Effect of nucleus entopeduncularis stimulation on thalamic nuclei motor neurons under normal conditions and after injury of the nigrostriatal dopaminergic system produced by the neurotoxin MPTP

Two groups of acute experiments were performed on cats anesthetized by ketamine and immobilized by myorelaxine to study reactions of neurons in ventral anterior (VA) and ventral lateral (VL) thalamic nuclei to stimulation of nucleus entopeduncularis (nEp) in normal animals and in those treated with chronic injections of neurotoxin--N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 5 mg/kg, i.m., daily, for five days). It was established that in normal cats 28% of the neurons studied have responded to nEp stimulation by inhibition with the latency shorter than 7 ms. In a half of inhibiting neurons after the first phase of inhibition which lasted 18 +/- 2 ms, the second inhibitory phase was registered. The duration of the latter was 25 +/- 4 ms. In MPTP-treated cats the number of neurons inhibited after nEp stimulation was practically the same as in normal ones (24.5%). A tendency of the first phase shortening and a statistically significant increase of the second inhibition phase duration up to 50 +/- 11 ms were found. It was suggested that changes in the inhibitory processes in VA-VL neurons receiving afferents from nEp might be explained by hyperpolarization of the nerve cell membrane evoked by increasing pallidothalamic inhibitory influences. That hyperpolarization created conditions for a decrease in Cl(-)-dependent and an increase in Ca(2+)-dependent K(+)-related phases of inhibitory postsynaptic potentials.     

Early Morphological Changes in the Thalamocortical Projection Onto the Parietal Cortex Following Ablation of the Motor Cortex in the Cat

Following a previous report that the cerebellar-induced cerebral response in the parietal cortex changes acutely after ablation of the frontal motor cortex, the present experiments tested whether morphological changes of the thalamo-parietal projection occur after ablation of the motor cortex. Anterograde and retrograde tracing with wheat germ agglutinin conjugated with horseradish peroxidase was used in intact and lesioned cats. The thalamocortical projection was labeled anterogradely by tracer injection into the thalamic ventral anterior and ventral lateral (VA-VL) nuclear complex that mainly relays the cerebello-cerebral projection, and thalamic neurons were labeled retrogradely by injection of the tracer into the parietal cortex. The labeled terminals in the parietal cortex of the intact animals were distributed densely in layer I and sparsely in layers III–IV, whereas those of the lesioned animals were distributed densely in layers I and III–IV. The distribution of the retrogradely labeled neurons after multiple tracer injections in layers III–IV of the parietal cortex was different in the intact and lesioned cats. In the intact animals, the labeled neurons were distributed sparsely in the central lateral nucleus and in the lateral posterior and pulvinar nuclear complex. In contrast, after ablation of the frontal cortex, the labeled neurons were also observed in the VA-VL nuclear complex. These differences between the intact and lesioned animals were detectable within 48 h after the lesion.     

Neurological disturbances, nigrostriate synapses, and iontophoretic dopamine and apomorphine after haloperidol

The hypothesis that haloperidol blocks the effects of dopamine in the caudate nucleus was tested. Nigrostriate synaptic transmission was studied by recording single-unit responses and evoked potentials and by microiontophoresis in the caudate nucleus of unanesthetized cats. The substantia nigra was stimulated with stereotaxically placed electrodes. Cats were chronically treated with doses of haloperidol sufficient to induce its motor system side effects. In acute experiments performed after the development of parkinsonian-like motor disorders including bradykinesia and tremor at rest, neurons responded to stimulation of the substantia nigra and to the microiontophoresis of dopamine in manners and in proportions indistinguishable from those seen in normal cats. Apomorphine inhibited three of nine neurons also inhibited by dopamine. Nigrostriate evoked potentials of normal waveform and amplitude were present. In another group of cats, nigrostriate evoked potentials were recorded before and after a single dose of haloperidol. This single dose did not modify the evoked potentials during the time when biochemical changes are known to be occurring. In additional experiments, the response of individual neurons to iontophoretically applied dopamine was recorded before, during, and after the administration of a single dose of haloperidol. The amount of dopamine necessary to reduce glutamate-evoked excitation by 50% was not changed by the injection of haloperidol. In conclusion, a change in the effectiveness of dopamine on neurons in the caudate nucleus (including some also influenced by apomorphine) could not be detected after systemic haloperidol. Nigrostriate synaptic transmission (including that to some neurons also influenced by dopamine) was not blocked. These findings are not consistent with the theory that the behavioral effects of systemically administered haloperidol are caused by a blockade of dopaminoceptive synapses in the caudate nucleus.     

Acetylcholinesterase activity and acetylcholine effects in the cerebello-rubro-thalamic pathway of the cat

Unilateral transections of the brachium conjunctivum (BC) of cats resulted, after 2–3 weeks, in marked loss of acetylcholinesterase (AChE) activity from the contralateral red nucleus (RN) and ventral tier nuclei of the thalamus (VA-VL). Significant changes in activity were not observed in other locations. Sensitivity of RN neurons to iontophoretically applied acetylcholine (ACh) was studied under conditions which should maximize ACh sensitivity, including AChE inhibition, but ACh was found to have only a weak depressant effect on excitability or no effect at all. Intravenous physostigmine usually increased spontaneous activity of RN neurons, and sometimes increased potentials evoked by electrical stimulation of cerebellar nuclei, to a small extent. Anticholinergic drugs were found not to influence such evoked responses, except to reverse the effects of physostigmine. It is concluded that ACh is not a major transmitter in the excitatory cerebello-rubral tract in spite of the relationship of AChE to this pathway.     

Astrocytic responses to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in cat and mouse brain

Glial fibrillary acidic protein immunohistochemistry was used as a selective marker for regional reactive gliosis in the striatum and ventral mesencephalon in cats and mice exposed to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Thirty mice (C-57 black strain) were injected with 30 mg/kg intraperitoneally (IP) MPTP.HCl for seven days. Five adult cats were injected with 10 mg/kg IP MPTP.HCl for seven days. Animals were killed five to seven days after the last MPTP injection. Reactive gliosis was observed throughout the mouse striatum but not in the substantia nigra. In contrast, reactive gliosis was topographically represented in the cat caudate nucleus with a dorsal-ventral and medial-lateral gradient evident. Gliosis was also observed in the putamen and the substantia nigra, pars compacta. Tyrosine hydroxylase immunocytochemistry revealed a loss of dopamine in the mouse striatum but no loss of substantia nigra neurons. Nigral neurons were destroyed in the cat. These results suggest that MPTP may destroy nigrostriatal dopamine cell bodies and terminals in the cat while destruction in the mouse is at least initially confined to striatal terminals.     

Supra- and juxtatrigeminal inhibitory premotor neurons with bifurcating axons projecting to masseter motoneurons on both sides

Inhibitory neurons participating in the bilateral disynaptic inhibition of jaw-closing motoneurons by stimulation of unilateral trigeminal sensory branches were searched for in the reticular formation around the trigeminal motor nucleus in cats anaesthetized with pentobarbital. Extracellular recordings were made from neurons which responded orthodromically after a monosynaptic latency to single shock stimulation of the ipsilateral infraorbital and/or inferior alveolar nerves. Direct inhibitory connection with contralateral masseter motoneurons was demonstrated in reticular neurons by the spike-triggered averaging technique, i.e., by averaging the intracellular potentials of a contralateral masseter motoneuron with respect to spontaneously occurring spikes of a reticular interneuron. By intraaxonal injection of neurobiotin, electrophysiologically identified inhibitory premotor reticular neurons were found to project to and to terminate in the trigeminal motor nuclei on both sides. Termination in the contralateral motor nucleus was demonstrated for four neurons that showed the peripheral input pattern stated above. The results provide hard evidence for contralaterally projecting interneurons in the reticular formation, participating in peripherally evoked disynaptic inhibition of masseter motoneurons on the contralateral side. Given the previously reported findings that the supratrigeminal region contains neurons which project to the ipsilateral motor nucleus and mediate disynaptic inhibition of masseter motoneurons, it is suggested that the supratrigeminal region contains bilaterally projecting interneurons, mediating peripherally evoked disynaptic inhibition of masseter motoneurons on both sides.     

Neuronal mechanisms of red nucleus interaction with brain stem structures

Axon collaterals of rubrospinal neurons to various brainstem structures were identified in acute experiments in cats using the technique of intracellular recording of antidromic action potentials in combination with collision testing. A systemic principle of organization of the rubrospinal influences as well as a tendency to synchronous arrival of rubral impulses at various brainstem centres are shown. Most of the brainstem centres are relay nuclei sending direct efferent projections to those cerebellar areas which, in turn, control the red nucleus activity. Besides this loop which provides dynamic cerebellar control of motor activity, the somatosensory information transmission from the dorsal column nuclei of the spinal cord directly to the red nucleus is shown. The recorded mono- and polysynaptic EPSPs evoked by stimulation of the dorsal column nuclei are characterized by peculiarities which suggest that they originate in various parts of the somadendritic membrane of the red nucleus neurons. The mechanisms of integration of the descending motor command by the red nucleus are discussed.     

Inhibition of hyperactive trigeminal subnucleus caudalis neurons after experimental trigeminal rhizotomy in response to thalamic sensory relay nucleus stimulation*

The effects of thalamic sensory relay nucleus stimulation on the single neuron activity and field potentials within the trigeminal subnucleus caudalis, which is a trigeminal equivalent of the dorsal horn were investigated in intact cats as well as in cats subjected to retro-Gasserian rhizotomy 1-6 months before the experiments. inhibition of nociceptive neural activity and a positive field potential were evoked by thalamic stimulation in the dorsal horn of the intact animals. A positive field potential followed double pulse stimulation with frequencies ranging up to approximately 50 Hz. The inhibitory periods ranged from 60 to 100 ms. Train pulse stimulation with frequencies ranging from 30 to 50 Hz produced long-lasting inhibition of nociceptive neural activity and a positive shift of the field potentials. Essentially identical inhibition of abnormal neural hyperactivity occurring in the rhizotomized dorsal horn was observed. The positive field potential corresponding to this inhibition also displayed characteristics similar to the field potential seen in the intact dorsal horn. These data indicate that the pathways involved in the inhibitory responses induced by thalamic. sensory relay nucleus stimulation, unlike some other pain inhibitory systems, can exert their influence even to the dorsal horn which has undergone reorganization of neural circuits after rhizotomy.     

Influence of norepinephrine-containing neurons derived from the locus coeruleus on lateral geniculate neuronal activities of cats

Facilitatory influences of conditioning stimulation of LC on evoked potentials in LGN to OTS were demonstrated in cats. These influences were observed when the stimulating electrode had been placed in areas histologically ascertained as having NE-containing cell bodies. The coeruleus modulation of geniculate potentials was not observed after reserpine pretreatment. However, a rapid recovery of the facilitation was produced by anl-dopa or NE injection. Injection of fusaric acid, a potent dopamine-β-hydroxylase inhibitor, also decreased the LC effects. In these cats, only an intraventricular NE injection was effective for the coeruleus modulation.The responsiveness of relay neurons to OTS, studied by extracellular recordings, was also enhanced y LC stimulation. Type-A interneurons, which responded to both orthodromic and antidromic stimulation, received influences similar to those on relay neurons after LC stimulation. Type-B interneurons, which failed to respond by antidromic spike discharges, received depressive effects. In reserpine-pretreated cats, LC effects on neuronal activities in the LGN were not observed. In these cats,l-dopa injection was effective in restoring the coeruleus modulation. It is suggested from these findings that enhanced responsiveness of relay neurons is due to an inhibitory effect on type-B interneurons after activation of NE-containing neurons derived from the LC.     

Inhibition of hyperactive trigeminal subnucleus caudalis neurons after experimental trigeminal rhizotomy in response to thalamic sensory relay nucleus stimulation

The effects of thalamic sensory relay nucleus stimulation on the single neuron activity and field potentials within the trigeminal subnucleus caudalis, which is trigeminal equivalent of the dorsal horn were investigated in intact cats as well as in cats subjected to retro-Gasserian rhizotomy 1-6 months before the experiments. Inhibition of nociceptive neural activity and a positive field potential were evoked by thalamic stimulation in the dorsal horn of the intact animals. A positive field potential followed double pulse stimulation with frequencies ranging up to approximately 50 Hz. The inhibitory periods ranged from 60 to 100 ms. Train pulse stimulation with frequencies ranging from 30 to 50 Hz produced long-lasting inhibition of nociceptive neural activity and a positive shift of the field potentials. Essentially identical inhibition of abnormal neural hyperactivity occurring in the rhizotomized dorsal horn was observed. The positive field potential corresponding to this inhibition also displayed characteristics similar to the field potential seen in the intact dorsal horn. These data indicate that the pathways involved in the inhibitory responses induced by thalamic sensory relay nucleus stimulation, unlike some other pain inhibitory systems, can exert their influence even to the dorsal horn which has undergone reorganization of neural circuits after rhizotomy.     

Corticoreticulospinal control of the tonic vibration reflex in the cat

The cortico-reticulospinal system has been investigated using vibration to produce a tonic reflex in an intact cat. Stimulation of the motor cortex potentiated the effects of medial medullary inhibition but not the facilitation evoked from the lateral medulla.The cortico-bulboreticular pathways were found to project bilaterally to the medulla. Medullary stimulation produced bilateral facilitation or inhibition of the tonic vibration reflex (TVR). Although the cortico-bulboreticular pathway projected bilaterally the effect evoked from the motor cortex was clearly contralateral in its end result. The cortico-reticulospinal system usually inhibits the tonic vibration reflex of both triceps surae and tibialis anterior, but on occasions inhibition of triceps surae was accompanied by a phasic contraction of the tibialis anterior. Stimulation of the contralateral caudate nucleus failed to influence the TVR directly or the response evoked by medullary stimulation. Stimulation of the contralateral red nucleus evoked a facilitation of the TVR which continued several seconds after red nucleus stimulation ceased.It was concluded that those medullary neurones which inhibit tone in flexor and extensor hind limb muscles of the cat are controlled directly by the motor cortex and are uninfluenced by caudate nucleus or red nucleus. The facilitatory neurones in the lateral medulla appear to be independent of cortical control.     

Responses of striatal neurons to peripheral sensory stimulation in symptomatic MPTP-exposed cats

Extracellular single unit activity was recorded in the dorsal lateral caudate nucleus of awake cats and the responses of these neurons to somatosensory, visual and auditory stimuli were assessed. Recordings were obtained when animals were normal and when they were symptomatic for a Parkinson-like syndrome as a result of exposure to the dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In normal animals, 22% of recorded neurons responded to tactile stimulation of the face, 7% had auditory responses, 6% had visual responses, and 6% were multimodal. The post-MPTP period was divided into an 'early' period, in which cats had received several MPTP injections but still remained asymptomatic, and a 'late' period, in which cats had severe motor and sensorimotor impairments. Unit responsiveness was essentially normal in the 'early' period but grossly abnormal in the 'late' period. When animals were symptomatic, only 6% of sampled neurons had responses to somatosensory stimulation, 0.8% had auditory responses and no cells were found with visual responses. Those cells that did respond to somatosensory stimulation did so in a non-specific fashion. Symptomatic animals had 93-96% depletion of dorsal striatal dopamine and extensive loss of substantia nigra pars compacta neurons. The results suggest that sensorimotor and motor abnormalities that accompany severe loss of striatal dopamine are at least in part due to a dopamine-dependent loss of sensory processing abilities of striatal neurons.     

Effects of an anxiogenic benzodiazepine receptor ligand on motor activity and dopamine release in nucleus accumbens and striatum in the rat

The effects of the anxiogenic beta-carboline FG 7142 (N-methyl-beta-carboline-3-carboxylate) on motor activity and dopamine release in nucleus accumbens and striatum were measured in the rat. Changes in extracellular homovanillic acid (HVA) concentration, monitored by computer-controlled linear sweep voltammetry with carbon-paste electrodes, were used as an index of changes in dopamine release. An intraperitoneal injection of FG 7142 was followed by an inhibition of the nocturnal rise in motor activity and in dopamine release in nucleus accumbens, but not striatum. Two days after the drug injection, dopamine release in nucleus accumbens returned to control level and then increased on days 3-6 after the injection; there was no delayed change in motor activity or in striatal dopamine release. In parallel experiments using ex vivo changes in the ratio of 3,4-dihydroxyphenylacetic acid (DOPAC) to dopamine as an index of changes in dopamine turnover, a similar early depression and delayed increase of dopamine turnover in nucleus accumbens, with no change in striatum, was found after an intraperitoneal injection of FG 7142. Regression analysis of motor activity versus dopamine release showed a decrease in correlation between these 2 parameters for nucleus accumbens but not striatum after FG 7142 injection. These results suggest that the inverse benzodiazepine receptor agonist FG 7142 has a biphasic effect on dopamine release from mesolimbic neurons and support the hypothesis that dopamine release in nucleus accumbens and striatum has a modulatory effect on the control of motor activity but does not play a determining role in the regulation of movement.     

Modulatory influences of red nucleus stimulation on the somatosensory responses of cat trigeminal subnucleus oralis neurons

Little is known of the effect of red nucleus (RN) stimulation on somatosensory neurons despite its known anatomic projections to somatosensory relay nuclei. The effect of RN stimulation on the somatosensory responses of trigeminal subnucleus oralis (Vo) neurons was investigated in chloralose- or barbiturate-anesthetized cats. Arrays of bipolar stimulating electrodes were inserted into the contralateral and ipsilateral RN and the contralateral thalamus. Extracellular single-unit recordings were obtained in Vo with tungsten microelectrodes. Neurons in Vo were excited to just suprathreshold by electrical stimulation within their receptive fields. Red nucleus influences were studied by applying 100-ms, 500-Hz conditioning trains to the contralateral or ipsilateral RN 130 ms prior to the peripheral test stimulus. The effect of RN stimulation was also tested on mechanically evoked responses of Vo cells. The somatosensory responses of most cells (70/73) were inhibited after RN stimulation. Some of these cells (15/70) could be antidromically activated from the contralateral thalamus. Stimulation of the RN resulted in excitation followed by inhibition in nine Vo cells. The results suggest that the RN may modulate transmission of somatosensory information through Vo.     

The spontaneous firing patterns of forebrain neurons. III. Prevention of induced asymmetries in caudate neuronal firing rates by unilateral thalamic lesions.

Unilateral lesions interrupting striatal outputs and inputs (MFB lesions) produce a marked slowing of neuronal firing in the caudate nucleus contralateral to the side of the lesions without affecting neuronal firing in the ipsilateral caudate nucleus. Although the MFB lesion also interrupts the nigrostriatal pathway and depletes the ipsilateral striatum of dipamine and its associated enzymes, the slowing of unit firing rates is apparently due to interruption of striatal outputs rather than inputs. Unilateral thalamic lesions palced ipsilateral to MFB lesions in iether the ventral anterior-ventrolateral nuclei (VA-VL) or in the center median-parafascicular nuclei (CM-PF) prevent the MFB lesion-induced asymmetry in caudate neuronal firing rates. These thalamic lesions do not, however, restore the striatal dopamine content depleted by the MFB lesion. Unilateral CM-PF lesions in otherwise intact cats do not alter caudate unit firing rates nor do they affect striatal dopamine. VA-VL lesions in otherwise intact cats produce a bilateral slowing in the spontaneous firing of neurons in the caudate nuclei, again, whithout altering caudate dopamine concentrations. These results provide further evidence that caudate dopamine concentration per se does not appear to be a potent variable in controlling the spontaneous firing rates of striatal neurons.     

Noradrenaline-mediated inhibition by locus coeruleus of spinal trigeminal neurons

Inhibitory effects of conditioning stimulation of the locus coeruleus (LC) on the neuron activity in spinal trigeminal nucleus (STN) were investigated in gallamine-immobilized cats. Field potentials of STN and spike potentials of single relay neurons in STN were orthodromically elicited by ipsilateral alveolar nerve stimulation and antidromically by stimulation of contralateral medial lemniscus. Conditioning stimuli were applied to LC and sensory cortex (SC) at various C-T intervals.

In tracking experiments near the LC region, conditioning stimulation of LC itself produced the most pronounced decrease in amplitude of the STN field potentials. Orthodromic spikes of STN single neurons were significantly reduced by conditioning stimulation of LC as well as SC. In reserpine-treated animals, however, conditioning stimulation of LC failed to produce a decrease in the number of orthodromic spikes, while the inhibitory effect of SC conditioning stimulation remained unaffected. Under these circumstances, intravenous L-dopa and intraventricular noradrenaline reproduced an inhibitory effect of LC conditioning stimulation on orthodromic spike generation, while such an effect was not seen with either dopamine or serotonin. Antidromic spike was unaltered by any of these treatments. Histochemically, catecholamine fluorescence in LC was entirely eliminated after reserpine-treatment, but was restored after L-dopa injection. These results strongly suggest that noradrenaline released from the terminals of neurons originating in LC produces an inhibition of transmission in the STN relay neurons.     

Intracellular analysis of the development of responses of caudate neurons to stimulation of cortex, thalamus and substantia nigra in the kitten

Intracellular recordings were made from caudate neurons in anesthetized kittens of 2-72 days of age. In adult cats, results of intracellular recordings indicate that caudate neurons respond most frequently to stimulation of their major afferents from cortex, thalamus and substantia nigra with a sequence of excitation followed by inhibition (EPSP-IPSP sequence). The results of the present study show that the prominent IPSP of this sequence is not well developed in young kittens and does not reach adult values in terms of frequency of occurrence until beyond 40 days of age. Amplitude and duration of the IPSP evoked by cortical stimulation also did not reach adult values until beyond 40 days of age. In contrast, EPSPs can be evoked in the youngest kittens by stimulation of afferents to the caudate. These findings suggest that the caudate nucleus may alter its role during development. In early postnatal periods it functions as a simple relay system transmitting incoming information to its outputs in a relatively unaltered fashion. Later in development it becomes a system capable of complex modulation and filtering of neural information.     

Physiological and morphological analyses of ventral anterior and ventral lateral thalamic neurons in the cat

Intracellular recordings were made from ventral anterior and ventral lateral (VA-VL) thalamic neurons in the cat. VA-VL neurons were tested for responsiveness to activation of cortical, pallidal and cerebellar afferents, and were identified morphologically by intracellular injection of HRP. Orthodromic activation of cortical and pallidal afferents produced primarily an initial inhibition (due in part to oligosynaptic circuitry) while activation of cerebellar afferents produced an initial excitation in the majority of neurons tested. Antidromic activation of thalamocortical relay neurons was observed in 32% of the neurons tested. Neurons showing short latency responses to activation of globus pallidus-entopeduncular nucleus and cerebellar peduncle were concentrated in the medical and ventral portions of the VA-VL complex, respectively. Neurons showing short latency responses to activation of the neocortex were located throughout the entire extent of the VA-VL complex. Only 3% of the neurons tested showed short-latency convergence of cortical, pallidal and cerebellar afferents. In contrast, 53% of neurons tested showed long latency triple convergence. Eight VA-VL neurons were stained intracellularly with HRP. Based on dendritic morphology, the labeled neurons were separated into two types: a stellate type with dendrites that spread radially from the soma, and a fusiform type with dendrites that were oriented mainly parallel to the long axis of the soma. Both types of neuron were aspiny although the dendrites of the stellate cells exhibited short appendages.     

Electrophysiologic study of descending effects of field 5b of the association cortex of the brain of the cat on the neurons of the ventroposterolateral nucleus of the thalamus

Responses of 65 thalamic ventroposterolateral (VPL) nucleus neurons to stimulation of the associative cortex (area 5b) were studied in acute experiments on cats anesthetized with ketamine (25 mg/kg) and immobilized with myorelaxine (2 mg/kg). Neurons studied were identified on the basis of peculiarities of their responses evoked by primary somatosensory cortex and medial lemniscus stimulation. Three neurons responded to stimulation of the area 5b antidromically. Primary orthodromic excitation and inhibition were observed in 17 (26.2%) VPL neurons. The role of the area 5b descending influences on the somatosensory impulses transmission through VPL relay neurons is discussed.     

Motor function in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mouse

Motor function was assessed by use of a swim test in C57 Black mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Thirty minutes after the last MPTP injection significant motor impairment was observed while striatal dopamine was reduced to 13.9% of control levels. At 24 h and 7 days post MPTP injection dopamine levels were still reduced to 17.3% and 26.4% of control values but swimming abilities of the mice were unimpaired. Histofluorescence of catecholaminergic neurons confirmed the presence of catecholamine depletion but showed little evidence of neuronal destruction. The use of MPTP as a non-invasive means of nigrostriatal dopamine depletion in rodents and higher animals allows a re-evaluation of the role of the dopaminergic system in the modulation of movement.