Relation of contraversive turning to unilateral release of dopamine from the nigrostriatal pathway in rats

In order to elucidate the functional role of the dopamine-containing nigrostriatal pathway, bipolar tungsten electrodes were implanted in the region of the substantia nigra and somewhat rostral to it. Stimulation with 100-Hz, 0.5-msec pulses in the medial part of the substantia nigra and the region medial to it elicited contraversive turning behavior. Turning, however, showed rapid fatigue with continued stimulation. Similar turning behavior could be seen with electrodes placed at a point anterior to the substantia nigra on the route probably followed by the nigrostriatal axons. When these electrode tips were used to make electrolytic lesions, the dopamine content of the caudate nucleus on the same side was reduced. If such animals were treated with methylamphetamine they showed a marked tendency to turn toward the side of the lesion These results are consistent with the hypothesis that unilateral activation of the dopamine-containing nigrostriatal pathway results in turning away from the activated side.     

Cobalt injections into the substantia nigra of the rat: effects on behavior and dopamine metabolism in the striatum

Small amounts of cobalt unilaterally injected into the substantia nigra of rats caused a strong, spontaneous contralateral turning which was suppressed by haloperidol. One to 2 days after intranigral cobalt microinjection, d-amphetamine decreased the intensity of the contralateral turning; 5 days after cobalt application, d-amphetamine changed the direction of the turning to the ipsilateral side. Intranigral cobalt microinjection initially caused a significant increase in the concentration of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the ipsilateral striatum. Thereafter, dopamine and its metabolites declined progressively to values significantly below control values. Similar biochemical changes in the striatum were also seen after partial electrolytic lesions of the substantia nigra. However, such lesions produced only mild contralateral turning. Frontal hemisection did not result in any increase of striatal metabolite values, and produced mild ipsilateral turning. Thus, there was no parallelism between the intensity and time course of the turning behavior induced by the different techniques and the changes in dopamine metabolism in the striatum. Within the cobalt-injected substantia nigra, γ-aminobutyric acid (GABA) and glutamic acid decarboxylase were decreased to less than 60% of the contralateral control values. The possibility is considered that the depression of a GABA-mediated inhibitory influence on the nigrostriatal or mesolimbic dopamine neurons may play a role in the cobalt-induced contralateral turning and altered striatal dopamine metabolism.     

Neural and behavioral plasticity: Crossed nigro-thalamic projections following unilateral substantia nigra lesions

Unilateral lesions of the substantia nigra of rats by injection of 6-hydroxydopamine or kainic acid induced ipsi- and contraversive turning behavior. Spontaneous turning was no longer exhibited one week after the lesions. This behavioral recovery was correlated in time with the development of crossed projections from the intact contralateral substantia nigra to the ventromedial thalamus of the lesioned hemisphere which, in the intact animal, receives projections only from the ipsilateral substantia nigra.     

Cobalt infections into the substantia nigra of the rat: Effects on behavior and dopamine metabolism in the striatum

Small amounts of cobalt unilaterally injected into the substantia nigra of rats caused a strong, spontaneous contralateral turning which was suppressed by haloperidol. One to 2 days after intranigral cobalt microinjection, d-amphetamine decreased the intensity of the contralateral turning; 5 days after cobalt application, d-amphetamine changed the direction of the turning to the ipsilateral side. Intranigral cobalt microinjection initially caused a significant increase in the concentration of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the ipsilateral striatum. Thereafter, dopamine and its metabolites declined progressively to values significantly below control values. Similar biochemical changes in the striatum were also seen after partial electrolytic lesions of the substantia nigra. However, such lesions produced only mild contralateral turning. Frontal hemisection did not result in any increase of striatal metabolite values, and produced mild ipsilateral turning. Thus, there was no parallelism between the intensity and time course of the turning behavior induced by the different techniques and the changes in dopamine metabolism in the striatum. Within the cobalt-injected substantia nigra, γ-aminobutyric acid (GABA) and glutamic acid decarboxylase were decreased to less than 60% of the contralateral control values. The possibility is considered that the depression of a GABA-mediated inhibitory influence on the nigrostriatal or mesolimbic dopamine neurons may play a role in the cobalt-induced contralateral turning and altered striatal dopamine metabolism.     

Accelerated recovery from eating behavior deficits after sequential lesions of cortex and hypothalamus: Is dopamine involved?

The roles of the nigrostriatal dopaminergic system and of the neostriatum in recovery from ingestive behavior deficits and body weight losses after damage to the nigrostriatal bundle in the lateral hypothalamus were investigated. Sequential removals of pairs of neostriatal afferent inputs (from cortex, substantia nigra, and dorsal raphe nucleus) were effected by making an initial lesion of one input followed in 30 days by a test lesion of a second input. The recovery of rats with combination lesions (initial + test) was compared with that of controls with only test lesions. An initial unilateral rostral cortex lesion prior to ipsilateral lateral hypothalamic test damage accelerated recovery of rats with these lesions (initial + test) from the eating behavior deficits and body weight losses suffered by animals with only unilateral hypothalamic test lesions. Because cortical lesions alone had no effect upon neostriatal dopamine content, sparing from subsequent hypothalamic test damage is not dependent on a dopamine increase caused by the initial cortical lesion. Also, this acceleration of recovery from unilateral lateral hypothalamic test damage by a prior lesion is an effect that appears to be specific to the ipsilateral cortex, because initial destruction of the contralateral cortex or of the midbrain dorsal raphe nucleus did not attenuate the deficits caused by hypothalamic test lesions. Furthermore, when an initial unilateral hypothalamic lesion preceded an ipsilateral cortical test lesion, recovery of eating behavior and of body weight was not accelerated. Thus, the order in which our cortical and hypothalamic lesions were made determined whether or not accelerated recovery from eating deficits occurred. Therefore, the ability to make the neuronal alterations underlying this accelerated recovery may be the property of a subcortical system such as substantia nigra, but not of cortex itself.     

Effect of forebrain commissurotomy on recovery from unilateral 6-OHDA lesions of the substantia nigra and circling induced by apomorphine

We studied the influence of transection of the interhemispheric fiber systems between the anterior and posterior commissures on recovery from turning behavior induced by a unilateral substantia nigra lesion in rats. It has been argued that the crossed nigrostriatal projection is involved in this recovery, and its site of crossing has been suggested to lie within the region split. Animals which received this transection did not differ from controls with respect to time-course and extent of recovery from lesion-induced asymmetries within the 7 postlesion days examined. Additionally, the commissurotomy did not prevent apomorphine-induced contraversive circling.     

Correlation of apomorphine- and amphetamine-induced turning with nigrostriatal dopamine content in unilateral 6-hydroxydopamine lesioned rats

In the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease, controversy exists concerning the use of apomorphine- ord-amphetamine-induced rotations as reliable indicators of nigrostriatal dopamine depletion. Our objective was to evaluate which, if either, drug-induced behavior is more predictive of the extent of nigrostriatal dopamine depletion. Fischer 344 and Sprague-Dawley rats were unilaterally injected with 9μg/4μl/4 min 6-hydroxydopamine into the medial forebrain bundle. The animals were behaviorally tested with apomorphine (0.05 mg/kg, s.c.) andd-amphetamine (5.0 mg/kg, s.c.). Following testing, the brains were removed and the right and left striata, substantia nigra and ventral tegmental area were dissected free and quickly frozen at −70°C for analysis of catecholamine content by high performance liquid chromatography coupled with electrochemical detection. Our results indicate that an animal which has greater than a 90% depletion of dopamine in the striatum might not rotate substantially on apomorphine, without a concomitant depletion of 50% of the DA content in the corresponding substantia nigra. No correlations were seen involving depletions of the ventral tegmental area and the extent of the lesions to the striatum. Submaximally lesioned (75–90% depleted) rats were found to rotate ond-amphetamine but not on apomorphine. In addition, control rats that did not receive lesions were often seen to rotate extensively ond-amphetamine. We therefore conclude that maximal lesions of the striatum and substantia nigra are required to generate rotations demonstrable with low dose apomorphine but not withd-amphetamine. Apomorphine, rather thand-amphetamine, is thus a better predictor of maximal lesions of the striatum produced by 6-OHDA.     

Comparative effects of electroconvulsive shock and haloperidol on in vivo tyrosine hydroxylation and tetrahydrobiopterin in the brain of rats with 6-hydroxydopamine lesions.

We have evaluated the effects of electroconvulsive shock (ECS) and haloperidol treatment on the in vivo tyrosine hydroxylation rate and the tetrahydrobiopterin levels in the nigrostriatal system of 6-OHDA-lesioned rats. The rate of DOPA accumulation was significantly decreased by 96% in the ipsilateral striatum and by 50% in substantia nigra of the 6-OHDA-lesioned rats compared to the control activity of contralateral non-lesioned striatum and substantia nigra. The loss of total biopterin was found to be 75% and 50% in the ipsilateral striatum and substantia nigra, respectively. Following administration of haloperidol, the rate of DOPA accumulation increased significantly in the striatum and substantia nigra on the lesioned side compared to that in the vehicle treatment group. Application of ECS also significantly increased the rate of DOPA accumulation in the ipsilateral striatum and substantia nigra compared to that obtained in the non-shocked rats. The biopterin levels in the nigrostriatal system of 6-OHDA-lesioned were elevated significantly in the striatum after haloperidol treatment; in contrast the biopterin levels were unchanged in response to ECS. Our results show that both haloperidol and ECS significantly enhanced the rate of in vivo tyrosine hydroxylation in the striatum and substantia nigra of rats with greater than 90% lesions. These results suggest that the nigrostriatal system, although up-regulated following 6-OHDA lesions, still maintains the potential for further up-regulation of dopaminergic function in response to haloperidol and ECS treatment.     

6-Hydroxydopamine-induced turning behaviour in the rat: the significance of acetylcholinesterase in cerebrospinal fluid

In the substantia nigra, acetylcholinesterase may have a novel function related not to cholinergic transmission, but to the homeostasis of dopaminergic nigrostriatal neurones. The initial aim of this study was thus to see whether, in the rat, release of the enzyme into cerebrospinal fluid would reflect turning behaviour following unilateral 6-hydroxydopamine lesions of varying severity. It was found that acetylcholinesterase levels, lower than those in the cerebrospinal fluid of control rats, were accompanied by marginal circling behaviour and a small loss of striatal dopamine: on the other hand, elevated acetylcholinesterase activity was observed in the cerebrospinal fluid of rats displaying vigorous turning behaviour and with large depletion of striatal dopamine. It has already been demonstrated that exogenous acetylcholinesterase, applied locally to nigral neurones, has both electrophysiological and behavioural effects reminiscent of dopamine agonists. Hence it is possible that exogenous acetylcholinesterase could modify turning behaviour resulting from unilateral striatal dopamine depletion. Purified acetylcholinesterase, administered by cisternal puncture, attenuated circling behaviour for up to 7 days. The possible mechanisms are discussed by which endogenous acetylcholinesterase in cerebrospinal fluid could serve as an index of dopamine depletion in the nigrostriatal pathway and how exogenous enzymes might alleviate the accompanying motor dysfunction.     

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.     

Nigral dopaminergic mechanisms in drug-induced circling

Unilateral injections of dopamine into the substantia nigra pars reticulata of pargyline-pretreated rats caused a prolonged, contralateral circling, similar in magnitude to that elicited by the injection of the same amount of dopamine intrastriatally. Contralateral circling was also elicited by the unilateral intranigral injection of amphetamine (after pargyline pretreatment), or by the dopamine agonists ergometrine and SKF 38393. In contrast, bilateral intranigral injection of the dopamine antagonist haloperidol greatly reduced the amphetamine-induced circling of rats with unilateral 6-hydroxydopamine-induced nigrostriatal lesions. These results support the hypothesis that dopaminergic mechanisms in the substantia nigra are involved in motor behavior.     

Effects of reducing sensory-motor feedback on the appearance of crossed nigro-thalamic projections and recovery from turning induced by unilateral substantia nigra lesions

This experiment addressed the question of whether the increase in interhemispheric nigrothalamic projections, found after unilateral lesions of the substantia nigra (SN), is related to recovery from the lesion-induced sensory-motor asymmetry. We examined the effects of diminished information feedback about the animals' own behavior on recovery from turning induced by unilateral substantia nigra lesions, and the appearance of an increase in number of crossed nigro-thalamic projections. The animals received unilateral 6-hydroxydopamine lesions and were placed in a hammock for the next 7 days. Thus, they were prevented from engaging in turning behavior. They were then implanted with horseradish peroxidase (HRP) in the thalamus ipsilateral to the lesion. No HRP-labeled cells were found in the SN contralateral to the HRP implantation in these animals. In rats, which were allowed 7 days normal interaction with the environment subsequent to unilateral SN damage, labeled cells were found in the undamaged SN when HRP was implanted in the thalamus ipsilateral to the lesion. Animals which were kept in the hammock and subsequently allowed a week of normal interaction with the environment showed the same pattern of recovery from turning behavior as the animals which were allowed to recover normally immediately after the unilateral SN lesion. It was concluded that the relationship between the appearance of the nigro-thalamic projections and the cessation of turning behavior is not fortuitous. Also, it would appear that some form of sensory-motor learning is involved in the recovery of function after unilateral SN lesions. Thus, the results substantiate the idea that these cross-projections form part of a physical basis of recovery from unilateral lesion-induced asymmetries.     

Reformation of the nigrostriatal pathway by fetal dopaminergic micrografts into the substantia nigra is critically dependent on the age of the host.

The aim of this study was to determine whether the growth of axons along the nigrostriatal pathway from fetal dopamine cells, transplanted into the substantia nigra of young postnatal 6-OHDA-lesioned rats, is dependent on the age of the host brain. Neonatal rats were lesioned bilaterally by intraventricular injection of 6-OHDA at postnatal day 1 (P1) and received grafts of E14 ventral mesencephalon at day 3 (group P3), day 10 (group P10), or day 20 (group P20) into the right substantia nigra. One lesioned group was left untransplanted. Six months after surgery the animals were subjected to analysis of drug-induced rotation following injection of amphetamine, apomorphine, a D1 agonist (SKF38393), or a D2 agonist (Quinpirole). Animals transplanted intranigrally at day 3 and day 10 showed a strong amphetamine-induced rotational bias toward the side contralateral to the transplant. Animals transplanted into substantia nigra at P20, like the lesioned control animals, showed no rotational bias. Apomorphine and selective D1 and D2 agonists induced ipsilateral turning behavior in the P3 and P10 group, but not in the P20 or the lesion control groups. Immunofluorescence histochemistry in combination with retrograde axonal tracing, using FluoroGold injection into the ipsilateral caudate-putamen showed colocalization of tyrosine hydroxylase and FluoroGold in large numbers of transplanted neurons in the animals transplanted at postnatal day 3 and postnatal day 10, which was not observed in the group P20. The lesion control group showed a 90% complete lesion of the TH-positive cells in the substantia nigra while largely sparing the neurons in the ventral tegmental area. The results indicate that intranigral grafts can be placed accurately and survive well within the substantia nigra region at various time points during postnatal development. Furthermore, embryonic dopamine neurons have the ability to extend axons along the nigrostriatal pathway and reconnect with the dopamine-depleted striatum when transplanted at postnatal day 3 and postnatal day 10, but not at postnatal day 20.     

Neonatal ablation of the nigrostriatal dopamine pathway does not influence limb development in rats

Hemiparkinson-hemiatrophy syndrome (HP-HA) is associated with skeletal hemiatrophy and the later development of parkinsonism. It is generally assumed that this phenotype is due to the combination of dysfunction of the basal ganglia (e.g., substantia nigra compacta and/or other related structures), causing parkinsonism, and of other areas (e.g., cerebral cortex), causing hemiatrophy. The occurrence of asymmetry of limb size in a patient with very asymmetric involvement of dopa-responsive dystonia encouraged Greene et al. (2000, Mov. Disord. 15: 537-541) to propose that lifelong deficits in nigrostriatal dopamine could account for limb asymmetry in HP-HA. The purpose of this study was to determine whether skeletal hemiatrophy could be produced in rats by unilateral, neonatal ablation of the nigrostriatal dopamine pathway. Infusion of 6-hydroxydopamine into the striatum of rat neonates resulted in loss of dopamine neurons in the ipsilateral substantia nigra, reduced striatal dopamine levels, and stimulant-induced motor asymmetry. Saline infusions neither altered the number of dopamine neurons nor produced behavioral changes. Both groups incurred discrete lesions of the ipsilateral motor cortex surrounding the infusion site and atrophy of the corresponding cerebral peduncle. Cortical, but not nigrostriatal, lesions were associated with significant atrophy of ipsilateral femora, humeri, and innominate bones, as assessed radiographically. Skeletal hemiatrophy was not observed in naive animals or in experimental animals that did not exhibit corticospinal abnormalities. The results of this study indicate that early skeletal development in rats is not affected by loss of nigrostriatal dopamine per se, but is markedly attenuated by corticospinal lesions sustained during the neonatal period.     

Spreading of slow cortical rhythms to the basal ganglia output nuclei in rats with nigrostriatal lesions

A high proportion of neurons in the basal ganglia display rhythmic burst firing after chronic nigrostriatal lesions. For instance, the periodic bursts exhibited by certain striatal and subthalamic nucleus neurons in 6-hydroxydopamine-lesioned rats seem to be driven by the approximately 1 Hz high-amplitude rhythm that is prevalent in the cerebral cortex of anaesthetized animals. Because the striatum and subthalamic nucleus are the main afferent structures of the substantia nigra pars reticulata, we examined the possibility that the low-frequency modulations (periodic bursts) that are evident in approximately 50% nigral pars reticulata neurons in the parkinsonian condition were also coupled to this slow cortical rhythm. By recording the frontal cortex field potential simultaneously with single-unit activity in the substantia nigra pars reticulata of anaesthetized rats, we proved the following. (i) The firing of nigral pars reticulata units from sham-lesioned rats is not coupled to the approximately 1 Hz frontal cortex slow oscillation. (ii) Approximately 50% nigral pars reticulata units from 6-hydroxydopamine-lesioned rats oscillate synchronously with the approximately 1 Hz cortical rhythm, with the cortex leading the substantia nigra by approximately 55 ms; the remaining approximately 50% nigral pars reticulata units behave as the units recorded from sham-lesioned rats. (iii) Periodic bursting in nigral pars reticulata units from 6-hydroxydopamine-lesioned rats is disrupted by episodes of desynchronization of cortical field potential activity. Our results strongly support that nigrostriatal lesions promote the spreading of low-frequency cortical rhythms to the substantia nigra pars reticulata and may be of outstanding relevance for understanding the pathophysiology of Parkinson's disease.     

Asymmetric dopamine and serotonin metabolism in nigrostriatal and limbic structures of the trained circling rat

The trained circling rat model was used to investigate dopamine and serotonin metabolism in extrapyramidal and limbic structures during turning behavior. We have previously reported that dopamine turnover is increased during circling in the caudate contralateral to the circling direction in this behavioral model. We have now studied changes in dopamine and serotonin turnover in nucleus accumbens, substantia nigra and amygdala. As in the caudate, dopamine production in nucleus accumbens was selectively increased on the contralateral side after 20 min of circling. By contrast, dopamine turnover in substantia nigra exhibited a relative decline on the contralateral side. Dopamine synthesis in the amygdala was not affected by circling. Selective changes in serotonin metabolism were also seen in these brain regions. In caudate and accumbens, serotonin turnover was unaffected by circling. However, both substantia nigra and amygdala showed significant, progressive increases in serotonin metabolism in the contralateral side after 20 and 70 min of circling. These results show that extrapyramidal and limbic dopamine and serotonin metabolism are involved in turning behavior of normal animals. Multiple transmitters of the nigrostriatal pathway and the limbic system appear to interact to modulate voluntary circling behavior.     

Relationship between interhemispheric nigrostriatal projections and the direction of rotational behavior induced by amphetamine

This experiment dealth with the relationship between the direction of amphetamine-induced turning and the distribution of crossed nigrostriatal projections in the rat. Animals that showed a high degree of asymmetry, as indicated by the consistency and amount of turning behavior elicited by repeated amphetamine administration, were implanted with horseradish peroxidase (HRP) in the striatum either ipsilateral or contralateral to their dominant direction of rotation. Microscopic analysis revealed a relationship between the direction of amphetamine-induced asymmetry and the number of HRP-labeled cells found in the substantia nigra contralateral to the striatum into which the tracer was implanted; i.e., animals with the HRP applied contralateral to their dominant turning direction had more labeled cells in the caudal part of the substantia nigra of the opposite hemisphere than those animals implanted ipsilaterally. There was no relationship between the direction and the number of labeled cells found in the ventral tegmental area and retrorubral area contralateral to the tracer implantation site. Moreover, there was no association between the direction of amphetamine-induced turning and the number of labeled cells found in the homolateral substantia nigra, or ventral tegmental and retrorubral areas.     

Non-dopaminergic mechanisms in the turning behavior evoked by intranigral opiates

The turning effects of the unilateral intranigral injection of morphine and of different analogs of dynorphin and enkephalin were studied. All injections were made in awake rats through cronically implanted guide cannulae. Dynorphin1-13 at a dose of 10 micrograms (0.6 nmol) and dynorphin1-17 at a dose of 2 micrograms (0.9 nmol) produced contralateral circling when injected unilaterally in the substantia nigra (SN), lasting for about 1 h. D-Ala-dynorphin1-17, a more stable analog of dynorphin, produced at a dose of 2 micrograms (0.9 nmol), a longer-lasting effect. Injections of different enkephalin analogs were also made into the SN, [D-Ser2]-Leu-enkephalin (10 micrograms, 14.5 nmol) and [D-Ala2,D-Ala3]-Met-enkephalin (10 micrograms, 15 nmol) also produced contralateral circling after unilateral intranigral injection. This behavior lasted for 60-90 min, depending on the different enkephalins used. As already reported by Iwamoto and Way18 morphine also produced contralateral circling when injected into the SN. The circling evoked by all these opiates was completely antagonized by 5 mg/kg of naltrexone s.c. In order to study the role of the dopaminergic nigrostriatal system, we made unilateral lesions of the medial forebrain bundle (MFB) with 6-hydroxydopamine (6-OHDA) and kainic acid lesions of the striatum and we looked at the effect elicited by these lesions on the behavior produced by the above compounds when injected into the SN. The lesion of the dopaminergic nigrostriatal system failed to affect either the number of turns or the duration of the contralateral circling produced by unilateral injections of morphine, dynorphin and enkephalin analogs into the SN correspondent to the lesioned side. On the other hand kainate lesions of the body of the caudate potentiated the turning induced by intra-SN morphine and dynorphin. Therefore it appears that the dopaminergic nigrostriatal system is not essential in the expression of the contraversive turning behavior produced by intranigral injections of endogenous opiates or morphine and that opiates might produce dopamine-like effects indirectly, through the inhibition of nigral non-dopaminergic output neurons.     

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.