Biomedical subjects

M Amalric

Publications and source records attributed to M Amalric.

At least 37 records · Page 2Linked to original sources

PubMed1994

N-methyl-D-aspartate receptor blockade impairs behavioural performance of rats in a reaction time task: new evidence for glutamatergic-dopaminergic interactions in the striatum.

The effects of blocking glutamate transmission at the N-methyl-D-aspartate receptor subtype were studied in rats performing a conditioned reaction time motor task. Rats were trained to release a lever after the onset of a visual stimulus within a time limit to obtain food reward. The results showed that the performances of the groups receiving the N-methyl-D-aspartate receptor antagonists dizocilpine maleate (0.1 mg/kg) injected systemically or DL-2-amino-5-phosphonovaleric acid at the highest dose tested (5.0 micrograms/microliter/side) injected locally into the striatum changed significantly as compared to controls. The effects of these antagonists, consisting of an increase in the number of lever releases occurring before the visual stimulus onset ("anticipated responses"), were similar to those induced by injecting dopamine into the same striatal location. Both dizocilpine maleate and DL-2-amino-5-phosphonovaleric acid (5.0 micrograms/microliter) reversed the motor deficits, resulting in an increase in the number of lever releases after the time limit ("delayed responses") that were induced by the D2 dopamine receptor antagonist raclopride. Although these results partly confirm the existence of a functional antagonism between the glutamatergic and the dopaminergic systems in the striatum, opposite findings were obtained with the group that received intrastriatal DL-2-amino-5-phosphonovaleric acid at the lowest dose (0.5 micrograms/microliter/side). When given alone, 0.5 micrograms/microliter DL-2-amino-5-phosphonovaleric acid had no behavioural effects, but when jointly administered with dopamine or raclopride, it was found to reverse the effects of dopamine and to potentiate the motor deficits induced by raclopride. These opposite effects on the reaction time task observed after the intrastriatal injection of DL-2-amino-5-phosphonovaleric acid, depending on the dose tested, occurred only after a combined treatment with a dopaminergic agonist or antagonist and suggest that the level of the striatal dopaminergic activity may play a critical role in regulating the glutamate transmission via the N-methyl-D-aspartate receptors during the performance of complex sensorimotor tasks of this kind.

2-Amino-5-phosphonovalerate↗

PubMed1993

Effects of dopamine D1 and D2 receptor blockade on MK-801-induced hyperlocomotion in rats.

Blocking glutamatergic transmission at the N-methyl-D-aspartate (NMDA) receptor complex with MK-801 (0.15-0.5 mg/kg, IP) was found to induce a robust, dose-dependent increase in locomotor activity. This behavioural activation was similar in intensity to that observed after d-amphetamine (1 mg/kg, SC). The locomotor stimulation induced by MK-801 at 0.3 mg/kg was significantly inhibited by the D2 dopamine receptor antagonist raclopride (0.1-0.3 mg/kg, SC) and by the D1 receptor antagonist SCH 23390 (0.04 mg/kg, SC). The locomotor activity induced by a higher dose of MK-801 (0.5 mg/kg) was reduced by higher doses of raclopride or SCH 23390 administered alone (0.3 and 0.08 mg/kg, respectively), and was inhibited by simultaneous administration of ineffective doses. Raclopride significantly reduced d-amphetamine-induced locomotor activity at a dose (0.2 mg/kg) that also blocked the effects of a low dose of MK-801. In contrast, SCH 23390 blocked the effects of d-amphetamine at a dose (i.e. 0.01 mg/kg) lower than that needed to block MK-801. These results suggest that the dopaminergic system may in part mediate the locomotor effects induced by the NMDA antagonist, MK-801, in rats. However, the locomotor activity induced by MK-801 appears to be less sensitive to dopaminergic receptor blockade than that induced by d-amphetamine, suggesting that the underlying mechanisms, although similar, are not identical.

Animals↗

PubMed1993

Functionally selective neurochemical afferents and efferents of the mesocorticolimbic and nigrostriatal dopamine system.

In summary, evidence is presented that the mesocorticolimbic and nigrostriatal dopamine systems form functionally selective afferents to different parts of the basal ganglia and these inputs are paralleled by functionally selective outputs. The ventral striatal region of the nucleus accumbens and olfactory tubercle has a dopamine input that is critical for locomotor activation produced by psychomotor stimulant drugs and some non-drug states. These regions also appear critical for the reinforcing actions of psychomotor stimulants such as cocaine and amphetamine, and these regions may also be involved in the activation associated with non-drug rewards. Both psychomotor stimulant-induced locomotor activation and reinforcement may selectively involve dopamine D1 receptors. The functional efferents of this system appear to involve the region of the ventral pallidum and more specifically GABAergic mechanisms of the posterior medial (sublenticular) ventral pallidum. The relationship of this circuitry with the revised concept of the "extended amygdala" is an area of current work. The nigrostriatal dopamine system forms a functionally selective afferent system to the dorsal striatum and appears to be critical for the focused stereotyped behavior associated with high doses of psychomotor stimulants. This dopamine input also appears to be involved in non-drug-induced conditioned reaction time performance and may selectively involve dopamine D2 receptors. The functional efferents of this system appear to involve both direct and indirect GABAergic connections to the substantia nigra reticulata and dorsal pallidum, respectively. Activation of the GABAergic connection to the dorsal pallidum (indirect connection) appears to mimic the action of dopamine in the dorsal striatum, whereas activation of the GABAergic connection to the substantia nigra reticulata (direct connection) appears to modulate striatal dopamine function. These results show an important functional role for the globus pallidus in the output of the dorsal striatum and emphasize the parallel functional processing of both dorsal and ventral striatum.

Afferent Pathways↗

PubMed1993

Selective effects of low-dose D2 dopamine receptor antagonism in a reaction-time task in rats.

Operant responses involving a cued discrimination are sensitively disrupted by neuroleptic drugs that block dopamine (DA) receptors in the brain; however, it is not clear which DA receptor subtypes may be involved in these effects. The role of D1 or D2 DA receptor antagonists on the execution of a conditioned reaction-time (RT) motor task was investigated in the present study. Rats were trained to release a lever after the presentation of a visual cue within a RT limit to be reinforced by a food pellet. The D1 receptor antagonist SCH-23390, at doses that significantly decrease the behavioral effects of cocaine, did not impair performance at any dose (5, 10, or 20 micrograms/kg) injected subcutaneously. In contrast, a selective D2 receptor antagonist raclopride (50, 100, or 200 micrograms/kg) induced a dose-dependent increase in the number of incorrect responses (release of the lever over the RT limit) associated with an increase in the RT. The results suggest that the dopaminergic nigrostriatal system, which has previously been shown to be specifically involved in this RT task (Amalric and Koob 1987), appears to be a sensitive site for sensorimotor integration, and that the execution of the conditioned RT motor task may depend preferentially on the activation of the dopaminergic D2 receptors in this system.

Animals↗

PubMed1992

Behavioral effects of modulators of ATP-sensitive K+ channels in the rat dorsal pallidum.

The effects of the potent ATP-sensitive K+ channel blocker glipizide were measured on the locomotor activity of rats after bilateral intracerebral administration into the dorsal pallidum. Glipizide (10 pmol) was found to reduce spontaneous locomotor activity measured during the night cycle of the rats, whereas the ATP-sensitive K+ channel activator (-)-cromakalim (5 fmol) enhanced spontaneous locomotor activity. Glipizide (0.5, 2.5 and 10 pmol) was also found to depress noticeably d-amphetamine-induced locomotor activity (1 mg/kg s.c.). These results are in agreement with the idea that ATP-dependent potassium channels within the dorsal pallidum are involved in controlling motor activity in the rat.

Adenosine Triphosphate↗

PubMed1991

Changes in motor performance and rubral single unit activity in cats after microinjections of serotonin into the red nucleus area.

The serotonergic control exerted on the red nucleus (RN) was studied in unrestrained cats during the performance of a simple reaction time task which consisted of releasing a lever in response to an auditory go-signal. The effects of microinjections of serotonin-oxalate salt into the rubral area on the motor activity and on the firing of neurons recorded concomitantly in the red nucleus were investigated. Injections of serotonin (5-HT) (200-400 ng) into the red nucleus or its dorsal border induced subtle alterations in the conditioned motor performances but had no major effects on the spontaneous motor behavior. The changes in the conditioned motor output (an increase in the static force exerted on the lever and a speeding up of the lever release) are reminiscent of the facilitatory influence of serotonin on various motor reflexes previously reported. Changes in the neuronal activity were observed concomitantly with the effects on the motor output: 5-HT either enhanced or reduced the firing rate of the rubral neurons. These effects were apparently dependent on the discharge pattern of the neurons during the static motor activity. The results suggest that the serotonergic input to the red nucleus may participate in motor control by exerting a dual modulatory action on the activity of rubral neurons.

Animals↗

PubMed1991

GABAergic control of rubral single unit activity during a reaction time task.

The activity of 61 rubral neurones was recorded in association with microinjections of GABA, muscimol, bicuculline-methiodide or saline, in cat Red Nucleus area, during the performance of a reaction time task. The depressing action of GABA and muscimol on the firing of most neurones (17/23) suggests that, in a behavioural situation, an inhibitory GABAergic control can be exerted on rubral neurones discharging with different patterns during the reaction time task. The motor slowing down induced by GABA and muscimol is in agreement with a general reduction of the rubral output. Injections of bicuculline, whose antagonistic effects on GABA transmission are well established in the Red Nucleus, had various consequences on the firing of rubral neurones: 1) the decreases of activity related to the reaction time task were never suppressed, suggesting that these task-related inactivations are probably not mediated by GABA A receptors; 2) an enhancement of the tonic and phasic discharges was found for 1/4 of the neurones (7/29), which were either activated or not modulated in relation to the reaction time task, suggesting that a sustained GABA A-mediated inhibition, blocked by bicuculline, could be exerted on these neurones; 3) a reduction of the tonic and phasic discharges was observed for other neurones (15/29), which were either activated, inactivated or not modulated in relation to the reaction time task, suggesting that the activity of these neurones could be controlled by inhibitory processes not mediated by GABA A receptors, possibly enhanced or released by bicuculline. The delay in motor triggering induced by bicuculline could be related to the disruption of the pattern or rubral output during the reaction time task, as a result of the opposite changes affecting the firing of rubral neurones. A well-balanced GABAergic activity appears to be critical in the control of rubral firing during the performance of the reaction time task.

Animals↗

PubMed1990

GABAergic mechanisms in the cat red nucleus: effects of intracerebral microinjections of muscimol or bicuculline on a conditioned motor task.

Interneurons in the Red Nucleus (RN) are known to be under cortical control and to exert an inhibitory action, mediated by GABAergic mechanisms, on the main output towards the spinal cord. The effects of discrete injections of a GABA receptor agonist (muscimol) or an antagonist (bicuculline) in the Red Nucleus were tested on a motor task performed by seven cats. The subjects were trained to release a lever with a flexion movement of the forelimb controlled by a reaction time (RT) paradigm. Muscimol as well as bicuculline increased RTs in a dose-dependent manner at doses below 100 ng. However the parameters of the force exerted on the lever were differentially altered by the two drugs. Muscimol increased RTs by slowing down the force change preceding movement as well as slightly delaying its latency. While bicuculline increased drastically the force change latency. It could also speed up the force change velocity for low doses. At higher doses (up to 500 ng) both drugs produced an arrest of the performance either associated with anxiety signs (bicuculline) or dystonic movements of the head followed by body rotations (muscimol). The strong motor impairments as well as the disruption of the conditioned performances following muscimol or bicuculline microinjection in the RN suggest an important functional role for GABAergic interneurons. Under the control of cortical afferences they can modulate rubrospinal activity and participate in the triggering of a conditioned movement.

Animals↗

PubMed1989

Dorsal pallidum as a functional motor output of the corpus striatum.

A major function of the dopamine in the striatum is to control the activity of its efferent systems which contain primarily GABAergic neurons. Direct intracerebral injections of haloperidol into the corpus striatum impaired the performance of rats trained to depress a lever in a sensitive reaction time task. Rats were trained to depress a lever until the presentation of a visual conditioned stimulus and then to release the lever within a time limit of 500 ms to obtain a food reward. The increase in reaction time produced by dopamine blockade of the corpus striatum was mimicked by injection of a GABA agonist muscimol in nanogram quantities into the region of the dorsal pallidum, but not into the substantia nigra reticulata. Injections of a GABA agonist into the substantia nigra impaired performance by increasing the number of anticipatory responses (increased number of lever releases before the conditioned stimulus). These results suggest that the dorsal pallidum may play an important role in the response initiation associated with activation of the corpus striatum, and that the dorsal pallidum may form a significant part of parallel striatal outputs that have different functional significance.

Animals↗

PubMed1989

Cat red nucleus activity preceding movement depends on initiation conditions.

The activity of 98 Red Nucleus neurons was recorded in 3 cats operantly conditioned to perform a ballistic forelimb 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. Fifty-eight task related neurons presented changes of activity in either one or both conditions. Forty-four of them were studied quantitatively and classified in 3 categories: 1) only 16% of the units presented similar changes of firing preceding the triggered or delayed movement; 2) most units (55%) presented different changes of activity in the two conditions: in the Delayed condition, the activation occurred earlier before the movement, and/or the change in magnitude was reduced or the pattern of activity was modified; 3) moreover, for 29% of the units, the change of activity observed before movement in the Reaction Time condition was severely reduced or even absent in the Delayed condition. For some of these neurons a building-up of activity was observed very early in the Reaction Time condition, during the preparatory period, well before the occurrence of the conditioned stimulus. These results show that the Red Nucleus activity preceding a movement is clearly dependent on its initiation conditions. The distinct patterns of unit firing observed in the Reaction Time condition and in the Delayed condition are tentatively related to the different preparation and initiation constraints determined by the behavioral conditions.

Action Potentials↗

PubMed1987

Rewarding properties of beta-endorphin as measured by conditioned place preference.

The role of beta-endorphin as a possible mediator in the reinforcing properties of opiates was investigated using a conditioned place preference paradigm. Heroin, a synthetic opiate known to have reinforcing properties, produced a strong preference for an environment previously paired with heroin injection at all doses tested (0.25, 0.5, 1.0, 2.0 mg/kg SC). No such place preference was observed following saline injections. Rats also showed dose-dependent place preference for the environment paired with beta-endorphin when injected intracerebroventricularly (significant dose was 2.5 micrograms). At higher doses (5.0 and 10.0 micrograms) rats showed no preference for the paired environment, but were catatonic. Pretreatment with naloxone (0.04, 0.2, 1.0 mg/kg SC) attenuated the rewarding effect of beta-endorphin (2.5 micrograms) at all doses tested. The lowest dose of naloxone which had no aversive effect when tested alone could also significantly block the positive effect of beta-endorphin. The reinforcing dose of beta-endorphin (2.5 micrograms) also produced an increase in locomotor activity, when tested in photocell cages. This suggests that the hyperactivity induced by beta-endorphin may contribute to the preference for an environment previously paired with the same drug. The reinforcing effect of beta-endorphin is most probably mediated by the mu and/or delta opioid subtype receptor, since beta-endorphin has a high affinity for these receptors. These results demonstrate positive reinforcing properties of beta-endorphin in the central nervous system.

Animals↗

PubMed1987

Nucleus accumbens opiate-dopamine interactions and locomotor activation in the rat: evidence for a pre-synaptic locus.

Locomotor activation produced by the indirect dopamine (DA) agonist amphetamine is reversed by the opiate-receptor antagonist naloxone. Since amphetamine-stimulated locomotion results from the release of DA within the nucleus accumbens (N.Acc.), it is possible that these effects of naloxone result either from a decrease in the pre-synaptic release of DA within the N.Acc. or from a disruption of the effects of DA at, or distal to, the post-synaptic DA receptor. In the present study, we investigated the effects of naloxone on the locomotor-activating properties of dopamine injected directly into the nucleus accumbens. Naloxone (0-2 mg/kg) had no significant effect of DA-stimulated locomotion; the lowest dose of naloxone tested (0.5 mg/kg) was shown to significantly disrupt the locomotor activation produced by amphetamine (0.5 mg/kg). In separate animals, very high doses of naloxone (5.0 mg/kg) had no significant effect on locomotor activation produced by the DA receptor agonist apomorphine in rats following 6-hydroxydopamine (6OHDA) denervation of the N.Acc. These results indicate that naloxone must disrupt amphetamine-stimulated locomotion through its action presynaptic to N.Acc. DA receptors.

Amphetamine↗

PubMed1987

Depletion of dopamine in the caudate nucleus but not in nucleus accumbens impairs reaction-time performance in rats.

Impairment of the dopaminergic system in the brain induced by dopamine-receptor antagonists or by specific neurotoxin terminal lesions results in motor disturbances in rats. In order to specify further the role of the different dopamine pathways in the brain on motor function, the performance of rats trained in an operant reaction-time task was examined after systemic administration of a dopamine-receptor antagonist, alpha-flupenthixol, and after specific destruction of dopamine neurons by 6-hydroxydopamine perfusion into the nucleus accumbens or caudate nucleus. Rats were trained to press a lever and release it as quickly as possible after a light-cue conditioned stimulus (CS). Reaction time was measured from the CS to the release of the lever for each trial. alpha-Flupenthixol (0.2 and 0.4 mg/kg) injected intraperitoneally impaired the reaction-time performance of the rats. While disruption of dopamine activity in the nucleus accumbens did not affect the performance of the rats, lesions of the dopamine terminals of the nigrostriatal pathway in the corpus striatum (59% decrease in posterior striatal dopamine) significantly impaired reaction-time performance. These results show that moderate decreases in dopamine function restricted to the corpus striatum can disrupt sensitive motor performance, and support the hypothesis that dopamine in the corpus striatum has a role in the initiation of complex goal-directed responses.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

"Selective" D-1 and D-2 receptor antagonists fail to differentially alter supersensitive locomotor behavior in the rat.

The dopamine receptor antagonists SCH 23390 and spiperone show highly selective in vitro affinity for D-1 and D-2 dopamine receptor subtypes, respectively. We studied the effects of these selective antagonists on the supersensitive locomotor response to apomorphine in rats following 6- hydroxydopamine (6OHDA) lesions of the nucleus accumbens (N. Acc.). Both D-1 and D-2 receptor antagonists produced dose-dependent blockade of the supersensitive locomotor response at doses that did not depress baseline locomotor activity. The behavioral properties of these D-1 and D-2 receptor antagonists were further examined using a simple step-down motor task. Both antagonists produced catalepsy as evidenced by dose-dependent increases in step- down latency. These results indicate that drugs with distinct in vitro dopamine binding affinities cannot be distinguished on the basis of their ability to inhibit supersensitive locomotor activity or simple motor tasks in rats in vivo.

Animals↗

PubMed1986

The role of the nucleus raphe pontis and the caudate nucleus in alfentanil rigidity in the rat.

Attempts to eliminate or reduce the rigidity induced with high-dose narcotic anesthesia in the operating room have been only partially successful. Previous investigations of opioid receptor sites mediating this rigidity have implicated two central regions: the nucleus raphe pontis (NRP) within the reticular formation and the caudate nucleus (CN) within the basal ganglia. The present study used systemically administered alfentanil (ALF), a potent, short-acting fentanyl analog, and intracerebrally infused methylnaloxonium (MN), a quaternary derivative of naloxone, to elucidate further the functional role of the NRP and CN in rigidity. ALF (0.5 mg/kg s.c.) produced a reliable model of rigidity, as documented by gastrocnemius electromyography. The onset of this rigidity was within 60 s of ALF administration, with a total duration of approximately 40-50 min. Intracerebroventricular (i.c.v.) injections of 2.0 or 4.0 micrograms of MN 15 min prior to ALF treatment prevented rigidity, while 0.125 or 0.5 microgram had no significant effect on rigidity. MN injected directly into the NRP at doses as low as 0.125 microgram significantly antagonized ALF-induced rigidity, while injections of MN into the caudate nucleus at doses as high as 4.0 micrograms failed to antagonize ALF-induced rigidity. These observations demonstrate that injection of MN into the NRP is at least 16-fold more effective in blocking ALF-induced rigidity than MN injected into the ventricle and, more importantly, at least 32-fold more effective than MN injected into the CN. The results suggest that the NRP may be an important site for the neural control of muscular rigidity associated with high-dose narcotic administration.

Alfentanil↗

PubMed1986

'Catatonia' produced by alfentanil is reversed by methylnaloxonium microinjections into the brain.

Alfentanil, a short-acting and powerful analgesic, when injected peripherally to rats (0.5 mg/kg) produced a catatonic state characterized by a rigid akinesia. The present study was designed to explore the neuroanatomical location of the opiate receptors mediating the alfentanil induced catatonia. The catatonic effect of alfentanil was measured using a bar test and depression of locomotor activity in rats tested in photocell cages during an active nocturnal phase of their cycle. Methylnaloxonium HCl (MN), a quaternary derivative of naloxone which does not readily cross the blood-brain barrier, injected into the lateral ventricle significantly reduced the catatonia at doses of 0.125-2.0 micrograms as measured in both the locomotor and bar test. MN perfusion of similar doses directly into the nucleus raphe pontis, but not in the caudate nucleus significantly antagonized the catatonia. These data complement results on alfentanil-induced muscular rigidity (Blasco et al., see companion paper) where EMG indices of rigidity in rats were reversed by microinjections of low doses of MN (0.125 and 0.5 microgram) in the nucleus raphe pontis, but not the caudate nucleus even at a high dose (4.0 micrograms). Together these results suggest that the region of the nucleus raphe pontis is an important neural substrate for opiate-induced muscular rigidity, and that the catatonic state produced by opiates depends on more diffuse opiate receptor activation of which one important component may be the nucleus raphe pontis.

Alfentanil↗

PubMed1986

Blockade of amphetamine but not opiate-induced locomotion following antagonism of dopamine function in the rat.

The effects of pharmacological blockade of dopamine (DA) receptors or 6-OHDA lesions of mesolimbic DA fibers on the locomotor-activating properties of systemic amphetamine (0.35 mg/kg) and heroin (0.5 mg/kg) were examined. Pharmacological blockade of DA receptors or lesions of mesolimbic DA neurons blocked amphetamine but not heroin-induced locomotion. These results show that the opiate receptors essential for opiate-induced locomotor activation are not located on mesolimbic DA neurons. It appears that DA plays a primary role in stimulant-induced locomotion, but may have only a secondary role in opiate locomotion.

Amphetamine↗

PubMed1986

The neural substrates for the motor-activating properties of psychostimulants: a review of recent findings.

Several different classes of pharmacological agents produce syndromes of behavioral activation in humans and infrahumans. While many of these agents, including direct and indirect sympathomimetics, methylxanthines, opiates and several neuropeptides have very distinct neurochemical profiles, it is not clear whether their behavioral stimulant action results from their action on a common neural substrate, or instead from their action on parallel but separate activation "circuits.' Using photocell measurements of motor activity in rats, it has been possible to demonstrate that some agents with very distinct neurochemical identities act on common neural substrates to produce behavioral activation, while other agents act on completely distinct brain regions. Specifically, the locomotor-activating properties of direct and indirect sympathomimetics and opiates appear to result from their action within the basal ganglia, including the ventral striatum and globus pallidus, while the activating properties of caffeine and the neuropeptide, corticotropin releasing factor (CRF) appear to be independent of this circuitry. These findings suggest the presence of at least two separate neural systems capable of mediating behavioral activation.

Animals↗