Differential effects of haloperidol and clozapine on attention

Haloperidol (0, 0.1, 0.3, or 1.0 mg/kg), the typical butyrophenone neuroleptic, decreased investigation of novel objects by gerbils following systemic injections. When given prior to apomorphine (1 or 3 mg/kg), haloperidol blocked apomorphine-induced disruption of selective attention in a dose-dependent manner. Thus, haloperidol acts like pimozide in this paradigm. In contrast, clozapine (0, 0.03, 0.1, 0.3, 1.0, or 3.0 mg/kg), the atypical dibenzodiazepine neuroleptic, increased frequency of investigation both soon after injection and 24 h later, suggesting interference with maintenance of attention. When given with apomorphine (1.0 mg/kg), clozapine did not block apomorphine effects on selective attention. The results are related to differential effects of these neuroleptics on other behaviors and to their individual pharmacological profiles.     

Conditioned tolerance to haloperidol- and droperidol-induced catalepsy

Summary The possible mechanisms of conditioned tolerance to the cataleptogenic effects of haloperidol and droperidol were studied in order to discriminate between classical and conditioned tolerance. Rats were conditioned by repeated administration (19–27 times) of haloperidol (1.5 mg/kg i. p.) or droperidol (1.5 mg/kg i. p.), respectively, in the presence of a sum of defined environmental (auditory, olfactory and tactile) stimuli. The animals were compared with pseudoconditioned rats, which underwent the same number of drug injections and exposures to the environmental stimuli, but neither were associated. In part of the experiments, one further group of rats was repeatedly treated with only solvent in the presence of the environmental stimuli. Rats conditioned with haloperidol or droperidol showed tolerance to the cataleptogenic effect of a test dose of haloperidol (1.5 mg/kg i. p.) or droperidol (1.5 mg/kg i.p.), respectively, when they were tested in presence of the defined conditioning stimuli. The rats conditioned with droperidol showed significantly less catalepsy than the pseudoconditioned animals 30 min after droperidol administration, whereas in rats conditioned with haloperidol, the catalepsy was less pronounced no sooner than 120 min after haloperidol administration. This was a manifestation of conditioned tolerance. In rats pseudoconditioned with droperidol, the catalepsy was similar to that produced by the drug in drug-naive rats, suggesting no classical tolerance due to repeated administration of the neuroleptic drug. The dopamine turnover in striatum or nucleus accumbens after administration of 1.5 mg/kg of haloperidol i.p. was not altered in rats conditioned with haloperidol when compared with pseudoconditioned animals. The stereotypies produced by apomorphine (0.16 mg/kg s. c.) were most pronounced in conditioned, less pronounced in pseudoconditioned and very small in drug-naive rats. These result suggest that the conditioned tolerance to the neuroleptic drugs is connected with an increased sensitivity of the basal ganglia to dopaminergic drugs. In another series of experiments, rats were conditioned with apomorphine 8 times and tested with 0.66 mg/kg of droperidol i.p. Rather unexpectedly, the catalepsy was significantly more pronounced in conditioned than in pseudoconditioned animals. This observation suggests that the type of conditioned effect, which becomes manifest, depends in part on the drug used in the presence of the conditioned stimuli.Send offprint requests to K. Kuschinsky     

Behavioral effects of apomorphine isomers in the rat: Selective locomotor-inhibitory effects of S(+)N-n-propylnorapomorphine

The optical isomers of apomorphine (APO) and N-n-propylnorapomorphine (NPA) were evaluated behaviorally in the rat. Both R(-) isomers induced motor-excitatory effects and strong stereotyped sniffing, licking, and gnawing, as has been reported previously. The S(+) isomers selectively inhibited locomotor activity and did not induce stereotypy or catalepsy. These actions of the S(+) aporphines were selective against locomotor activity stimulated by low doses of R(-) isomers. (+)NPA (ID₅₀=0.2 mg/kg) was 20 times more potent than (+)APO (ID₅₀=4 mg/kg) in antagonizing the locomotor arousal-inducing effects of (-)APO (at ED₅₀=0.3 mg/kg). (+)NPA also inhibited spontaneous locomotor activity much more potently (ID₅₀=3.0 mg/kg) than did (+)APO (ID₅₀>50 mg/kg). Neither S(+) aporphine had a significant effect against stereotypy induced by the R(-) isomers, even at high doses (up to 30 mg/kg). Inhibition of the effects of (-)APO by (+)NPA appeared not to be due to altered uptake of (-)APO into brain. These results suggest that S(+)NPA or its congeners and analogs may have selective antidopaminergic actions in limbic rather than striatal areas of mammalian brain.     

Selective antidopaminergic effects of S(+)N-n-propylnoraporphines in limbic versus extrapyramidal sites in rat brain: comparisons with typical and atypical antipsychotic agents

Dopamine (DA), injected unilaterally into rat forebrain after pretreatment with a monoamine oxidase inhibitor, equipotently induced locomotor arousal when placed in the nucleus accumbens septi (a limbic site) and contralateral deviation of the head when placed in the corpus striatum (an extrapyramidal target); testing was done with an ED₅₀ dose of DA (16 µg). Systemic injections (IP) of the representative typical neuroleptic haloperidol showed high potency and minorstriatal selectivity against the behavioral effects of intracerebral DA [accumbens ID₅₀=0.090, striatum=0.027 mg/kg (0.24 and 0.072 µmol/kg); ID₅₀ ratio=3.3, favoring striatum]. The atypical antipsychotic agent clozapine was less potent against DA in both brain regions but, paradoxically, showed ever greater striatal selectivity [ID₅₀=12 and 1.4 mg/kg (37 and 4.2 µmol/kg); ratio=8.8, favoring striatum], while its analog, the piperazinyl-dibenzothiazepine ICI-204,636 showed intermediate potency and the lowest striatal selectivity of these three neuroleptic agents [ID₅₀=1.8 and 0.88 mg/kg (4.1 and 2.0 µmol/kg); ratio=2.1]. In striking contrast, the S(+) isomers of N-n-propylnorapomorphine, its orally active 10,11-methylenedioxy prodrug derivative, and its 11-monohydroxy analog all induced potent antagonism oflimbic DA but had little effect on extrapyramidal injections of DA except at high systemic doses [ID₅₀, accumbens=0.18–0.52, striatal=10–15 mg/kg (0.50–1.6 and 29–42 µmol/kg); regional ID₅₀ ratios=18–69, favoring accumbens]. The S(+)aporphines showed limbic potency similar to that of haloperidol and 25–73 times greater than that of clozapine. The S(+)11-OH-aporphine was 2.7–3.1 times more potent (on a molar dose basis) than the other aporphines against DA in accumbens, and 0.5, 8 and 73 times as potent as haloperidol, ICI-204,636 and clozapine. The significantly dissimilar slopes of dose-effect functions for the two groups of agents suggest that different actions may mediate the limbic effects of the aporphines and the neuroleptics tested. ICI-204-636 appears to be pharmacologically similar to clozapine, but 2.1 times more potents versus limbic-DA. The S(+)N-n-propylnoraporphines are potent and regionally highly selectivelimbic DA antagonists and S(+)-11-hydroxy-N-n-propylnoraporphine is orally active. These and other aporphine analogs are proposed for development as potential atypical antipsychotic agents with a low risk of extrapyramidal neurological side effects, and the present methods are proposed for predicting relative limbic versus extrapyramidal antidopaminergic activity.     

Actions and interactions of cocaine on self-stimulation behavior in rats

The effect of cocaine, over a dose range of 2–60 mg/kg, i.p., on self-stimulation (SS) behavior was studied in rats with electrodes either in the posterior hypothalamus (PH, monoaminergic) or the area ventralis tegmentum (A10, dopaminergic). The drug increased SS behavior with peak effects at 30 mg/kg in PH rats and 20 mg/kg in A10 rats. Azaperone (an -adrenergic blocker) and haloperidol (an antidopaminergic neuroleptic) given at doses that did not affect baseline SS responses reduced cocaine-induced enhancement of SS in both PH and A10 rats, showing the involvement of both noradrenergic and dopaminergic mechanisms in SS behavior. A scopolamine dose that itself facilitated SS responding enhanced the effect of cocaine on this behavior, thus suggesting an additional involvement of cholinergic mechanism in cocaine effect.     

Differences between antipsychotic drugs in persistence of brain levels and behavioral effects

After a single dose of the butyrophenone neuroleptic haloperidol, behavioral effects and detectable drug levels in rat brain can last for several weeks. To determine if such persistence is a general property of neuroleptics, we compared drug levels and effects after IP administration of two butyrophenones (haloperidol and bromperidol), a high potency (fluphenazine) and a low potency (chlorpromazine) phenothiazine. Drug levels in brain tissue were measured by high pressure liquid chromatography and behavioral effects monitored as inhibition of apomorphine-induced stereotypy. Estimated near terminal elimination half-lives (t_1/2) from brain for acutely administered chlorpromazine (20 mg/kg) and fluphenazine (1 mg/kg) were 0.41 and 0.62 days, respectively, and neither drug was detectable after 4 days. Fluphenazine given daily for 5 days showed an only slightly slower elimination (t_1/2=1.1 days). In contrast, near-terminal elimination half-lives from brain for haloperidol and bromperidol (both at 1 mg/kg, IP) were much longer (6.6 and 5.8 days, respectively), and each was detectable for 21 days after dosing. Inhibition of apomorphine-induced stereotypy correlated highly (r=0.95) with brain levels of haloperidol. For fluphenazine, given once or repeatedly, early inhibition was replaced within 1 week by supersensitivity to apomorphine which persisted for up to 3 weeks. These findings, indicating marked differences in clearance and recovery times after dosing with butyrophenones and phenothiazines, have clear implications for studies of the effects of neuroleptic drugs in rats. While there are limits to the extrapolation of these findings to other species, our results and those from studies in human subjects suggest similarly persistent drug levels and effects may be seen when patients are withdrawn from neuroleptic drugs.     

Effects of acute and long‐term typical or atypical neuroleptics on morphine‐induced behavioural effects in mice

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Progressive changes in the acute dyskinetic syndrome as a function of repeated elicitation in squirrel monkeys

Various neuroleptic-induced motor disorders that appear in primates previously treated with neuroleptics are collectively designated the acute dyskinetic syndrome. The relative incidence of these motor disorders was examined as the syndrome was repeatedly elicited by haloperidol and other dopamine antagonists in individual monkeys. After several weekly or biweekly treatments with haloperidol (1.25 mg/kg orally), catalepsy began to appear, which was then accompanied by athetoid movements (writhing and limb extensions) as intermittent neuroleptic treatment continued. Other dyskinetic movements (duck walk, oral dyskinesias, pushing of the head into a cage corner, and perseverative circling) that were suggestive of hyperkinesia subsequently began to be clicited by haloperidol and other neuroleptics after additional treatments with these drugs had intervened. As intermittent treatments continued, tolerance to the athetoid movements gradually developed and, eventually, only circling and pushing could be consistently elicited by haloperidol. In monkeys that had reached this phase, the athetoid movements were not again induced by higher doses of haloperidol (up to 5 mg/kg), chlorpromazine (3 mg/kg), or metoclopramide (3 mg/kg). In these tolerant monkeys, haloperidol impaired Sidman avoidance performance less and benztropine more than in drugnaive monkeys. Neither pharmacokinetic changes nor behavioral tolerance could readily account for these results. It is hypothesized that they reflect progressive functional alterations in dopaminergic or cholinergic neurotransmission.     

The effects of yohimbine and neuroleptics on apomorphine-induced pecking behaviour in the pigeon

The effects of yohimbine and some neuroleptics were investigated on pecking behaviour, induced by apomorphine. The total pecking counts, recorded for 18 min, elicited by a standard dose of apomorphine (1 mg/kg) were inhibited dose-dependently by yohimbine and the neuroleptics. Haloperidol was found to be the most potent, trifluoperazine, yohimbine, chlorpromazine and the atypical neuroleptics were less effective in decreasing order. Chronic treatment with yohimbine (2.5 mg/kg per day for 20 days) caused an increase in pecking behaviour. These results suggest that apomorphine-induced pecking behaviour in the pigeon could be used as a reliable method for screening neuroleptic drugs and the antidopaminergic activity of yohimbine is verified in this model.     

Involvement of different dopamine receptors in rat diphasic motility response to apomorphine

A critical dose of apomorphine (300 g/kg SC) given immediately before placing rats into a novel environment produced a diphasic motility response (initial sedation followed by enhanced locomotion). Various neuroleptics having different clinical and/or pharmacological profiles were studied by using such a model. (–)-Sulpiride and sultopride preferentially antagonized apomorphine inhibition; haloperidol and tiapride antagonized both phases of apomorphine response at similar doses; chlorpromazine, fluphenazine, thioridazine, metoclopramide and SCH 23390 preferentially antagonized apomorphine stimulation. The results are discussed in terms of the dopamine receptor subtypes involved in the two phases of apomorphine effect. Apomorphine stimulation can be antagonized by D-1 as well as D-2 receptor blockade. A higher affinity for D-2 receptors seems a necessary requisite for the antagonism of apomorphine inhibition; moreover, the ability of neuroleptics to antagonize apomorphine inhibition seems to depend on the ratio of their presynaptic versus postsynaptic D-2 activity. Offprint requests to: N. Montanaro     

Effects of cannabidiol in animal models predictive of antipsychotic activity

The effects of cannabidiol (CBD) were compared to those produced by haloperidol in rats submitted to experimental models predictive of antipsychotic activity. Several doses of CBD (15–480 mg/kg) and haloperidol (0.062–1.0 mg/kg) were tested in each model. First, CBD increased the effective doses 50% (or) ED₅₀ of apomorphine for induction of the sniffing and biting stereotyped behaviors. In addition, both CBD and haloperidol reduced the occurrence of stereotyped biting induced by apomorphine (6.4 mg/kg), increased plasma prolactin levels and produced palpebral ptosis, as compared to control solutions. However, CBD did not induce catalepsy even at the highest doses, in contrast to haloperidol. Such a pharmacological profile is compatible with that of an atypical antipsychotic agent, though the mechanism of action is uncertain and may not be identical to that of the dopamine antagonists.     

Antiemetic specificity of dopamine antagonists

Twelve antagonists of apomorphine-induced emesis in dogs were studied in different tests to evaluate their antiemetic specificity. Ten of these antagonists were neuroleptics: benzquinamide, clebopride, bromopride, prochlorperazine, haloperidol, chlorpromazine, thiethylperazine, metoclopramide, droperidol, and pimozide blocked conditioned responding in dogs and apomorphine-induced stereotyped behavior in rats. The use of these compounds as anti-emetics entails a risk of neurological side effects. Metopimazine and domperidone were devoid of neuroleptic activity. Metopimazine, however, showed potent -adrenergic blocking activity, showed histamine H₁ antagonism, and induced palpebral ptosis. Therapeutic doses of metopimazine are, therefore, likely to produce sedation and side-effects related to autonomic blockade. Domperidone showed potent antiemetic activity and, up to high doses, no other central or peripheral effects. Therefore, domperidone is the only specific antiemetic known.     

Effects of apomorphine and haloperidol on “spontaneous” stereotyped licking behaviour in the Cebus monkey

Three recently arrived drug naive Cebus apella monkeys with spontaneous stereotyped oral movements were treated with apomorphine and haloperidol using a wide dose range. Low doses of apomorphine (0.05–0.1 mg/kg) suppressed the oral stereotypies without affecting normal behaviour such as grooming and scratching. Higher doses of apomorphine (0.25–1.0 mg/kg) and haloperidol (0.01–0.1 mg/kg) also decreased or abolished the oral stereotypies, but induced generalized stereotypies (apomorphine) or dystonia/parkinsonism (haloperidol), suppressing normal behaviour. The findings indicate that dopamine is involved in these presumably stress-induced (not drug-induced) stereotypies.     

Effects of neuroleptic drugs on the inhibition of exploratory behaviour induced by a low dose of apomorphine: implications for the identity of dopamine receptors

Apomorphine in low doses inhibits spontaneous exploratory behaviour in rats. This effect is commonly referred to as an expression of selective stimulation of dopaminergic autoreceptors. The aim of the present study was to investigate the influence of neuroleptic drugs with different pharmacological profiles on this apomorphine induced inhibition of exploration using techniques for detailed recording of behaviour and multivariate statistical analysis of the results. By comparison with dose response analyses of apomorphine it was possible to determine whether a neuroleptic specifically antagonised the apomorphine effect or if the pattern of behaviour was qualitatively changed in some way. Apomorphine (0.05 mg/kg) was tested against cis-flupenthixol (0.01-0.5 mg/kg), haloperidol (0.01-0.1 mg/kg), metoclopramide (0.2-5 mg-kg), sulpiride (0.5-50 mg/kg) and SCH 23390 (0.005-0.05 mg/kg). Metoclopramide and haloperidol had weak antagonising effects against apomorphine while cis-flupenthixol and SCH 23390 was completely inefficient in this respect. The multivariate analysis indicated that the effects of haloperidol was restricted to only some aspects of the behavioural effects of apomorphine. Only sulpiride did selectively and dose-dependently antagonise the apomorphine induced behavioural suppression. The data provide evidence for a functional subdivision of dopamine receptors at the behavioural level.     

Synergistic blockade of some dopamine-mediated behaviours by (−)-sulpiride and SCH 23390 in the rat

Several studies have indicated that the D2 dopamine receptors mediate the antidopaminergic activity of the neuroleptics; nevertheless, the selective blocker (–)-sulpiride weakly inhibits dopamine-mediated behaviour. The present study investigated whether the concomitant injection of doses of the D1 antagonist SCH 23390, which by themselves are without effect, would enable (–)-sulpiride to express fully neuroleptic activity in the rat. The benzamide YM 09151-2 that strongly inhibits dopamine-mediated behaviour was also studied. Rats receiving different doses of (–)-sulpiride, YM 09151-2 and SCH 23390 given alone or in combination were tested for exploratory activity, apomorphine-induced stereotyped behaviour and hyperactivity elicited by the D2 agonist LY 171555. When given alone, (–)-sulpiride (10, 20 and 40 mg/kg IP) had no effect on exploratory activity and stereotypy. When (–)-sulpiride was administered in combination with an ineffective dose of SCH 23390 (5 g/kg) both responses were significantly inhibited. The combined administration of subthreshold doses of (–)-sulpiride (2.5 mg/kg) and SCH 23390 (2.5 g/kg) significantly inhibited hypermotility induced by LY 171555. Moreover, the combined administration of ineffective doses of YM 09151-2 with subthreshold doses of SCH 23390 strongly inhibited all the behavioural responses. The results indicate that SCH 23390 allowed (–)-sulpiride to exhibit a wider spectrum of neuroleptic activity and potentiated the antidopaminergic activity of YM 09151-2.     

Behavioural correlates of modified dopaminergic/anticholinergic responses following chronic treatment with neuroleptic agents of differing activity spectra.

An attempt was made to differentiate the mechanisms of action of these “neuroleptic” agents having antidyskinetic properties from the classical neuroleptics by studying the effects of chronic treatment on the responses to a dopamine agonist and cholinergic antagonist. Rats were chronically treated with haloperidol (2 mg/kg i.p.), oxiperomide (8 mg/kg i.p.), pimozide (8 mg/kg p.o.), tiapride (100 mg/kg i.p.), sultopride (100 mg/kg i.p.), sulpiride (100 mg/kg p.o.) and metoclopramide (100 mg/kg i.p.) for 7 consecutive days. On days 1, 3 and 7 after neuroleptic withdrawal rats were assessed for their sensitivity to the stereotypic effects of apomorphine (0.25–1.0 mg/kg s.c.) and the locomotor stimulant effects of dexetimide (0.32–1.25 mg/kg s.c.). A supersensitivity phase to apomorphine, persisting for 1–3 days, was noted in all drug-treated groups and, during this time, the responses to dexetimide were decreased (haloperidol, oxiperomide and pimozide groups), increased (metoclopramide group) or remained similar to control values (sultopride-, sulpiride- and tiapride-treated animals). The responses to dexetimide returned to control values in all treatment groups as the apomorphine sensitivity phase declined. It is suggested that chronic treatment with neuroleptic agents may enhance the sensitivity of those cerebral receptors responsible for mediating the stereotypic effects of apomorphine, and that the relationship between such dopamine function and interacting cholinergic mechanisms may differ for the different groups of neuroleptic agent. However, these differentiations did not directly correlate with the known ability of the neuroleptics to induce or antagonise dyskinetic phenomena.     

Atypical neuroleptics suppress dopaminergic behavioral supersensitivity

Seven days after bilateral 6-OHDA denervation of the nucleus accumbens locomotor activity was recorded in rats. 6-OHDA lesion strongly enhanced hypermotility induced by apomorphine (1.0 mg/kg IP) as a sign of behavioral dopaminergic supersensitivity. The potency of the classical neuroleptic haloperidol (0.03–0.25 mg/kg IP) to antagonize apomorphine-induced hypermotility was reduced in 6-OHDA-pretreated rats. The atypical neuroleptics sulpiride (5.0–20.0 mg/kg IP), thioridazine (1.0–5.25 mg/kg IP) and clozapine (0.5–2.0 mg/kg IP) and the 5-HT antagonists cyproheptadine (0.2 mg/kg IP) and ritanserin (0.01 mg/kg IP) suppressed the augmented apomorphine response in 6-OHDA-lesioned animals to the level of the apomorphine effect in controls. It is concluded that the model of denervation supersensitivity is capable of differentiating typical and atypical neuroleptics. The abolition of the 6-OHDA-induced increase of the apomorphine hypermotility by the atypical neuroleptics cannot be explained solely by postsynaptic dopamine receptor antagonism. Serotonergic mechanism may be involved in this action.     

7-OH-DPAT,a dopamine D3-selective receptor agonist,produces contralateral rotation in 6-hydroxydopamine-lesioned rats

The purpose of the present study was to characterize the rotational behavior in unilateral 6-OHDA-lesioned rats produced by the high affinity and selective dopamine D₃ receptor ligand 7-OH-DPAT. Qualitatively similar to the direct-acting DA agonist apomorphine, 7-OH-DPAT causes rats to rotate in a direction contralateral to the side of the nigrostriatal DA pathway lesion. This effect is dose-dependent and the minimum effective dose is 0.03 mg (0.12 m?mol)/kg. 7-OH-DPAT-induced rotation is blocked in a dose-dependent manner by oral pretreatment with the “D₂-like” receptor antagonists haloperidol, eticlopride, or clozapine, but not by the “D₁-like” antagonist SCH 23390. The rank order potency for inhibition of 7-OH-DPAT rotation for haloperidol [ID₅₀ = 0.067 mg (0.18 m?mol)/kg], eticlopride [ID₅₀ = 0.41 mg (1.2 m?mol)/kg], clozapine [ID₅₀ = 13 mg (40 m?mol)/kg], and SCH 23390 [ID₅₀ > 90 mg (313 m?mol)/kg] closely parallels their rank order affinity for binding to either the D₂ or the D₃ receptor. Pretreatment with the non-DA receptor antagonists ritanserin (serotonin 5HT₂), scopolamine (muscarinic cholinergic), propranolol (betaadrenergic), or naltrexone (opiate), each at relevant pharmacological doses, failed to reduce 7-OH-DPAT rotation. Taken together, these results are consistent with mediation of 7-OH-DPAT-induced rotational behavior via an agonist interaction with one or more DA receptors. ©1995 Wiley-Liss, Inc.     

Behavioral effects of apomorphine and diisobutyrylapomorphine in the mouse

Stereotyped climbing and clinging responses of the mouse to apomorphine or its ester prodrug, O,O-diisobutyrylapomorphine were evaluated. Acute doses of the ester up to 0.3 mmoles/kg were tolerated without apparent ill effects. Both aporphines produced dose-dependent behavioral responses that were blocked by neuroleptics. The duration of action of the ester was much greater than that of apomorphine. When maximal initial behavior during the first hour was evaluated, low equimolar doses of apomorphine and the ester were similar in potency; in contrast, the total behavioral response to larger doses of the ester was greater than to apomorphine, evidently reflecting the greater duration of action of the ester. Behavioral responses to both agents during the first hour decreased at doses above 0.1 mmoles/kg. Oxidized or O-methylated apomorphine did not antagonize the behavioral effects of apomorphine. Systemic injection of apomorphine or diisobutyrylapomorphine led to detectable levels of free apomorphine as estimated by a sensitive and selective fluorimetric assay. The time-course and magnitude of the behavioral effects of both agents corresponded closely with brain levels of apomorphine. Apomorphine and dopamine (but not diisobutyrylapomorphine) stimulated adenylate cyclase activity in mouse striatal homogenates—an effect antagonized by neuroleptic drugs but not propranolol. Apomorphine exerted a biphasic effect on the cyclase in vitro and increased cyclic AMP levels in the striatum in vivo. The prolonged activity of apomorphine esters as depot prodrug agonists of putative dopaminergic mechanisms in the brain may provide clinically desirable characteristics.