Electrophysiological characterization of substantia nigra dopaminergic neurons in partially lesioned rats: effects of subthalamotomy and levodopa treatment

Progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta is the main histopathological characteristic of Parkinson's disease. We studied the electrophysiological characteristics of the spontaneous activity of substantia nigra pars compacta dopaminergic neurons in rats with a partial, unilateral, 6-hydroxydopamine lesion of the nigrostriatal pathway. In addition, the effects of subthalamotomy and prolonged levodopa treatment on the activity of dopaminergic neurons were investigated. As a result of the lesion ( approximately 50% neuronal loss), the number of spontaneously active neurons was significantly reduced. Basal firing rate, burst firing and responsiveness to intravenously administered apomorphine remained unchanged. In contrast, the variation coefficient, a measure of interspike interval regularity, was significantly increased. Ibotenic acid (10 microg) lesion of the ipsilateral subthalamic nucleus in lesioned rats did not modify the electrophysiological parameters. However, prolonged levodopa treatment (100 mg/kg/day + benserazide 25 mg/kg/day, 14 days) reversed the irregularity observed in cells from lesioned rats, while it induced an irregular firing pattern in cells from intact rats. Our results using an experimental model of moderate Parkinson's disease indicate that surviving substantia nigra pars compacta dopaminergic neurons fire irregularly. In this model, subthalamotomy does not modify the firing pattern while levodopa treatment efficiently restores normal firing of SNpc neurons and does not appear to be toxic to them.     

Subthalamic Nucleus Lesion in Rats Prevents Dopaminergic Nigral Neuron Degeneration After Striatal 6-OHDA Injection: Behavioural and Immunohistochemical Studies

Several studies have shown that antagonists of N -methyl-D-aspartate receptors provide protection of the dopaminergic nigrostriatal pathway in animal models of Parkinson's disease. Since the substantia nigra compacta receives a moderate glutamatergic innervation from the subthalamic nucleus, we tried to determine whether subthalamic nucleus lesion could prevent the toxicity of the selective dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA). Experiments were carried out on four groups of rats. Group 1 ( n = 10) received a unilateral injection of 6-hydroxydopamine in the striatum and group 2 ( n = 10) received kainic acid in the subthalamic nucleus. Group 3 ( n = 10) received an injection of kainic acid in the subthalamic nucleus and 1 week later an injection of 6-OHDA in the striatum. Group 4 ( n = 5) received the same treatment but kainic acid was replaced by saline. Apomorphine induced an ipsilateral rotation in rats of groups 2 and 3 and a contralateral rotation in rats of groups 1 and 4. The number of tyrosine hydroxylase-immunoreactive cells in the pars compacta of the substantia nigra was not significantly different between injected and non-injected sides in rats of groups 2 and 3, but was significantly decreased on the side ipsilateral to 6-OHDA striatal injection in rats of groups 1 and 4. These results show that subthalamic nucleus lesion provides neuroprotection of the dopaminergic nigrostriatal pathway against 6-OHDA toxicity and opens a new way for slowing or stopping the progression of Parkinson's disease.     

Autoradiographic evidence for nicotine receptors on nigrostriatal and mesolimbic dopaminergic neurons

Rats received unilateral injections of 6-hydroxydopamine into the medial forebrain bundle, resulting in an ipsilateral loss of striatal dopamine and of dopaminergic perikarya. A concimitant reduction of displaceable tritiated nicotine binding was observed autoradiographically in the ipsilateral substantia nigra, ventral tegmental area, striatum, nucleus accumbens, and olfactory tubercle. Thus, nicotine receptors appear to be located on nigrostriatal and mesolimbic dopaminergic neurons at the level of perikarya and terminals.     

Demonstration of the nigrostriatal projection by silver staining after nigral injections of 6-hydroxydopamine

Lesions of the substantia nigra of rats were made by local injections of 6-hydroxydopamine. The degenerative changes in the brain were studied by means of the Fink-Heimer technique. Survival times of 2 or 3 days were optimal for the demonstration of degeneration. Extensive necrotic changes were observed in neurons of the substantia nigra pars compacta following 6-hydroxydopamine injections; control injections did not produce necrosis. Dense fields of terminal degeneration were observed in the caudate of the 6-hydroxydopamine treated rats but not in the caudates of the control animals. A comparison was made on the amount of degeneration present in the ventral nucleus of the thalamus after three types of lesions: (a) nigral injection of 6-hydroxydopamine; (b) nigral injection of carrier solution (control); and (c) electrolytic lesion of the substantia nigra. Lesions (a) and (b) produced only small amounts of thalamic degeneration, while lesion (c) produced extensive terminal degeneration in the ventral thalamic nucleus. The toxic effects of nigral injections of 6-hydroxydopamine were confined to the dopaminergic neurons of the substantia nigra pars compacta; nondopaminergic neurons of the substantia nigra pars reticulata, and their thalamic projection field, appeared normal in silver stains.     

Neuroleptic-like disruption of the conditioned avoidance response requires destruction of both the mesolimbic and nigrostriatal dopamine systems

An examination of the ability to learn an active avoidance response was made in rats subjected to 6-hydroxydopamine (6-OHDA) lesions of the individual terminal areas of the midbrain dopamine (DA) system or a lesion to all these terminal regions in one group. Lesions were made by infusing 8 micrograms (base) of 6-OHDA in 2 microliter of vehicle into the following forebrain regions (each region representing a separate group of rats); frontal cortex, nucleus accumbens, corpus striatum and a double lesion of nucleus accumbens and corpus striatum. A separate group of rats received a smaller 6-OHDA lesion of the ventral substantia nigra. Only those rats with the combined double lesion of both the nucleus accumbens and corpus striatum (90% total depletion of dopamine) showed a severe deficit in acquisition of active avoidance. However, the rats with the separate 6-OHDA lesions to the mesolimbic or nigrostriatal DA systems did show the appropriate blockade of the amphetamine-induced locomotion or stereotyped behavior, respectively. In contrast, the rats with the double lesion showed no response to a low or high dose of amphetamine, remained cataleptic for the duration of the experiment but rapidly recovered from transient aphagia and adipsia (less than 10 days post lesion). Results suggest that a severe deficit in acquisition of an active avoidance response, similar to that observed with high doses of neuroleptics, requires destruction of all of the dopamine innervation of nucleus accumbens and corpus striatum. Results also suggest that both the mesolimbic and nigrostriatal dopamine systems act in concert to produce response enabling to important environmental events, and that the severe response enabling deficits observed in Parkinson's disease involves not only degeneration of the nigrostriatal dopamine system, but of the mesolimbic dopamine system as well.     

Time-course of nigrostriatal damage, basal ganglia metabolic changes and behavioural alterations following intrastriatal injection of 6-hydroxydopamine in the rat: new clues from an old model

Despite the progressive development of innovative animal models for Parkinson's disease, the intracerebral infusion of neurotoxin 6-hydroxydopamine (6-OHDA) remains the most widely used means to induce an experimental lesion of the nigrostriatal pathway in the animal, due to its relatively low complexity and cost, coupled with the high reproducibility of the lesion obtained. To gain new information from such a classic model, we studied the time-course of the nigrostriatal damage, metabolic changes in the basal ganglia nuclei (cytochrome oxidase activity) and behavioural modifications (rotational response to apomorphine) following unilateral injection of 6-OHDA into the corpus striatum of rat, over a 4-week period. Striatal infusion of 6-OHDA caused early damage of dopaminergic terminals, followed by a slowly evolving loss of dopaminergic cell bodies in the substantia nigra pars compacta, which became apparent during the second week post-injection and peaked at the 28th day post-infusion; the rotational response to apomorphine was already present at the first time point considered (Day 1), and remained substantially stable throughout the 4-week period of observation. The evolution of the nigrostriatal lesion was accompanied by complex changes in the metabolic activity of the other basal ganglia nuclei investigated (substantia nigra pars reticulata, entopeduncular nucleus, globus pallidus and subthalamic nucleus), which led, ultimately, to a generalized, metabolic hyperactivity, ipsilaterally to the lesion. However, peculiar patterns of metabolic activation, or inhibition, characterized the post-lesional responses of each nucleus, in the early and intermediate phases, with peculiar response profiles that varied closely related to the functional position occupied within the basal ganglia circuitry.     

Neuronal localization of cannabinoid receptors in the basal ganglia of the rat

Cannabinoid receptors have recently been characterized and localized using a high-affinity radiolabeled cannabinoid analog in section binding assays. In rat brain, the highest receptor densities are in the globus pallidus and substantia nigra pars reticulata. Receptors are also dense in the caudate-putamen. In order to determine the neuronal localization of these receptors, selective lesions of key striatal afferent and efferent systems were made. Striatal neurons and efferent projections were selectively destroyed by unilateral infusion of ibotenic acid into the caudate-putamen. The nigrostriatal pathway was selectively destroyed in another set of animals by infusion of 6-hydroxydopamine into the medial forebrain bundle. After 2- or 4-week survivals, slide-mounted brain sections were incubated with ligands selective for cannabinoid ([3H]CP 55,940), dopamine D1 3H]SCH-23390) and D2 ([3H]raclopride) receptors, and dopamine uptake sites ([3H]GBR-12935). Slides were exposed to 3H-sensitive film. The resulting autoradiography showed ibotenate-induced losses of cannabinoid, D1 and D2 receptors in the caudate-putamen and topographic losses of cannabinoid and D1 receptors in the globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata at both survivals. Four weeks after medial forebrain bundle lesions (which resulted in amphetamine-induced rotations), there was loss of dopamine uptake sites in the striatum and substantia nigra pars compacta but no change in cannabinoid receptor binding. The data show that cannabinoid receptors in the basal ganglia are neuronally located on striatal projection neurons, including their axons and terminals. Cannabinoid receptors may be co-localized with D1 receptors on striatonigral neurons. Cannabinoid receptors are not localized on dopaminergic nigrostriatal cell bodies or terminals.     

Neuroleptic-like distruption of the conditioned avoidance response requires destruction of both the mesolimbic and nigrostriatal dopamine systems

An examination of the ability to learn an active avoidance response was made in rats subjected to 6-hydroxydopamine (6-OHDA) lesions of the individual terminal areas of the midbrain dopamine (DA) system or a lesion to all these terminal regions in one group. Lesions were made by infusing 8 μg (base) of 6-OHDA in 2 μl of vehicle into the following forebrain regions (each region representing a separate group of rats); frontal cortex, nucleus accumbens, corpus striatum and a double lesion of nucleus accumbensand corpus striatum. A separate group of rats received a smaller 6-OHDA lesion of the ventral substantia nigra. Only those rats with the combined double lesion of both the nucleus accumbens and corpus striatum (90% total depletion of dopamine) showed a severe deficit in acquisition of active avoidance. However, the rats with the separate 6-OHDA lesions to the mesolimbic or nigrostriatal DA systems did show the appropriate blockade of the amphetamine-induced locomotion or stereotyped behavior, respectively. In contrast, the rats with the double lesion showed no response to a low or high dose of amphetamine, remained cataleptic for the duration of the experiment but rapidly recovered from transient aphagia and adipsia (< 10days post lesion). Results suggest that a severe deficit in acquisition of an active avoidance response, similar to that observed with high doses of neuroleptics, requires destruction of all of the dopamine innervation of nucleus accumbens and corpus striatum. Results also suggest that both the mesolimbic and nigrostriatal dopamine systems act in concert to produce response enabling to important environmental events, and that the severe response enabling deficits observed in Parkinson's disease involves not only degeneration of the nigrostriatal dopamine system, but of the mesolimbic dopamine system as well.     

Substantia nigra opiate receptors on basal ganglia efferents

Many behavioral effects of opiate narcotics and peptides have been linked to effects on dopamine neurons originating in the substantia nigra pars compacta and ventral tegmental area. Selective brain lesions were combined with quantitative autoradiography to determine whether opiate receptors are on dopaminergic somata and/or processes in the substantia nigra pars compacta and ventral tegmental area. 6-Hydroxydopamine lesions that eliminated dopamine neurons produced little change in the pattern or density of [³H]-naloxone binding in the substantia nigra pars compacta or ventral tegmental area. Radiofrequency lesions of the internal capsule or globus pallidus and kainic acid lesions of the striatum markedly decreased [³H]-naloxone binding in the pars compacta and pars reticulata. These results are consistent with a dense distribution of opiate receptors on pallido-nigral and/or striato-nigral fibers and strengthen the likelihood that local effects of opiates on dopamine function in the nigrostriatal pathway are mediated indirectly by actions on nondopaminergic processes.     

High molecular weight basic fibroblast growth factor-like protein is localized to a subpopulation of mesencephalic dopaminergic neurons in the rat brain

A rabbit antiserum (R917) was raised to a purified fraction of bovine brain basic fibroblast growth factor (bFGF). On Western blots of rat midbrain extract, the antiserum did not recognize low molecular weight forms of bFGF. Instead, it recognized a single band of 27-28 kDa. Immunohistochemically, the antiserum preferentially stained a subpopulation of calbindin-negative mesencephalic dopaminergic neurons. The positive somata were mainly packed in a ventral portion of the tegmentum including the A10 region, the ventral tegmental area and the pars compacta of the medial substantia nigra, but were also scattered in both the pars compacta and reticulata portions of the lateral substantia nigra. Processes of dendrites and axons were clearly visible. Terminal fields were located in striosomes, the dorsolateral rim of the neostriatum, the anterodorsal aspect of the nucleus accumbens shell, the infralimbic cortex, and the medial prefrontal cortex. These results suggest that trophic specialization in subpopulations may occur in all three of these dopaminergic projection systems, i.e. the nigrostriatal, mesolimbic and mesocortical pathways.     

Caspase inhibition protects nigral neurons against 6-OHDA-induced retrograde degeneration

6-Hydroxydopamine (6-OHDA) administered intrastriatally to adult rats in a single injection causes neurodegeneration of the nigrostriatal pathway and loss of > 50% of dopamine neurons in substantia nigra pars compacta 30 days after administration. The death of nigral neurons occurs, at least partially, by a caspase-mediated mechanism. The nigral loss of dopaminergic neurons could be prevented by stereotaxical administration of zVAD.fmk, a caspase inhibitor, into the substantia nigra, indicating that 6-OHDA-induced nigrostriatal degeneration involves caspase activation. These results suggest that caspases are probably involved in neurodegenerative chronic processes such as Parkinson's disease and might be considered as possible targets in the treatment of such neurological disorders.     

Responses of substantia nigra pars reticulata neurons to GABA and SKF 38393 in 6-hydroxydopamine-lesioned rats are differentially affected by continuous and intermittent levodopa administration

Systemic administration of the selective D1 agonist, SKF 38393, to rats with unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopamine pathway induces contralateral turning and reduces firing rates of substantia nigra pars reticulata neurons. Previous studies have shown that chronically administered levodopa diminishes the contralateral turning induced by SKF 38393 in these animals. The present study demonstrates that twice daily injections (45-50 mg/kg, i.p.) of levodopa for 19 days also diminishes the effects of SKF 38393 on substantia nigra pars reticulata activity. Concomitant with this change, chronic levodopa injections reversed the lesion-induced supersensitivity of substantia nigra pars reticulata neurons to iontophoresed GABA. Neither of these effects were produced by the continuous infusion of levodopa (90-100 mg/kg/day, i.p. by osmotic pump) for 19 days, a treatment that produces average daily blood levodopa levels similar to those produced by chronic levodopa injection. These results suggest that large variations in circulating levodopa levels in 6-hydroxydopamine lesioned rats may desensitize the behavioral responses to D1 dopamine agonist administration by down-regulating D1 and GABA receptor-mediated mechanisms of basal ganglia output through the substantia nigra pars reticulata.     

Unilateral lesion of the pedunculopontine nucleus induces hyperactivity in the subthalamic nucleus and substantia nigra in the rat

Recent data suggest a role for the pedunculopontine nucleus (PPN) in the pathophysiology of Parkinson's disease. Although there is anatomical evidence that the PPN and the basal ganglia are reciprocally connected, the functional importance of these connections is poorly understood. Lesioning of the PPN was shown to induce akinesia in primates, whereas in the 6-hydroxydopamine rat model the PPN was found to be hyperactive. As both nigrostriatal dopamine depletion and lesioning of the PPN were shown to induce akinesia and parkinsonism, the present study was performed in order to investigate the changes in neuronal activity of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) after unilateral ibotenic acid lesioning of the PPN and after unilateral 6-hydroxydopamine lesioning of the substantia nigra pars compacta (SNc). The firing rate of STN neurones significantly increased from 10.2 +/- 6.2 (mean +/- SD) to 14.6 +/- 11.7 spikes/s after lesion of the PPN and to 18.6 +/- 14.5 spikes/s after lesion of the SNc. The activity of the SNr significantly increased from 19.6 +/- 10.5 to 28.7 +/- 13.4 spikes/s after PPN lesioning and to 23.5 +/- 10.8 spikes/s after SNc lesioning. Furthermore, PPN lesion decreased the number of spontaneously firing dopaminergic SNc cells, while having no effect on their firing rate. The results of our study show that lesion of the PPN leads to hyperactivity of the STN and SNr, similar to the changes induced by lesion of the SNc. Moreover, the decreased activity of SNc cells observed after PPN lesion might be at the origin of activity changes in the STN and SNr.     

6-Hydroxydopamine-lesioning of the nigrostriatal pathway in rats alters basal ganglia mRNA for copper, zinc- and manganese-superoxide dismutase, but not glutathione peroxidase

The effects of nigrostriatal pathway destruction on the mRNA levels of copper, zinc-dependent superoxide dismutase (Cu,Zn-SOD), manganese-dependent superoxide dismutase (Mn-SOD), and glutathione peroxidase in basal ganglia of adult rat were investigated using in situ hybridization histochemistry and oligodeoxynucleotide (single-stranded complementary DNA) probes. The 6-hydroxydopamine (6-OHDA)-induced destruction of the nigrostriatal pathway resulted in contralateral rotation to apomorphine and a marked loss of specific [(3)H]mazindol binding in the striatum (93%; P<0.05) and of tyrosine hydroxylase mRNA in substantia nigra pars compacta (SC) (93%; P<0.05) compared with control rats. Levels of Cu,Zn-SOD mRNA were decreased in the striatum, globus pallidus, and SC on the lesioned side of 6-OHDA-lesioned rats compared with sham-lesioned rats (P<0.05). Levels of Mn-SOD mRNA were increased in the nucleus accumbens (P<0.05), but decreased in the SC (P<0.05) on the lesioned side of 6-OHDA-treated rats compared with sham-lesioned rats. Lesioning with 6-OHDA had no effect on glutathione peroxidase mRNA levels in any region of basal ganglia examined. The significant changes in Cu,Zn-SOD and Mn-SOD mRNA indicate that SOD is primarily expressed by dopaminergic neurons of the nigrostriatal pathway, and that the Mn-SOD gene appears to be inducible in rat basal ganglia in response to both physical and chemical damage 5 weeks after 6-OHDA-lesioning. These findings may clarify the status of antioxidant enzymes, particularly Mn-SOD, in patients with Parkinson's disease and their relevance to disease pathogenesis.     

Tau gene transfer, but not alpha-synuclein, induces both progressive dopamine neuron degeneration and rotational behavior in the rat

Using a viral vector for mutant (P301L) tau, we studied the effects of gene transfer to the rat substantia nigra in terms of structural and functional properties of dopaminergic neurons. The mutant tau vector caused progressive loss of pars compacta dopaminergic neurons over time, reduced striatal dopamine content, and amphetamine-stimulated rotational behavior consistent with a specific lesion effect. In addition, structural studies demonstrated neurofibrillary tangles and neuritic pathology. Wild-type tau had similar effects on neuronal loss and rotational behavior. In contrast, mutant alpha-synuclein vectors did not induce rotational behavior, although alpha-synuclein filaments formed in nigrostriatal axons. Dopamine neuron function is affected by tau gene transfer and appears to be more susceptible to tau- rather than alpha-synuclein-related damage in this model. Both tau and alpha-synuclein are important for substantia nigra neurodegeneration models in rats, further indicating their potential as therapeutic targets for human diseases involving loss of dopamine neurons.     

Intranigral GR-113808, a selective 5-HT4 receptor antagonist, attenuates morphine-stimulated dopamine release in the rat striatum

GR-113808, a potent and selective 5-HT₄ receptor antagonist, was infused through a microdialysis probe into the striatum and nucleus accumbens of awake rats, and basal and morphine-stimulated extracellular concentrations of dopamine (DA) were measured in these regions. At 1 and 10 μM GR-113808 did not effect the extracellular concentrations of DA in either region and 100 μM significantly reduced dialysate DA only in the striatum. A subcutaneous dose of 5 mg/kg morphine significantly raised extracellular concentrations of DA in the striatum and nucleus accumbens from 60 to 120 min after injection and the effect was not modified by 10 μM GR-113808 infused through the probe 20 min before and for 60 min after morphine. Bilateral injections of GR-113808 (1, 2.5 and 10 μg/0.5 μl) in the substantia nigra pars compacta did not affect dialysate DA in the striatum, except for a significant increase 120 min after the injection of 10 μg but the highest dose of GR-113808 prevented the increase of striatal DA caused by 5 mg/kg morphine s.c. The results suggest that 5-HT₄ receptors in the substantia nigra modulate the activity of the dopaminergic nigrostriatal system only when the neurons are activated.     

N-methyl-D-aspartate receptor blockade attenuates D1 dopamine receptor modulation of neuronal activity in rat substantia nigra

It has been proposed that dopamine and glutamate affect basal ganglia output, in part, through interactions between D1 receptors and NMDA receptors. The present study examined whether N-methyl-D-aspartate (NMDA) receptor antagonists affect the neurophysiological responses of substantia nigra pars compacta (SNpc; dopaminergic) and pars reticulata (SNpr; non-dopaminergic) neurons to a systemically administered D1 dopamine agonist in two animals models of Parkinson's disease, reserpine treatment and nigrostriatal lesion. Previous studies using extracellular single unit recording techniques have shown that the D1 dopamine agonist SKF 38393 (10 mg/kg) exerts different effects on the firing rates of SNpr neurons after these two dopamine-depleting treatments, suggesting the involvement of multiple mechanisms. SKF 38393 consistently increased the firing rates of SNpr neurons in rats treated subchronically with reserpine, and markedly decreased SNpr firing rates in rats with nigrostriatal damage. Pretreatment with the non-competitive NMDA antagonist MK-801 (0.15 mg/kg i.v.) blocked, and the competitive NMDA antagonist (±)-CPP (30 mg/kg i.p.) attenuated, the rate effects of SKF 38393 in both dopamine-depleted preparations. SKF 38393 consistently inhibited the firing rate of SNpc dopamine neurons after acute reserpine treatment (10 mg/kg, 4–7 hours), an effect specifically mediated by D1 receptors. Pretreatment with MK-801 (0.1 mg/kg i.v.) or the competitive NMDA antagonist (+)-HA-966 (30 mg/kg i.v.) also effectively attenuated SKF 38393's inhibitory effect on SNpc dopamine neurons. Therefore, NMDA receptor blockade markedly reduces the ability of D1 receptor stimulation to modulate firing rates of both dopaminergic and non-dopaminergic cells in the substantia nigra. Although multiple mechanisms appear to underlie D1-mediated effects on substantia nigra firing rates in reserpine and 6-OHDA-treated rats, these results demonstrate a common dependence on glutamatergic transmission and a permissive role for NMDA receptor activation in the ability of D1 receptor stimulation to both enhance and reduce neuronal activity in the substantia nigra. Synapse 30:18–29, 1998. Published 1998 Wiley-Liss, Inc.     

Separation of the motivational and motor consequences of 6-hydroxydopamine lesions of the mesolimbic or nigrostriatal system in rats

The effects of 6-hydroxydopamine (6-OHDA) lesions in the ventral tegmental area (VTA) or substantia nigra, pars compacta (SN/pC) on the behaviour of hungry rats were examined in a Columbia obstruction box test. The lesions of dopaminergic neurones in the VTA as well as in the SN/pC decreased the number of crossings of an electric obstruction for food. After the lesion in the VTA the reaction of rats became independent of the level of hunger--the number of their crossings was similar at different levels of hunger. In contrast, no effect of the lesion was found when the animals were trained and tested in the absence of shock. The 6-OHDA lesion in the SN/pC also decreased the number of crossings, but the animals remained sensitive to motivational hunger stimuli: they were still crossing the obstruction in a hunger-dependent manner. Lesions in neither the VTA nor the SN/pC significantly altered the spontaneous food intake and sensitivity to painful electric stimuli. In the Rotarod test only the SN/pC-lesioned rats showed a substantial motor impairment; lesions in the VTA had no effect in that test. The obtained results are discussed in terms of the role of the dopaminergic mesolimbic and nigrostriatal systems in mediation of the motivational arousal and motor performance of an instrumental food response.