Chronic Levodopa Administration Research Articles

Effects of Chronic Levodopa Therapy on Dopa Pharmacokinetics

We reevaluate here the effects of chronic administration of levodopa on its peripheral pharmacokinetics and the contribution of the pharmacokinetics to the pathogenesis of the wearing-off phenomenon. The peak levodopa concentration (Cmax) and the area under the time-concentration curve (AUC) were markedly increased after long-term levodopa therapy, whereas the time to the peak concentration (Tmax) and the elimination half-life (T(1/2)) were decreased. These results suggest that long-term levodopa therapy accelerates the absorption of levodopa. Furthermore, the wearing-off group had a markedly higher Cmax and AUC, and a shorter Tmax and T(1/2) than the stable group. We speculate that the clinical expression of 'stable' or 'wearing-off' depends on the absorption of levodopa as well as the presynaptic terminal and postsynaptic receptors.

Behavioral and neurochemical effects induced by chronic L-DOPA administration

L-DOPA, in combination with benserazide, in the ratio 4:1 (w/w), was administered orally to rats. In the staircase maze test a low dose of L-DOPA (3 mg/kg/day) reduced the increase in errors caused by 20 days interruption of daily training, while a higher dose (30 mg/kg/day) was ineffective. A decrease in levels of dopamine in the olfactory system and DOPAC in the striatum was seen at all tested doses of L-DOPA, while an increase in 5-HT levels was seen in the hippocampus and in the striatum. 5-HIAA levels did not change. Levels of ACh in the olfactory system were reduced at all doses of L-DOPA, while in the hippocampus this effect was seen only at the dose of 90 mg/kg/day. The density of muscarinic receptors was not altered. AI1 tested doses of L-DOPA caused norepinephrine levels to fall in the hippocampus and increase in the striatum. The density of α 1-adrenoceptors was reduced only at the two lower doses of L-DOPA. A comparison of the neurochemical results with the behavioral modifications seen in the staircase maze test suggests that the catecolaminergic systems are implicated in the memory process.

L-DOPA regulates glutamate decarboxylases mRNA levels in MPTP-treated monkeys.

The effect of dopaminergic denervation, alone or followed by chronic intermittent L-DOPA administration, on the levels of mRNAs encoding for the two isoforms of the GABA-synthesizing enzyme, glutamate decarboxylase (GAD65 and GAD67), were measured by in-situ hybridization in the caudate and putamen of macaque monkeys. When compared to control monkeys, the level of GAD67 mRNA was increased in the putamen and caudate of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. On the other hand, GAD65 mRNA labeling in MPTP-treated monkeys was not significantly different from the controls. In MPTP-treated monkeys that received L-DOPA, a significant increase in both GAD67 and GAD65 mRNA levels was measured in the putamen when compared to control or MPTP-treated monkeys. The results suggest that the dyskinetic effect of L-DOPA is paralleled by an increased GABAergic activity in the striatum.

Dopamine D 3 receptors in the basal ganglia of the common marmoset and following MPTP and l-DOPA treatment

The distribution of the dopamine D3 receptor was studied by receptor autoradiography using [ 3H]7-OH-DPAT in striatal and extrastriatal brain regions of the common marmoset ( Callithrix jacchus). Saturation studies demonstrated that [ 3H]7-OH-DPAT bound with similar affinity to different regions of marmoset brain. In normal marmosets, specific [ 3H]7-OH-DPAT binding was found in both striatal and extrastriatal regions. Very high levels of specific [ 3H]7-OH-DPAT binding were detected in the islands of Calleja and nucleus accumbens but in addition high levels of binding were detected in rostral caudate nucleus and putamen. In common marmosets treated with the selective nigral neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the levels of specific [ 3H]7-OH-DPAT binding in striatal and extrastriatal regions were not different to those in normal animals. Chronic treatment of MPTP-treated marmosets with l-DOPA/carbidopa did not alter the levels of specific [ 3H]7-OH-DPAT binding in any brain region. These results demonstrate that in common marmosets D 3 receptors are located in both striatal and limbic regions. The receptor density is not altered by dopaminergic denervation or by chronic l-DOPA administration. The D 3 receptor may, therefore, be important in both the therapeutic and adverse effects of drugs used to treat Parkinson's disease.

Reversal of levodopa-induced motor fluctuations in experimental parkinsonism by NMDA receptor blockade

Dopaminoceptive system alterations in the basal ganglia have been implicated in the pathogenesis of wearing-off fluctuations that complicate levodopa therapy of Parkinson's disease. To evaluate the contribution of glutamatergic mechanisms to the associated changes in striatal efferent pathway function, we examined the ability of N-methyl- d-aspartate (NMDA) receptor blockade to modify the motor response changes produced by chronic levodopa administration to hemiparkinsonian rats. Unilaterally 6-hydroxydopamine lesioned rats, given levodopa/benserazide (25/6.25 mg/kg) twice daily for 3 weeks, developed a progressive shortening in the duration of their motor response to levodopa similar to that occurring in parkinsonian patients with wearing-off phenomenon. The acute systemic administration of MK-801 (0.1 mg/kg) to these animals completely reversed the decrease in turning duration ( P < 0.01). Intrastriatal injection of the NMDA antagonist was even more effective in prolonging the levodopa response ( P < 0.01), while intranigrally injected MK-801 produced no statistically significant change in the duration of levodopa-induced rotation. Rotational intensity was unaffected by all routes of MK-801 administration. These results suggest that drugs capable of blocking NMDA receptors, especially in striatum, may help ameliorate motor fluctuations in patients with advanced Parkinson's disease.

MK-801 reverses effects of chronic levodopa on D1 and D2 dopamine agonist-induced rotational behavior

The effect of dizocilpine (MK-801) on dopaminergic agonist-induced rotational behavior was investigated in rats with 6-hydroxydopamine lesions of the nigrostriatal pathway after chronic administration of levodopa. The rotational response to the D2 agonist quinpirole was markedly increased in levodopa-treated animals compared with rats chronically administered saline. The increase in responsiveness to quinpirole was reversed by co-administered MK-801. Conversely, the rotational response to the D1 agonist SKF 38393 was reduced following chronic treatment with levodopa. The decrease in response to SKF 38393 was also reversed by MK-801. Chronic treatment with levodopa failed to alter the rotational responses to two other D1 preferring agonists SKF 81297 and SKF 82968, but responses to both agonists were increased by the co-administration of MK-801. These data support the hypothesis the MK-801 may reverse the differential changes in D1 and D2 agonist-induced motor responses which result from chronic treatment with levodopa.

Antiparkinsonian therapies and brain mitochondrial complex I activity

Alterations in complex I activity, one of the enzymatic units of the mitochondrial respiratory chain, have been demonstrated in different tissues from patients with Parkinson's disease (PD). Subsequently, we showed that the chronic administration of levodopa can cause alterations in mitochondrial respiratory chain activity in rats, which suggests that the observed deficit in complex I activity in PD might be, at least in part, related to chronic levodopa therapy. Our study assessed the in vitro effects of different antiparkinsonian agents on complex I activity in rat brain. As previously reported, both levodopa and dopamine inhibit complex I activity in a dose-dependent manner. In contrast, the two major metabolites of dopamine, homovanillic acid and 3,4-dihydroxyphenylacetic acid as well as 3-O-methyl-dopa, had little or no effect on complex I activities. Bromocriptine, pergolide, trihexyphenidyl, molindone, and clozapine were all without significant inhibitory effects on mitochondrial function. Although vitamin C and deprenyl did not alter complex I activity, they did prevent the inhibitory effect of both levodopa and dopamine on complex I activity. This work indicates that among the different and usual antiparkinsonian agents, only levodopa and dopamine induced reductions in complex I activity. It also indicates that vitamin C and deprenyl are both effective in preventing the levodopa-induced complex I inhibition. This latter finding provides further support to the use of antioxidants and monoamine oxidase inhibitors as therapeutic strategies in attempts to slow the progression of PD.

Effect of chronic l-DOPA administration on serum luteinizing hormone levels in male rats

We examined whether the repeated oral administration with a high dose of l-3-(3,4-dihydroxyphenyl)-alanine ( l-DOPA) in 0.5% carboxymethyl cellulose increases serum luteinizing hormone (LH) levels in male rats. Serum LH levels were increased 4 h after a single administration of 1000 mg/kg l-DOPA to male rats, and returned to control levels within 8 h after administration. Four hours after a single administration, serum LH levels were significantly increased by l-DOPA at 1000 mg/kg, but not at 20, 100 or 200 mg/kg. Decreases in body weight and relative weight of the prostate were observed after 7 and 14 days of administration of 1000 mg/kg per day l-DOPA, but no changes were observed in weight of the testis, epididymis or seminal vesicle. The administration of l-DOPA at 500 or 1000 mg/kg per day for 7 or 14 days resulted in increased basal serum LH levels and decreased basal serum prolactin levels 24 h after the last administration. Serum testosterone levels tended to be higher in treated than in control rats. The levels of two metabolites of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in rats treated with 500 mg/kg per day tended to be slightly higher than those in control rats after 7 days of administration. Levels of DA, DOPAC and HVA were significantly increased after 7 and 14 days of administration of 1000 mg/kg per day and after 14 days of administration of 500 mg/kg per day. The level of norepinephrine, but not its metabolite 3-methoxy-4-hydroxyphenylglycol, was significantly increased after only 7 days of administration of 1000 mg/kg per day. No significant changes were observed in levels of 5-hydroxytryptamine or its metabolite 5-hydroxyindole-3-acetic acid with administration of 500 or 1000 mg/kg per day. These findings suggest that a prolonged treatment with a high dose of l-DOPA in male rats induces release of LH from the pituitary, resulting in sustained elevation of LH levels in peripheral circulation.

The abnormality of N30 somatosensory evoked potential in idiopathic Parkinson's disease is unrelated to disease stage or clinical scores and insensitive to dopamine manipulations

We recorded short latency somatosensory evoked potentials (SEPs) to median nerve stimuli in 40 patients affected by idiopathic Parkinson's disease (PD) classified from I to IV on the Hoehn and Yahr disability scale. SEPs were recorded before and after chronic administration of L-Dopa and bromocriptine, before and after acute administration of L-Dopa. Fourteen patients experiencing wearing off and dystonic-dyskinetic disturbances were recorded during the occurrence of these oscillations of their clinical status. Absent or reduced N30 components were found in 32.5% of patients. SEPs were not modified by acute or chronic administration of L-Dopa or bromocriptine or during off and dystonic or dyskinetic conditions. Multiple correlations of N30 with scores of the Unified Parkinson's Disease Rating Scale showed that N30 abnormality did not classify patients with prominent clinical features, nor did it predict the outcome of treatment.

Chronic administration does not alter the accumulation of L-dopa into muscle.

Rats were treated for 12 months with L-dopa (191.4-210.4 mg/kg/day) plus carbidopa (23.9-26.2 mg/kg/day), or carbidopa (24.4-26.3 mg/kg/day) alone. Four days after drug withdrawal, animals received an acute challenge with either L-dopa (50 mg/kg p.o.) alone or following acute carbidopa (25 mg/kg i.p.) pretreatment, and the uptake and metabolism of L-dopa in muscle was studied. Following the acute bolus challenge, plasma levels of L-dopa peaked between 0.5 and 3 h after L-dopa alone and between 1.5 and 2 h after L-dopa plus carbidopa. Peak levels in muscle were observed between 1.5 and 4 h after L-dopa administration, and this accumulation was enhanced by the acute pretreatment with carbidopa. Chronic administration of L-dopa plus carbidopa or carbidopa alone for 12 months had no effect on the accumulation of L-dopa into muscle following the acute challenge with L-dopa alone or after carbidopa pretreatment. 3-O-Methyldopa, dopamine, DOPAC, and HVA levels were elevated in both plasma and muscle following acute oral challenge with L-dopa or L-dopa plus carbidopa. Levels of these metabolites were unaffected by chronic administration of L-dopa plus carbidopa or carbidopa alone. In conclusion, chronic administration of L-dopa plus carbidopa did not alter the accumulation of L-dopa into muscle following an acute oral challenge with the drug, with or without carbidopa pretreatment.

Levodopa and dopamine agonists in the treatment of Parkinson's disease: advantages and disadvantages.

Recent studies have suggested that free radicals play a key role in the progression of Parkinson's disease (PD). Although levodopa is the most effective therapeutic agent in the treatment of PD and has improved the quality of life and increased life expectancy, its beneficial effects are not permanent. Long-term treatment with levodopa produces a variety of side effects in patients with PD. We have previously reported that levodopa may accelerate the progression of PD in certain patients. To determine whether neuronal damage can be caused by levodopa overdoses, we estimated the effects of levodopa on free radical formation. Electron spin resonance spectrometry showed that levodopa oxidation produced levodopa radicals. Furthermore, chronic administration of levodopa increased thiobarbituric acid-reacting substances (TBARS) in various brain regions of 6-hydroxydopamine (6-OHDA; i.c.v.)-pretreated mice, although levodopa administration in control mice had no effect on TBARS. These results indicate that high dose levodopa accelerates neuronal degeneration in some parkinsonian brains. We then evaluated the protective effects of bromocriptine on striatal dopaminergic neurons, with determination of dopamine (DA) and its metabolites as markers. Pretreatment of bromocriptine completely protected mice against the decreases in striatal DA and its metabolites induced by intracerebroventricular injection of 6-OHDA, while levodopa/carbidopa had no protective effects. Furthermore, in an in vitro system that generated .OH from FeSO4-H2O2, bromocriptine dose-dependently scavenged .OH. These findings clearly indicate that bromocriptine has neuroprotective effects against neurotoxins such as 6-OHDA, probably due in part to its free redical scavenging activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic levodopa administration alters cerebral mitochondrial respiratory chain activity.

Parkinson's disease (PD) is characterized mainly by a loss of nigrostriatal dopamine neurons. Thus far, the actual physiopathology of PD remains uncertain, although recent studies have found decreased activity of complex I, one of the enzymatic units of the mitochondrial respiratory chain, in various tissues of PD patients. Because most, if not all, of PD patients are treated chronically with levodopa, the precursor of dopamine, and because we have shown previously that catecholamines may alter mitochondrial respiration, we assessed the effects of chronic administration of levodopa on complex I activity in rat brain. We found that chronic administration of levodopa, at a dose used in PD patients, caused a significant reduction in complex I activity while it did not affect the activities of complex II, complex IV, and citrate synthase. Reduction in complex I activity correlated well with catecholamine innervation as the reduction was observed mainly in the striatum and substantia nigra and to a lesser extent in the frontal cortex but not in the cerebellum. Moreover, the levodopa-induced decrease of complex I activity was reversible since activities at 1, 3, and 7 days after the last injection showed a progressive return to control values. Incubation of whole brain mitochondria in vitro showed that both levodopa and dopamine inhibit complex I activity in a dose- and time-dependent manner. In contrast, other compounds such as homovanillic acid, 3,4-dihydroxyphenylacetic acid, and 3-O-methyl-dopa were minimally effective. Reduced glutathione, ascorbate, superoxide dismutase, and catalase prevented the effect of levodopa and dopamine on complex I. Various inhibitors of monoamine oxidase also prevented the effect of dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral pulse levodopa therapy in mild Parkinson's disease

Chronic levodopa administration in Parkinson's disease (PD) is associated with long-term motor side effects. To reduce the cumulative amount of levodopa intake by patients with mild PD, we investigated the clinical efficacy of short periods of treatment with levodopa scheduled at different daily dosages and administered in a conventional design (ie, three times a day) compared with a standard oral dose of the drug administered once every 3 days. The latter dose regimen, designated "oral pulse levodopa therapy" (OPLT), allowed us to obtain a clinical response comparable to that obtained by conventional treatments that involve cumulative daily levodopa dosages up to seven times higher than OPLT. The clinical efficacy of OPLT could be related to the preservation of compensatory mechanisms in Parkinson's disease that are masked by conventional intermittent replacement therapy.

Chronic administration of L-dopa affects the movement-related cortical potentials of patients with Parkinson's disease.

The chronic effect of L-Dopa administration on the movement-related cortical potentials (MRCPs) was studied in two groups of patients with Parkinson's disease (PD): patients de novo (DN) and patients with on-off fluctuations. The BP and NS' premovement components of MRCPs associated with wrist flexion were assessed by their gradients and by their distribution on the midline (CZ) and the ipsilateral and contralateral hand sensorimotor areas. The treatment efficacy was controlled by a decrease in PD score (Columbia University Rating Scale). The BP component was absent in four out of nine patients DN. After 3 months of treatment, BP and NS' were recorded in six out of seven patients, and the NS' slope was significantly increased in all patients. In the off phase, MRCPs from patients with on-off fluctuations did not present a BP component. In the on phase, the NS' slope was increased and the BP was recorded in two out of nine patients. These patients exhibited an earlier PD stage (Hoehn and Yahr, stage 3). These two patterns of changes in the MRCPs induced by L-Dopa treatment suggest that the BP component was recorded in patients DN when a partial resolution of the nigrostriatal activity could occur. In patients with severe fluctuations, the dopaminergic striatal pathway was more severely affected and the increase of the NS' component demonstrated the activation of extrastriatal dopamine sites within the central nervous system (limbic and cortical structures, in particular).

Short- and long-term effects ofl-dopa administration on striatal acetylcholinesterase activity

Exogenously applied dopamine may interfere with cholinergic activity in the brain. The aim of the present work was to study the effect of L-dopa administration on acetylcholinesterase (EC 3.1.1.7) activity in rat (Wistar) brain striatum. Short-term administration of a mixture of L-dopa (10 mg/kg) and carbidopa (1 mg/kg) resulted in an increase in dopamine content and a decrease in acetylcholinesterase activity of the tissue. The greatest changes were found 30 min postinjection, and activity returned to near-control values after 2 h. When the drug mixture was injected for a period of 30 d and the animals were killed 24 h after the last injection, a lower dopamine content and higher enzyme activity were seen, compared to control values. It would appear that chronic administration of L-dopa gradually reduced the dopamine-storage capacity of the striatum and that the activity of acetylcholinesterase might be controlled by the levels of dopamine in the brain striatum.

Chronic levodopa treatment alters basal and dopamine agonist-stimulated cerebral glucose utilization

The effect of chronic levodopa administration on the functional activity of the basal ganglia and its output regions was evaluated by means of the 2-deoxyglucose (2-DG) autoradiographic technique in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. The rates of local cerebral glucose utilization were studied under basal conditions as well as in response to challenge with a selective D1 or D2 dopamine-receptor agonist. Levodopa (100 mg/kg/d, i.p.) was administered for 19 d either continuously via infusion with an osmotic pump or intermittently by twice-daily injections. Following a 3-d washout, glucose utilization was found to be decreased by both levodopa regimens in the nucleus accumbens; intermittent levodopa also decreased glucose utilization in the entopeduncular nucleus, subthalamic nucleus, ventrolateral thalamus, ventromedial thalamus, ventroposterolateral thalamus, and lateral habenula. In control (lesioned and treated chronically with saline) rats, the D1 agonist SKF 38393 (5 mg/kg, i.v.) increased 2-DG uptake in the substantia nigra pars reticulata and entopeduncular nucleus ipsilateral to the lesion by 84% and 56%, respectively. Both continuous and intermittent levodopa blunted the SKF 38393-induced elevation in glucose metabolism in the substantia nigra pars reticulata, while intermittent levodopa also attenuated the increase in the entopeduncular nucleus. The D2 agonist quinpirole (0.4 mg/kg, i.v.) did not increase glucose utilization in any brain region in control animals; following intermittent levodopa treatment, however, quinpirole increased 2-DG uptake by 64% in the subthalamic nucleus and by 39% in the deep layers of the superior colliculus on the ipsilateral side.(ABSTRACT TRUNCATED AT 250 WORDS)

Continuous and intermittent levodopa differentially affect rotation induced by D-1 and D-2 dopamine agonists

The effects of continuous and intermittent levodopa treatment on rotational behavior induced by dopamine agonists were examined in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway. Chronic administration of levodopa by continuous infusion (90–100 mg/kg per day i.p. by osmotic pump for 19 days with a 3 day washout) enhanced the rotational response to the D-2 dopamine receptor agonist quinpirole, but had no effect on rotation induced by the D-1 agonist SKF 38393 or that due to the non-selective dopamine agonist apomorphine. The rotational responses to the selective dopamine agonists differed dramatically in rats treated with levodopa by intermittent injection (45–50 mg/kg i.p., b.i.d. for 19 days with a 3 day washout): they showed a markedly increased response to quinpirole, a greatly diminished response to SKF 38393, and a modestly enhanced response to apomorphine. Continuous and intermittent treatment resulted in equivalent daily plasma levodopa levels. These findings suggest that the intermittence of central dopamine receptor stimulation may be an important factor in determining the subsequent responses of the dopamine system. The dissociation between the effects of both continuous and intermittent levodopa on D-1 and D-2 agonist-induced rotation indicates that D-1 and D-2 dopamine receptor-mediated mechanisms respond differently to chronic levodopa treatment.

Continuous and intermittent levodopa differentially affect basal ganglia function.

The effects of continuous and intermittent levodopa treatment on behavioral and biochemical indexes of basal ganglia function were compared in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway. Animals treated for 30 days with intermittent levodopa exhibited behavioral sensitization manifested by an enhanced rotational response to apomorphine; the rotational response of rats treated with an equivalent dose of levodopa by continuous infusion did not differ from that of saline-treated controls. Dopamine receptor up-regulation in the denervated striatum relative to the intact striatum was statistically significant for D1 but not D2 receptors: This asymmetry in dopamine receptor levels was diminished following intermittent levodopa treatment. Glutamic acid decarboxylase activity, modestly elevated in all groups in the denervated striatum relative to the intact striatum, increased substantially over control values bilaterally as a result of intermittent, but not continuous, levodopa treatment. These findings suggest a relation between the schedule of chronic levodopa administration and the development of behavioral sensitization, possibly as a consequence of alterations in neuronal systems located downstream from striatal dopamine receptors. The behavioral sensitization induced by chronic, intermittent dopaminomimetic treatment may serve as a model for motor fluctuations in Parkinson's disease.

Behavioral and biochemical evidence for a different effect of repeated administration of l-DOPA and bromocriptine on denervated versus non-denervated striatal dopamine receptors

The effect of repeated administration of bromocriptine and l-3,4-dihydroxyphenylalanine ( l-DOPA) was studied behaviorally and biochemically in rats with a unilateral lesion of the nigrostriatal pathway. Groups of rats injected eight times with bromocriptine or l-DOPA significantly increased their contraversive circling. Rats receiving only two injections of bromocriptine did not. Animals receiving two injections of l-DOPA showed a slight but significant increase in circling. The affinity of the binding of [ 3H]spiperone to the dopamine receptors was unchanged by the lesion or the treatments, while the density of the binding was significantly modified. Chronic treatment with bromocriptine induced a significant decrease in the density of D 2 dopamine receptors in the intact striata, while on the lesioned side, it remained unchanged. By contrast, chronic administration of l-DOPA induced a significant increase in density of the striatal dopamine receptors in the lesioned striata in addition to that caused by denervation, while the decrease on the intact side was not significant. It seems that contrary to the intact striatum, the lesioned side had a defective down-regulation mechanism in response to chronic treatment with a dopamine agonist. The results also show that l-DOPA was more potent than bromocriptine in inducing agonist supersensitivity in a denervated striatum. This may explain why chronic treatment with bromocriptine has a lesser tendency to induce dyskinesia in patients with Parkinson's disease.

Chronic pharmacological manipulation of dopamine receptors in brain

Dopamine receptors in the brain play an important role in the treatment of schizophrenia and in the development of tardive dyskinesia. In Parkinson's disease the loss of dopamine innervation and the use of chronic administration of l-DOPA or therapy with dopamine agonists also affects the function of dopamine receptors in brain. Subacute administration of neuroleptic drugs to rodents for a few weeks followed by the withdrawal of the drug induces supersensitivity of dopamine receptors in the striatum. However, the long-term administration of neuroleptic drugs to rodents shows that typical neuroleptic drugs can induce functional supersensitivity of dopamine receptors despite continued administration of drug. In contrast, atypical neuroleptics such as sulpiride, do not appear to induce the same changes in the activity of dopamine receptors. The functional supersensitivity of dopamine receptors produced by repeated administration of neuroleptic is reflected in changes in cholinergic, γ-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT) and peptide neuronal systems. Chronic treatment of parkinsonian patients with drugs may obscure the changes in the function of dopamine receptors caused by the disease process. However, chronic administration of l-DOPA to normal rats and to rats with a unilateral lesions of the nigrostriatal pathway induced with 6-hydroxydopamine does not produce a down-regulation of the number of dopamine receptors. Rather, these experiments indicate the development of a functional supersensitivity of dopamine receptors in the absence of any obvious change in the nature of dopamine receptor populations in brain. In conclusion, while pharmacological manipulation, using neuroleptic drugs, produces the expected development of receptor supersensitivity, studies involving chronic treatment with agonists suggests that dopamine receptors do not always respond as would be predicted. It appears that there are aspects of the regulation of dopamine receptors in brain following pharmacological manipulation which remain to be resolved.