Biomedical subjects

M Amalric

Publications and source records attributed to M Amalric.

At least 19 recordsLinked to original sources

PubMed2005

The metabotropic glutamate receptor subtype 5 antagonist MPEP and the Na+ channel blocker riluzole show different neuroprotective profiles in reversing behavioral deficits induced by excitotoxic prefrontal cortex lesions.

Overactivation of excitatory amino acid receptors has been involved in several neurodegenerative diseases. The present study aims at investigating the potential neuroprotective action of 2-methyl-6-(phenylethylnyl)-pyridine (MPEP), a selective non-competitive antagonist of metabotropic glutamate receptor subtype 5, and 2-amino-6-trifluoro methoxy-benzothiole (riluzole), a Na+ channel blocker exhibiting anti-glutamatergic properties, on the ibotenate-induced damage to the rat medial prefrontal cortex. The neuroprotective efficacy of these compounds was assessed on the recovery from behavioral deficits induced by prefrontal cortical excitotoxic lesions in a reaction time task. MPEP (3, 10 or 30 mg/kg) or riluzole (2, 4 or 8 mg/kg) was administered i.p. 30 min before and after medial prefrontal cortex lesions. As previously found, lesions to the medial prefrontal cortex significantly altered the motor preparatory processes involved in the reaction time task. These deficits were prevented by MPEP 3 mg/kg and riluzole 2 mg/kg while higher doses of either compound were ineffective. Furthermore, the neuron-specific nuclear protein immunostaining of the lesioned cortical area in animals treated with the efficient dose of either compound revealed that MPEP reduced the volume of the lesion whereas riluzole reversed the decrease of neuronal density within the lesioned area. Altogether, these results suggest a neuroprotective action of MPEP as well as riluzole at both behavioral and cellular levels on excitatory amino acid-induced toxicity.

Animals↗

PubMed2003

Insight into the function of Group I and Group II metabotropic glutamate (mGlu) receptors: behavioural characterization and implications for the treatment of CNS disorders.

Following the molecular cloning in the early 1990s of the metabotropic glutamate receptors (mGlu1-8), research that focused on the physiology, pharmacology and function of these receptors revealed their potential role in CNS disorders. Numerous psychiatric and neurological dis-orders are indeed linked to changes in excitatory processes, in which glutamate plays a key role. In contrast to ligand-gated ion channels [N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) and kainate], which are responsible for fast excitatory transmission, mGlu receptors have a more modulatory role, by contributing to fine-tuning of synaptic efficacy, and control of the accuracy and sharpness of the transmission. Given the fact that the mGlu receptors are G-protein coupled, they obviously constitute new 'drugable' targets for the treatment of various CNS disorders. Due to the recent emergence of subtype-specific ligands for Group I and II mGlu receptors, this review will concentrate on the molecular characteristics, brain localization, pharmacology and physiological role of these receptors, in order to provide further insights into their therapeutic potential.

Animals↗

PubMed2002

Effect of bilateral 6-hydroxydopamine lesions of the medial forebrain bundle on reaction time.

Overt symptoms of Parkinson's disease do not manifest themselves until there is a substantial loss of the dopaminergic nigrostriatal projection. However, as neuroprotective strategies are developed, it will be essential to detect the disease in its preclinical phase. Performance on conditioned reaction time tasks is known to be impaired by extensive 6-hydroxydopamine-induced lesions of the nigrostriatal dopamine pathway. However, the effect of smaller lesions on a reaction time task has not been systematically assessed. We, therefore, used this test to examine behavioral deficits as a function of striatal dopamine loss. When injected at doses that produced striatal DA depletion <50%, 6-hydroxydopamine infused in the medial forebrain bundle produced no reliable impairment in the reaction time task. Higher doses producing > or = 60% DA depletion in the striatum produced a decrease in the percent correct responding throughout the 5 week testing period and akinetic deficits expressed by an increase in delayed responding. In addition, larger DA depletions (> or = 95%) profoundly altered motor control with decreases in percent correct responses, increases in delayed responses and increases in reaction time. These results suggest that reaction time may be a relatively sensitive measure of preclinical or subtle deficits, although it might be even more useful in quantitating the severity of depletion once overt deficits or symptoms appear and has the advantage of measuring such deficits over time to follow recovery of function. Furthermore since reaction time deficits required extensive loss of dopamine, these results are consistent with a predominant role of extrasynaptic dopamine in the mediation of relatively skilled motor tasks.

Adrenergic Agents↗

PubMed2002

[Dopaminergic receptors: structural features and functional implications].

During the last decade, molecular biology methods have primarily contributed to the fine characterisation of five subtypes of dopaminergic receptors leading to the classification of the D1-like (D1 and D5) and D2-like (D2, D3 and D4) subclasses. Biochemical methods have provided evidences for a large diversity of transduction mechanisms associated to these different receptors which can contribute to explain the multiple actions of dopamine at cellular level in the brain, from changes in membrane excitability to influences of gene expression. Moreover, the characteristic intracerebral distribution of these receptors subtypes supports the involvement of the neurotransmitter in different aspects of behaviour, from motor to limbic and cognitive aspects. In this respect, in Parkinson's disease dopamine depletion will favour adaptive responses at the cellular level which likely involve differentially the dopaminergic receptor subtypes. Such adaptive responses involving long-lasting processes of intercellular communication will either act to limit the symptoms of the disease or, more likely, to contribute to the expression of clinical signs. The development of appropriate agonists to selectively stimulate the different subsets of receptors still remains a challenge but, actually, already contributes to efficiently compensate for the motor signs of Parkinson's disease. In any case, such dopaminergic agonists are considered as an essential strategy to limit the motor side effects of L-DOPAtherapy. Thus, the development of more selective agonists of the different subsets of the dopamine receptors may contribute to compensate for the other clinical signs of the disease, and particularly for cognitive deficits.

Dopamine↗

PubMed2000

Differential effects of dopamine receptor subtype blockade on performance of rats in a reaction-time paradigm.

RATIONALE: Pharmacological manipulation of the dopaminergic system with antipsychotic agents disrupts motor behavior. Although most antipsychotic drugs have high affinity for D2 receptors, they also interact with other dopamine receptor subtypes. Therefore, the role of each of these receptor subtypes on motor performance is unclear. OBJECTIVE: The present study sought to investigate the relative importance of D1, D2, and D3 receptors on performance in a conditioned reaction-time task known to be extremely sensitive to dysfunction of the dopaminergic nigrostriatal pathway. METHODS: Rats were trained to release a lever in response to a visual cue within a reaction-time limit to receive a reinforcer (45mg food pellet). After the behavior of the rats had stabilized, the effects of a D1 (A69024), D2 (eticlopride), and D3 (nafadotride) receptor antagonists were assessed. RESULTS: A-69024 had no effect on performance at any dose tested (0.3, 0.6, and 1.3 mg/kg s.c.). Nafadotride (0.1, 0.3, and 1 mg/kg s.c.) produced only a mild deficit in performance at the highest dose. This deficit was characterized by an increase in the number of delayed responses with a non-significant decrease in the number of premature responses indicative of non-specific sedative effects. In contrast, the D2 receptor antagonist eticlopride (0.005, 0.01, and 0.02 mg/kg s.c.) produced profound deficits in performance as evidenced by a dose-dependent decrease in the number of correct responses. This decrease was accompanied by an increase in the number of delayed responses and a lengthening of the reaction time at the highest doses. CONCLUSIONS: These results provide further evidence that the execution of the reaction-time task is dependent preferentially upon the activation of D2 receptors, but not D1 or D3 receptors.

Animals↗

PubMed1999

Down-regulation of striatin, a neuronal calmodulin-binding protein, impairs rat locomotor activity.

Striatin, an intraneuronal, calmodulin-binding protein addressed to dendrites and spines, is expressed in the motor system, particularly the striatum and motoneurons. Striatin contains a high number of domains mediating protein-protein interactions, suggesting a role within a dendritic Ca(2+)-signaling pathway. Here, we explored the hypothesis of a direct role of striatin in the motor control of behaving rats, by using an antisense strategy based on oligodeoxynucleotides (ODN). Rats were treated by intracerebroventricular infusion of a striatin antisense ODN (A-ODN) or mismatch ODN (M-ODN) delivered by osmotic pumps over 6 days. A significant decrease in the nocturnal locomotor activity of A-ODN-treated rats was observed after 5 days of treatment. Hypomotricity was correlated with a 60% decrease in striatin content of the striata of A-ODN-treated rats sacrificed on day 6. Striatin thus plays a role in the control of motor function. To approach the cellular mechanisms in which striatin is involved, striatin down-regulation was studied in a comparatively simpler model: purified rat spinal motoneurons which retain their polarity in culture. Treatment of cells by the striatin A-ODN resulted in the impairement of the growth of dendrites but not axon. The decrease in dendritic growth paralleled the loss of striatin. This model allows analysis of the molecular basis of striatin function in the dynamic changes occurring in growing dendrites, and offers clues to unravel its function within spines.

Animals↗

PubMed1998

Impaired performance in a conditioned reaction time task after thermocoagulatory lesions of the fronto-parietal cortex in rats.

The present study examined whether cortical damage in rats may disrupt the integrative processes and motor control involved in the performance of a reaction time (RT) task. To investigate the nature of the deficits in the conditioned task, rats were subjected, after learning, to a coagulation of pia brain surface of varying extent, including the frontal and parietal cortical areas. They were then tested daily for over one month. The behavioural task required the rats to hold a lever down during a variable and random delay and react quickly to the onset of a visual cue by releasing the lever within a RT limit for food reinforcement. Extensive bilateral cortical lesions had no effect on spontaneous motor activity, but severely impaired RT performance. Latencies to release the lever after the cue were dramatically increased during the first postoperative sessions and gradually returned to baseline levels within 3 weeks, whereas less dramatic but long-lasting increase in premature responding (anticipatory response before the visual cue) was observed throughout the testing sessions. More restricted lesions to the frontoparietal cortex produced a similar pattern of incorrect responding with a faster recovery of delayed responses and a strong deficit in premature responding. The major effects of lesions confined to the rostral pole of the frontal cortex were observed on premature responding, however. The present results demonstrate that the impairment in movement initiation is rapidly recovered within 2-3 weeks even after extensive thermocoagulatory lesions of the frontal and parietal areas. This recovery suggests the involvement of adaptive processes developing progressively and probably reflecting the remarkable synaptic plasticity of the extrapyramidal motor output. In contrast, the long-lasting increase in premature responding, supposed to reflect some attentional deficits, may produce anatomofunctional long-term disorganization of subcortical structures such as the basal ganglia. Interestingly enough, these results show that the rat neocortex supports functions very similar to those of primates and provide a good model for studying these higher functions in operant motor procedures that require prior associative learning and appropriate motor coordination.

Animals↗

PubMed1997

Microinfusion of the metabotropic glutamate receptor agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid into the nucleus accumbens induces dopamine-dependent locomotor activation in the rat.

Although the striatum has one of the highest densities of metabotropic glutamate receptor (mGluR) binding sites in the brain, little is known about their physiological role. In this study we characterized the contribution of mGluRs located in the ventral part of the striatum (the nucleus accumbens) to the control of extrapyramidal motor function. Activation of mGluRs by local infusion of the selective agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD; 25, 50 and 100 nmol/0.5 microl) into the nucleus accumbens induced a dose-dependent increase in locomotor activity in rats. Intra-accumbens infusion of a selective antagonist of mGluRs, alpha-methyl-4-carboxyphenylglycine (MCPG) did not modify spontaneous locomotion but decreased the locomotor response to 1S,3R-ACPD. This effect appeared to be mediated by dopamine, since blockade of dopamine receptors with haloperidol (0.05 and 0.1 mg/kg i.p.) dose-dependently reduced 1S,3R-ACPD-induced locomotor activation. Furthermore, D-amphetamine (0.5 mg/kg, i.p.) combined with intra-accumbens infusion of 1S,3R-ACPD (100 nmol) potentiated the locomotor hyperactivity response to a higher level than that seen with a single treatment with either drug. In contrast, D-amphetamine-induced hypermotility was abolished by infusion of MCPG (100 nmol) into the nucleus accumbens. These results demonstrate that glutamate may control extrapyramidal motor function through metabotropic receptors. Furthermore, activation of metabotropic glutamate receptors appears to act in synergy with the dopamine system at the level of the nucleus accumbens to produce a motor stimulant response.

Analysis of Variance↗

PubMed1996

Evidence for functional differences between entopeduncular nucleus and substantia nigra: effects of APV (DL-2-amino-5-phosphonovaleric acid) microinfusion on reaction time performance in the rat.

Overactivity of the excitatory amino acid outputs of the subthalamic nucleus (STN) has recently been found to be one of the cascade of subsequent disruptions caused by nigrostriatal dopaminergic degeneration in Parkinson's disease. The respective contribution of the excitatory glutamatergic output structures of the STN [i.e. the globus pallidus (GP), entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr)] to the control of movement is not known, however. To investigate further the function of glutamatergic transmission through NMDA receptor subtypes in these three structures, the effects of discrete local infusion of a competitive receptor antagonist, DL-2-amino-5-phosphonovaleric acid (APV), into the EP, GP and SNr were tested in rats performing a reaction time task. Bilateral infusion of APV into the different output structures of the STN differentially impaired the performance of rats trained to release a lever after the onset of a visual stimulus within a time limit to obtain a food reward. Infusion of APV (0.25 and 0.5 microgram/0.5 microliter) into the SNr was found to induce behavioural deficits characterized by a dramatic increase in the number of premature lever releases and decreased mean reaction time. In contrast, the infusion of APV at a dose of 0.25 microgram into the GP or EP was found to induce a motor initiation deficit characterized by an increased number of delayed responses (lever release after the time limit) and increased mean reaction time. At a dose of 0.5 microgram, a premature responding deficit was added to the previous motor impairment. Interestingly, when APV was infused simultaneously into the GP and SNr in the same animals, the behavioural effects tended to be similar to those observed after a single infusion into the SNr. Altogether, these results reveal that the different functional weight of the three main output pathways originating at the STN level is t.o. The behavioural deficits induced by NMDA receptor blockade in the SNr were similar to those observed previously after a neurotoxic lesion of the STN, suggesting that NMDA receptors in this structure play a major role as a functional output of the STN. Furthermore, regarding the differential effects produced by the same dose of APV in the SNr and the EP, these two structures, which are classically believed to be functionally linked should not be considered as the same functional entity in the organization of basal ganglia outflow.

2-Amino-5-phosphonovalerate↗

PubMed1995

Competitive NMDA receptor antagonists do not produce locomotor hyperactivity by a dopamine-dependent mechanism.

The involvement of dopaminergic activity in the mediation of the behavioural effects produced by blockade of NMDA receptors in the nucleus accumbens was investigated. Intra-accumbens infusion of the competitive NMDA receptor antagonist, DL-2-amino-5-phosphonovaleric acid (AP-5) (2, 4 and 10 micrograms/0.5 microliters) induced a dose-dependent increase in locomotor activity in rats. Pharmacological blockade of dopamine receptors locally in the nucleus accumbens with haloperidol (5 micrograms/microliters) failed to reduce the locomotor effects of AP-5 (10 micrograms), but antagonized the effects induced by the non-competitive NMDA receptor antagonist, MK-801 ((+)-5-methyl-10,11-dihydro(a,d)-cyclohepten-5,10-imine hydrogen maleate salt) (10 micrograms). The effects of dopamine co-administered with AP-5 at various doses in the nucleus accumbens were also examined. When the level of locomotor activity induced by AP-5 (10 micrograms) was similar to that produced by dopamine (10 micrograms), the simultaneous infusion of both compounds at this dose did not increase or decrease the locomotor response. When the level of locomotor activity induced by AP-5 (10 or 4 micrograms) was lower than that produced by a higher dose of dopamine (20 micrograms), the combined infusion of both compounds resulted in a locomotor response similar to that induced by AP-5 alone, indicating a reduction of dopamine locomotor effects. These results show that the locomotor hyperactivity induced by AP-5 was not modified when the dopaminergic activity in the nucleus accumbens was either reduced or enhanced, suggesting that the behavioural effects resulting from the blockade of NMDA receptors with the competitive NMDA receptor antagonist, AP-5, is not mediated by endogenous dopamine in this brain area.

2-Amino-5-phosphonovalerate↗

PubMed1995

Complex deficits on reaction time performance following bilateral intrastriatal 6-OHDA infusion in the rat.

The present study examined the ability of rats subjected to bilateral 6-hydroxydopamine lesions of the terminal area of the nigrostriatal dopamine system to perform a prelearned reaction time task. This lesion model, the induction of a partial dopamine denervation of the striatum (74% depletion of dopamine striatal tissue content) with a retrograde degeneration of dopamine cell bodies in the substantia nigra, sparing the mesolimbic dopaminergic pathway, closely approximates the neuronal degeneration observed in human idiopathic Parkinson's disease. Rats were trained previously to release a lever, within a reaction time limit, after the presentation of a visual cue through reinforcement with food pellets. The onset of the light stimulus varied randomly after an unpredictable delay period of 0.25-1.0 s. Rats with dopaminergic lesions showed moderate to extensive performance deficits which were not compensated for the five postoperative weeks. More than half of the lesioned animals (64%) showed severe deficits, characterized by a concomitant increase in the number of anticipated (premature release of the lever before the visual cue) and delayed responses (lever release after the reaction time limit) with shortened reaction times in some cases. A smaller proportion (36%) of lesioned animals exhibited mild impairment of performance with a large increase in delayed responses and lengthening of reaction times but with no change in the number of anticipated responses. Asymmetric lesions had no effect on the reaction time performance. Examination of tyrosine hydroxylase immunostaining revealed that in the most impaired animals dopamine depletion was extensive in the medial striatum, whereas it was restricted to the dorsolateral striatum in the least impaired animals.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Dopamine and complex sensorimotor integration: further studies in a conditioned motor task in the rat.

Rats were trained to depress a lever and wait for the onset of a light stimulus, occurring after four equiprobable and variable intervals. At the stimulus onset, they had to release the lever within a reaction time limit for food reinforcement. This paradigm required time estimation of the various intervals and high attentional load for correct performance. Following activation of the dopaminergic transmission after systemic injection of d-amphetamine (0.6 and 0.8 mg/kg) or intrastriatal injection of dopamine (2.5 microgram/microliters), the rat's performance was impaired. Compared with control animals, the performance deficits were expressed as an increased number of premature lever releases before the conditional stimulus onset ("premature responses") and decreased reaction times. Indeed, the reaction times distribution was shifted to the left towards shortened reaction times. Although the number of premature responses was increased, the time estimation of the four different equiprobable intervals was not disturbed after stimulation of dopaminergic activity. A delay-dependent shortening of reaction times as a result of the conditional probability of the stimulus occurrence (i.e. reaction times are shorter as the duration of the delay increases) was found in control and drug sessions, indicating that the animals were still able to prepare their motor response (lever release) even after overstimulation of the dopaminergic transmission. In contrast, blocking dopamine receptors with the selective D2 antagonist raclopride was found to induce opposite effects on the reaction time performance. The number of delayed responses (i.e. occurring with a latency > 600 ms) was found to be significantly enhanced. Furthermore, the reaction times distribution showed a shift of the values to the right revealing a general tendency to lengthened reaction times. These results indicate that a "critical level" of dopamine activity (neither too low nor too high) in the striatum is necessary for a correct execution of the movement in a conditioned motor task with temporal constraint. Moreover, while delayed responses might reflect a motor impairment, anticipatory responses might reflect a "motor facilitation" revealed by a higher level of motor readiness, without disturbing time estimation nor attentional processes.

Animals↗

PubMed1995

In a rat model of parkinsonism, lesions of the subthalamic nucleus reverse increases of reaction time but induce a dramatic premature responding deficit.

Lesions of the subthalamic nucleus (STN) have been found to reduce the severe akinetic motor symptom produced in animal models of Parkinson's disease, such as in monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or in monoamine-depleted rats. However, little is known about the effect of STN exclusion on subtle motor deficits induced by moderate dopaminergic lesions in complex motor tasks. The present study was thus performed on rats trained in a reaction time (RT) task known to be extremely sensitive to variations of dopamine transmission in the striatum. Animals were trained to release a lever after the onset of a visual stimulus within a time limit to obtain a food reward. Discrete dopamine depletion produced by infusing the neurotoxin 6-hydroxydopamine (6-OHDA) bilaterally into the dorsal part of the striatum, produced motor initiation deficits which were revealed by an increase in the number of delayed responses (lever release after the time limit) and a lengthening of RTs. In contrast, bilateral excitotoxic lesion of the STN with ibotenic acid induced severe behavioral deficits which were opposite to those produced by the dopaminergic lesion, as shown by an increase in the number of premature responses (lever release before the onset of the visual stimulus) and a decrease of RTs. Surprisingly, the performance of the animals bearing a double lesion (striatal dopaminergic lesion followed 14 d later by STN ibotenic lesion) was still impaired 40 d after the ibotenic lesion. As expected, the 6-OHDA-induced motor initiation deficits were reversed by a subsequent STN lesion. However, the dramatic increase of premature responses contributing to major behavioral deficits induced by the STN lesion remained unchanged. Thus, the bilateral lesion of the STN was found to alleviate the motor deficits in this model of parkinsonism, but essentially produced over time, long lasting deficits that might be related to dyskinesia or cognitive impairment. The present results strongly support the recent concept of a predominant control of the STN on basal ganglia output structures.

Animals↗

PubMed1994

Locomotor activation induced by MK-801 in the rat: postsynaptic interactions with dopamine receptors in the ventral striatum.

The effects of bilateral 6-hydroxydopamine-induced destruction of the dopamine nerve terminals in the ventral striatum (nucleus accumbens) or pharmacological blockade of dopamine receptors with haloperidol injected locally into this area were examined on the locomotor hyperactivity induced by systemic administration of the non-competitive NMDA receptor antagonist, MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d) cyclohepten-5,10-imine hydrogen maleate salt). The locomotor stimulation induced by two doses of MK-801 (0.15 and 0.3 mg/kg, i.p.) was not attenuated by 6-hydroxydopamine bilateral lesions to the ventral striatum, either 7 or 14 days after the operation. The same lesion however reduced the locomotor activation induced by 0.5 mg/kg d-amphetamine 14 days after surgery. Bilateral intra-accumbens injection of haloperidol at a dose (2.5 micrograms/side) that blocked d-amphetamine-induced hypermotility did not reduce the locomotor response to 0.3 mg/kg MK-801, while 5 micrograms/side haloperidol decreased the MK-801-induced locomotor stimulation. These results suggest that the locomotor response to MK-801 is dependent on an interaction between dopaminergic and excitatory amino acid transmission occurring postsynaptically rather than presynaptically in the ventral striatum.

Amphetamine↗

PubMed1994

The role of putamen and pallidum in motor initiation in the cat. I. Timing of movement-related single-unit activity.

The participation of basal ganglia in motor initiation was studied in six cats operantly trained to perform a ballistic flexion movement, triggered after a brief sound in a simple reaction time condition or delayed after the same sound in the presence of a tone cue. The activity of 356 neurons was recorded in the putamen and in the pallidum (globus pallidus and entopeduncular nucleus). A total of 19.4% of the neurons were not related to the conditioned flexion movement: they were either unrelated to the task (10.1%) or related to other periods of the motor performance such as trial beginning or reward delivery (9.3%). About 60% of the remaining neurons--defined as task-related--exhibited changes in firing rate that occurred, in the reaction time condition, less than 100 ms after the go signal and therefore began prior to movement onset. For most neurons, in the delayed condition, these early changes were absent, suggesting that their occurrence in the reaction time condition was not a sensory response but rather was related to the movement initiation. In addition, for many neurons these changes shifted in time, remaining time-locked to the movement. Correlations between these early changes in activity and motor parameters were demonstrated, suggesting that these changes were movement-related. For most neurons the firing levels observed during intertrial intervals and during foreperiod were similar. The mean discharge rate during the foreperiod was 19.2 impulses/s. Three patterns of activity were observed before movement: increases in discharge rate (61% of task-related neurons), transient decreases followed by increases (11%), or prolonged decreases (28%). Only minor differences were found between the characteristics of the populations of neurons recorded in the three sites under study: on average the neurons recorded in the globus pallidus were more active than the neurons recorded in the putamen or in the entopeduncular nucleus. The fact that, for certain neurons, the changes of activity prior to movement were different in reaction time condition and in delayed condition showed that the pattern of activity preceding movement might depend on the temporal requirements for motor initiation. Taken together with the motor effects obtained in the same task following GABA-receptor activation with muscimol microinjections in these structures, the present results suggest that putamen and pallidal neurons participate in the initiation of the conditioned movement under study.

Animals↗

PubMed1994

GABA-receptor activation in the globus pallidus and entopeduncular nucleus: opposite effects on reaction time performance in the cat.

The possible role of GABAergic mechanisms in the control of the basal ganglia output structures, the globus pallidus (GP) and the entopeduncular nucleus (EP), was studied in cats performing a conditioned flexion movement triggered by an auditory stimulus. The effects of discrete unilateral microinjections of low doses of the GABAA receptor agonist (muscimol 5-100 ng/0.5 microliter) and antagonist (bicuculline methiodide 25-150 ng/0.5 microliter) in the GP and the EP were tested on the motor performance of eight animals trained to release a lever in a simple reaction time (RT) schedule after an auditory stimulus. Control injections in neighboring structures did not induce any effect except with five- to tenfold higher doses in the closest injection sites. The dose of 20 ng muscimol injected into the ventral and medial part of the GP produced an arrest of the performance after a few unsuccessful trials (over the RT reinforcement limit of 500 ms), while muscimol injected in sites located in the lateral GP resulted in a dose-dependent lengthening in RTs, with a concomitant increase in the force change latency. In most of the subjects, the force exerted on the lever was higher after muscimol than after vehicle injection. Force change velocity was then significantly increased. In contrast, muscimol injected in the ventral and rostral region of the EP produced a decrease in RTs or a complete cessation of responding after a high number of anticipatory responses (release of the lever before the trigger stimulus). No significant changes in the force change latency could be observed while there was a non-significant tendency for the force levels to be lowered. Bicuculline injections in the EP were found to increase RTs with a concomitant increase in force change latency and a slowness of velocity, while no significant effect was observed following injections in the GP. These results suggest that a balance between GABAergic activity in the two output nuclei of the basal ganglia, the GP and the EP, is crucial for the correct initiation and execution of the conditioned motor task.

Animals↗

PubMed1994

Functional interactions between glutamate and dopamine in the rat striatum.

The functional role of NMDA receptors in a spontaneous (locomotion) and a conditioned behaviour (reaction-time task) known to preferentially involve dopamine transmission in the ventral or the dorsal part of the striatum, respectively, was studied in the rat. The non-competitive NMDA receptor antagonist MK-801 systemically injected produced a dose-dependent increase in locomotor activity and impaired the performance of the animals trained to release a lever after a visual stimulus within a time limit by increasing the number of anticipatory errors (lever releases occurring before the stimulus onset). Similar behavioural changes were obtained after bilateral striatal microinjections of the competitive NMDA-antagonist APV into the ventral or dorsal striatum, respectively, suggesting that MK-801-induced behavioral effects after systemic injection might be mediated through a blockade of EAA transmission within the striatum. Dopamine injected in the same striatal locations induced effects similar to APV on locomotion and reaction-time performance, in agreement with the proposal for a functional antagonism between the glutamatergic and the dopaminergic transmission at striatal level. The conjoint administration of APV and dopamine directly into the striatum did not alter the behavioural effect induced by each compound injected alone showing that these effects are not additive. This latter observation actually suggests the occurrence of a functional interaction between the two neuronal systems probably acting on a common striatal target relaying dopaminergic and glutamatergic antagonistic influences on locomotion and conditioned motor behaviours.

2-Amino-5-phosphonovalerate↗

PubMed1994

Behavioural recovery of rats grafted with dopamine cells after partial striatal dopaminergic depletion in a conditioned reaction-time task.

The functional effects of grafts of dopamine-rich ventral mesencephalic suspension transplanted in a partially dopamine-depleted striatum were studied in rats performing a reaction-time motor task. The animals were trained to depress a lever, hold it down and release it within a limited period of time (700 ms) after the onset of a visual conditioned stimulus to obtain a food reward. The animals' performances were tested daily for up to two months after transplantation and for up to three months in the case of the animals with lesion only (bilateral striatal 6-hydroxydopamine injection). The baseline performances of the sham-operated control animals tended to improve, whereas the performances of the lesioned rats were significantly disrupted throughout the three months test. The majority of the animals (13/21) in the lesion group showed severe deficits mainly reflected in an increase in the number of the anticipated responses (premature release of the lever before the visual stimulus), and also in the number of the delayed responses (lever release after the time limit) recorded after dopamine depletion. The remaining animals (8/21) exhibited mild deficits (delayed responses only). These differences in the performance deficits appeared to be in relation to the extent of the dopamine denervation within the striatum assessed by the tyrosine hydroxylase immunostaining. Grafted animals showed a large number of dopamine fibers in the reinnervated striata and most of them (73%) significantly improved the reaction-time performance after transplantation. In the most severely impaired animals the number of anticipated errors was totally reversed within one month post-grafting, while the number of delayed responses remained high after transplantation. The performances of the less severely impaired animals returned more rapidly (within three weeks) to the pre-operative levels. The results show that intrastriatal ventral mesencephalic transplants are able to induce substantial or complete recovery in a complex reaction-time task. In the present model for partial dopamine depletion of the striatum, the mechanisms underlying the graft-induced recovery probably involve the participation of endogenous dopamine neurons acting in addition to, and/or in synergy with the dopamine-rich grafted tissue so that a functional level of dopaminergic transmission is restored in transplanted animals.

Animals↗