict the magnitude of elicited stepping. Stimulation electrodes were implanted in 15 locomotor sites of 10 anesthetized rats (urethane, 800 mg/kg). Hindlimb stepping was elicited by a single control train of electrical stimulation presented once every 62 s. On test trials, a test train at the same intensity followed the control train at varying control/test intervals (15–36 s) to assess the priming effect on stepping. The priming pattern determined whether hippocampal 3–6 Hz power predicted the amount of stepping to be elicited by a stimulation train. Positive correlation (0.47> r>0.22) was found for seven out of eight sites showing positive priming effects. Correlation was absent for three other sites that showed non-significant priming effects and were mixed for four sites that showed negative effects. Sites with positive priming patterns, compared to sites with inconsistent or negative priming patterns, had similar trends in post-stimulation 3–6 Hz power, smaller increases in 6–8 Hz power during the control train and lower 1–3 Hz power during the periods immediately before the control stimulation. For six of 15 sites, regardless of the priming pattern, 1–3 Hz power was inversely related to subsequent stepping, and in three cases provided an independent predictor of stepping. Stimulation at two sites produced discrete episodes of post-stimulation stepping. In one of these cases, a 0.5-Hz increase in peak frequency of hippocampal activity preceded stepping. The results show that the association between hippocampal 3–6 Hz activity and the excitability of locomotor initiation is sufficiently specific to allow prediction of the magnitude of stepping by the prior levels of 3–6 Hz power. However, the occurrence of negative priming effects during prominent 3–6 Hz activity indicates that other factors determine the actual stepping and they can suppress the correlation between theta activity and subsequent locomotion.

Hippocampal theta activity and facilitated locomotor stepping produced by GABA injections in the midbrain raphe region

Inactivation of neurons in the midbrain raphe region produces increases in locomotor activity, and it appears that they function to suppress locomotion. Inactivation of neurons there also produces hippocampal slow wave (theta) activity and it appears that they also function to inhibit rhythmic activity in the hippocampus. We determined whether the degree of association between the two effects was consistent with the operation of a single mechanism. Stimulation electrodes were implanted into locomotor sites of the hypothalamus of 34 urethane-anesthetized rats. Hindlimb stepping was elicited by 5.12-s trains of perifornical electrical stimulation presented once per minute. Hippocampal theta activity was recorded across the CA1 layer of the dorsal hippocampus. GABA injections were used to locate raphe sites at which neuronal inactivation influenced stepping and hippocampal activity. A glass pipette (80-μm tip) was inserted into the midbrain, and injections of GABA (50–100 mg/0.1–0.2 μl) were made in 70 sites in the midbrain. Injections at 34 sites facilitated stimulation-elicited stepping, and at 17 sites, they also produced intertrial stepping. Facilitating injections, but not ineffective or suppressive injections, increased the mean peak frequency of hippocampal activity, and increased power in the 4–5 Hz band during the period that preceded the stimulation trains, but did not change the 5–6 Hz activity produced during the stimulation trains. Priming locomotor stimulation which also facilitated stepping produced generally similar increases in pre-stimulation peak frequency and 4-Hz power. The magnitudes of the increases in stepping and 4-Hz power were uncorrelated. The increase in 4-Hz power appeared earlier than the increase in stepping in 18 of 34 cases, and later in 11 cases; no increases in 4-Hz power were apparent in five cases. The results indicate that pre-locomotor 4-Hz hippocampal activity in the urethane-anesthetized rat is loosely coupled with facilitated locomotor initiation. Neurons in the midbrain raphe region appear to suppress both processes, but the low degree of association between the magnitudes and onset times of increases in stepping and hippocampal 4-Hz power indicate the operation of multiple mechanisms.

Paradoxical Locomotor Behavior of Dopamine D1 Receptor Transgenic Mice

The behavioral effects of augmenting dopamine D1 receptor expression in the brain were investigated in mice incorporating additional copies of the mouse D1 receptor gene. Two transgenic lines showed increases in brain D1 receptor binding sites, which were greatest in extrastriatal regions. The full D1 agonist SKF 81297, when administered systemically to control animals, stimulated a dose-dependent increase in locomotor activity. In contrast, in D1 receptor overexpressing transgenic mice, this drug caused a marked suppression of locomotion due to a decrease in the frequency of movement initiation. Amphetamine and cocaine induced comparable locomotor activation in both transgenic animals and their control littermates. In the transgenic animals, D1 agonist-induced rearing and climbing behaviors were suppressed. However, on rotarod testing, the agonist-treated transgenic and control mice performed comparably, indicating that sensorimotor coordination was unaffected. These studies demonstrate that altering the levels of D1 receptor expression reverses the effects of D1 agonism on locomotor initiation and rearing.

Locomotion and head scanning initiated by hypothalamic stimulation are inversely related

Stimulation in the hypothalamus elicits locomotor stepping. Before stepping is initiated, head scanning movements occur. We determined the relationships between the latency of locomotor initiation and the number, extent and direction of the head scanning movements. Chronic stimulation electrodes were stereotaxically implanted in and around the hypothalamus of 29 rats. Under awake conditions, 38 locomotor sites were tested in a runway apparatus. Behaviors occurring between the onset of stimulation and the first step were recorded on videotape. Points on the rat were digitized at sampling rate of 6 Hz to produce measures of head angles in the vertical, horizontal, and sagittal planes. The priming paradigm was used with a current selected for each site that was minimally sufficient to produce reliable stepping. In trials at approximately 1-min intervals, a 5-s train of stimulation (the control) was followed by a second train (the test) delivered 5–20 s later. Initiation latency on control trains was strongly correlated with head movement measures. Vertical and lateral head movements were independent of one another. Together, their frequency and extent accounted for 85% of the variance in locomotor initiation latencies. In effective priming trials, when locomotor initiation latencies were reduced on the test train, the frequency and extent of vertical and lateral head movements were also reduced. In non-effective priming trials, when latencies were not reduced, head movements were not reduced. Head scanning and locomotor initiation reflect reciprocal processes.

Locomotion and head scanning initiated by hypothalamic stimulation are inversely related.

Stimulation in the hypothalamus elicits locomotor stepping. Before stepping is initiated, head scanning movements occur. We determined the relationships between the latency of locomotor initiation and the number, extent and direction of the head scanning movements. Chronic stimulation electrodes were stereotaxically implanted in and around the hypothalamus of 29 rats. Under awake conditions, 38 locomotor sites were tested in a runway apparatus. Behaviors occurring between the onset of stimulation and the first step were recorded on videotape. Points on the rat were digitized at sampling rate of 6 Hz to produce measures of head angles in the vertical, horizontal, and sagittal planes. The priming paradigm was used with a current selected for each site that was minimally sufficient to produce reliable stepping. In trials at approximately 1-min intervals, a 5-s train of stimulation (the control) was followed by a second train (the test) delivered 5–20 s later. Initiation latency on control trains was strongly correlated with head movement measures. Vertical and lateral head movements were independent of one another. Together, their frequency and extent accounted for 85% of the variance in locomotor initiation latencies. In effective priming trials, when locomotor initiation latencies were reduced on the test train, the frequency and extent of vertical and lateral head movements were also reduced. In non-effective priming trials, when latencies were not reduced, head movements were not reduced. Head scanning and locomotor initiation reflect reciprocal processes. © 1999 Elsevier Science B.V. All rights reserved.

GABA injected into the anterior dorsal tegmentum (ADT) of the midbrain blocks stepping initiated by stimulation of the hypothalamus

Previous work showed that the activity rates of certain neurons in the anterior dorsal tegmentum (ADT) of the midbrain correlated with the onset of stepping elicited by hypothalamic stimulation. This study determined if reversible inactivation of the ADT would block locomotion elicited by hypothalamic stimulation of anesthetized rats (urethane, 800 mg/kg). GABA (concentrations 0.25–1.0 mg/ μl in saline) were injected in 52 sites in 21 rats. GABA at volumes of 0.1 or 0.2 μl blocked hindlimb stepping in 18 cases. Locomotor blocks occurred within 5 min of the injection, and typically recovered within 10–20 min. The effective blocking sites were clustered around the interstitial nucleus of the medial longitudinal fasciculus. Sites more dorsal and more anterior were not as effective as sites in and ventral to this nucleus. The data are consistent with a role for the ADT of the midbrain in locomotor initiation.

Impairments of movement initiation and execution induced by a blockade of dopamine D1 or D2 receptors are reversed by a blockade of N-methyl-D-aspartate receptors.

The effects of a dopamine D1 or D2 receptor blockade on initiation and execution of movements were examined using a simple reaction time task for rats. The task demands stimulus-triggered rapid initiation of locomotion to get a food reward. Time and force parameters of the transition from stance to gait were recorded allowing a detailed and separate analysis of the initiation and initial execution of locomotor initiation. Systemic administration of the preferential dopamine D2 antagonist haloperidol (0.1; 0.15 mg/kg, i.p.) caused a delayed movement initiation, as indicated by an increase in reaction time. In addition, movement execution was slowed, as measured by an increase in movement time, a decrease in the rate of development and in the maximum of the accelerative force component. Systemic administration of the selective dopamine D1 antagonist 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390) (0.15 mg/kg, i.p.) induced a similar pattern of impairments as haloperidol. Dizocilpine, an antagonist of the N-methyl-D-aspartate subtype of glutamate receptors in a dose which was largely ineffective when given alone (0.08 mg/kg, i.p.) reversed impairments of movement initiation and execution that were induced by the high dose of dopamine D1 or D2 antagonists (0.15 mg/kg, i.p., respectively). It is concluded that dopamine D1 and D2 receptors are both involved in movement initiation and execution processes, which control the onset and speed of a conditioned movement, as shown here for locomotor initiation of rats. According to our results, the processes related to movement initiation and execution may be mediated by separate neuronal mechanisms, as there were no correlations between impairments of movement initiation and execution, regardless of the treatment animals received. The reversal of SCH 23390- and haloperidol-induced impairments by dizocilpine suggests a functionally antagonistic involvement of dopamine D1/D2 and N-methyl-D-aspartate receptors in the control of movement initiation and execution. The results further imply that neuroleptics blocking dopamine D1 receptors probably induce similar extrapyramidal side effects as classical neuroleptics blocking dopamine D2 receptors.

Priming of locomotor initiation by electrical stimulation in the hypothalamus and preoptic region in the anesthetized rat

electrical stimulation at a locomotor site can prime (i.e., shorten the latency to initiate) stepping elicited by subsequent stimulation of the same or a different site. We tested for the priming effect in representative sites along the medial forebrain bundle, and determined if its magnitude showed regional differences. Rats ( n = 20) were anesthetized with Nembutal and held in a stereotaxic apparatus over a wheel. Stepping was detected by accelerometers attached to the hindlimbs. Priming and test trains of stimulation (0.5-ms cathodal pulses, 50 Hz, 25–75 MA, 7–9-s train duration) separated by 20 s were delivered every 90 s. When the priming and test stimulations were applied to the same site, the priming effects were similar along the entire extent of the medial forebrain bundle. When the priming and test sites were different, the priming effect depended on their relative positions. Anterior stimulation primed posterior sites at magnitudes comparable to those produced by stimulating the same posterior site. Posterior stimulation primed anterior sites at a level half of that produced by stimulation of the same anterior site. This pattern was found for priming and test sites that were ipsilateral and contralateral. Priming is a general and robust phenomenon with properties that may be useful for studying locomotor initiation pathways.

Neural activity in the midbrain correlated with hindlimb extension initiated by locomotor stimulation of the hypothalamus of the anesthetized rat

Midbrain neuronal activity that correlated with the initiation of locomotion produced by hypothalamic stimulation was studied. Locomotion was elicited by electrical stimulation in the perifornical hypothalamus of 59 rats anesthetized with Nembutal. The first hindlimb extension indexed stepping onset. Single and multiple neurons were recorded ipsilateral to the stimulation site at 2230 sites in the anterior and posterior midbrain. To classify responses, activity patterns averaged around stimulation onset and around the extension onset were examined. Responses with specific correlations to extension onset were Type I; responses not specifically related to the extension onset were Type II. In the anterior midbrain, 6% of sites were Type I and 8% were Type II. The larger Type I responses were frequent in the anterior tegmentum near the central gray. The relative frequency of Type I patterns in the posterior ventrolateral tegmentum was similar. Other regions showed relatively more Type II responses; they included the ventral tegmental area, and the regions near the superior cerebellar peduncle and the posterior central gray. Regional population profiles showed that during the initiation of locomotion, neurons in the posterior peribrachial region responded early and neurons in the anterior dorsal and the posterior ventrolateral tegmentum responded later. The initiation-related activity of Type I neurons in the anterior and posterior midbrain tegmentum suggest that they warrant further study for a role in locomotor initiation.

Functional regeneration and recovery of locomotor activity in spinally transected lamprey.

Spinally transected lamprey recovery locomotor function within 3-6 weeks, and recovery is due, in part, to functional regeneration of neural pathways in the central nervous system (CNS). Our data demonstrate for the first time in the lamprey that descending axons arising from brainstem command neurons can functionally regenerate and restore locomotor initiation below a healed spinal transection site. Immediately after behavioral recovery (3-6 weeks) the locomotor pattern was incomplete but returned to normal during the remainder of the recovery period (6-40 weeks). Initially, the extent of regeneration of descending axons was limited but increased to at least 30-50 mm at recovery times of 24-40 weeks. Regenerated giant Muller axons do not contribute significantly to recovery of locomotor function; rather, regenerated axons of smaller reticulospinal neurons appear to restore locomotor initiation. The restoration of locomotor coordination across a spinal lesion is dependent on two mechanisms: regeneration of spinal coordinating neurons and mechanosensory inputs. Comparisons are made to spinal cord regeneration in other lower vertebrates and to the relative lack of CNS regeneration and behavioral recovery in higher vertebrates.

Anticataleptic potencies of glutamate-antagonists

The anticataleptic effects of non-competitive and competitive NMDA antagonists as well as those of an agonist at the allosteric glycine binding site of the NMDA receptor were tested in the catalepsy model. Some of these drugs were further tested in a reaction time task demanding rapid locomotor initiation. The results show that the non-competitive NMDA antagonists dizocilpine and memantine as well as the competitive antagonists CGP 39551, CGP 37849 and CPPene antagonized dopamine D2 receptor mediated catalepsy induced by haloperidol. D-cycloserine, a partial glycine agonist per se had no effects, but it enhanced the anticataleptic effects of dizocilpine when coadministered. However, the effects of CGP 37849 were abolished. Dopamine D1 receptor mediated catalepsy induced by SCH 23390 was antagonized by dizocilpine, memantine, CPPene, but not by CGP 37849. In the reaction time task dizocilpine, memantine and CGP 37849 were tested for their anti-akinetic and anti-bradykinetic potencies. All these compounds improved haloperidolinduced slowing of reaction time. However, they acted differentially on haloperidol-induced slowing of movement execution and decreased initial acceleration. Thus, antagonists at the NMDA receptor may have a therapeutic potential in the treatment of Parkinson's disease. Their potency can be manipulated specifically at the glycine binding site.