Direct-acting Dopamine Agonist Research Articles

REINFORCER MAGNITUDE ATTENUATES APOMORPHINE'S EFFECTS ON OPERANT PECKING

When given to pigeons, the direct-acting dopamine agonist apomorphine elicits pecking. The response has been likened to foraging pecking because it bears remarkable similarity to foraging behavior, and it is enhanced by food deprivation. On the other hand, other data suggest the response is not related to foraging behavior and may even interfere with food ingestion. Although elicited pecking interferes with food capture, it may selectively alter procurement phases of feeding, which can be isolated in operant preparations. To explore the relation between operant and elicited pecking, we provided pigeons the opportunity to earn different reinforcer magnitudes during experimental sessions. During signaled components, each of 4 pigeons could earn 2-, 4-, or 8-s access to grain for a single peck made at the end of a 5-min interval. In general, responding increased as a function of reinforcer magnitude. Apomorphine increased pecking for 2 pigeons and decreased pecking for the other 2. In both cases, apomorphine was more potent under the component providing the smallest reinforcer magnitude. Analysis of the pattern of pecking across the interval indicated that behavior lost its temporal organization as dose increased. Because apomorphine-induced pecking varied inversely with reinforcer magnitude, we conclude that elicited pecks are not functionally related to food procurement. The data are consistent with the literature on behavioral resistance to change and suggest that the effects of apomorphine may be modulated by prevailing stimulus-reinforcer relationships.

Effects of pramipexole on impulsive choice in male wistar rats.

Clinical reports, primarily with Parkinson's disease patients, note an association between the prescribed use of pramipexole (and other direct-acting dopamine agonist medications) and impulse control disorders, particularly pathological gambling. Two experiments examined the effects of acute pramipexole on rats' impulsive choices where impulsivity was defined as selecting a smaller-sooner over a larger-later food reward. In Experiment 1, pramipexole (0.1 to 0.3 mg/kg) significantly increased impulsive choices in a condition in which few impulsive choices were made during a stable baseline. In a control condition, in which impulsive choices predominated during baseline, pramipexole did not significantly change the same rats' choices. Experiment 2 explored a wider range of doses (0.01 to 0.3 mg/kg) using a choice procedure in which delays to the larger-later reinforcer delivery increased across trial blocks within each session. At the doses used in Experiment 1, pramipexole shifted choice toward indifference regardless of the operative delay. At lower doses of pramipexole (0.01 and 0.03 mg/kg), a trend toward more impulsive choice was observed at the 0.03 mg/kg dose. The difference in outcomes across experiments may be due to the more complex discriminations required in Experiment 2, that is, multiple discriminations between changing delays within each session.

Novel Insights in Pharmacogenetics of Drug Response in Parkinson‘s Disease

receptor DRD2 gene, the dopamine transporter (DAT ) gene and μ1 opioid receptor (OPRM1) gene. Motor fluctuations have been associated with a DRD2 gene polymorphism [6], although other studies could not replicate this finding. Conflicting results have been reported concerning the relationship between the occurrence of drug-induced hallucinations in PD and genetic polymorphisms. While some studies demonstrated significant associations between hallucinations and polymorphisms in the DAT gene, the cholecystokinin (CCK ) gene and the apolipoprotein E (APOE) gene, others failed to replicate these results. Associations were found between sleep attacks without warning signs and a polymorphism in the DRD4 gene, the preprohypocretin (HCRT ) gene, the DRD2 gene and the catechol-O-methyl transferase (COMT ) gene. In addition, similar findings were found in recent studies investigating polymorphisms in genes encoding dopamine D 2 and D 3 receptors [7–9] and COMT [10]. Lin and colleagues investigated the role of angiotensin I-converting enzyme in levodopa response [11]. They demonstrated that patients with a homozygote (ins/ins) genotype of the ACE gene had a 2.5-times higher risk of levodopa-induced psychosis, a disabling complication, particularly in the later stage of the disease. The role of angiotensin I-converting enzyme in the development of levodopa-induced psychosis is relatively unexplored. It is necessary to reproduce this study in independent cohorts. We concluded that, in comparison with other subject areas such as psychiatry [12], relatively few efforts have been made to investigate the role of pharmacogenetics in the individual response to anti-PD drugs. The focus of pharmacogenetic studies in patients with PD was mainly on genes coding for drug receptors, drug transporters and synaptic drug-metabolizing enzymes (pharmacodynamics). The pharmacogenetic studies in both PD and psychiatry did not, for the most part, Parkinson’s disease (PD) is characterized by brady kinesia, rigidity and tremor, and is the result of degeneration of dopaminergic neurones in the substantia nigra pars compacta. PD has a prevalence of approximately 0.5–1% in persons of 65–69 years, rising to 1–3% among persons of 80 years and older [1]. Twin studies suggest a limited role for genetic factors in the etiology of PD, perhaps most prominently in early-onset forms [2]. The etiology of the common late-onset forms of PD remains largely to be elucidated. Anti-PD drugs, such as levodopa and the direct-acting dopamine agonists, are effective in reducing the motor symptoms of PD. However, these drugs are also associated with the development of motor complications, such as levodopainduced dyskinesia (LID), response fluctuations and side effects, such as hallucinations and excessive daytime sleepiness. In clinical practice, a large interindividual variability in drug response has been noticed. For example, up to 45% of levodopa users develop LID within 5 years, while others remain free of LID for many years [3]. Up to 25% of users of dopaminergic drugs develop hallucinations, whereas others do not [4].

Mechanisms and Issues Relating to the Use of D1-like Dopamine Receptor Agonists for Age-related Illnesses: Parkinson?s Disease and Memory and Cognition

Parkinson's disease is the second most common age related neurodegenerative disorder that, along with age-related declines in memory and cognition, represents an area of medicine in which there have not been major advances in decades. This paper will focus on the great potential that D 1 -like dopamine agonists may have in these arenas. Although levodopa has been the most effective treatment for Parkinson's disease (PD), pharmacokinetic and bioconversion problems have led to efforts to develop direct acting dopamine agonists for PD. Although the large majority of research and development has been focused on D 2 -like direct agonists, this talk will show data illustrating why D 1 agonists should be a high priority pharmacotherapeutic target for treatment of PD. This presentation will review the neurobiological and molecular pharmacological evidence that supports this hypothesis, some of the scientific hurdles, and the current state of the medicinal chemistry of D 1 agonist development. The concluding portion of the talk will review the experimental evidence suggesting that D 1 -like agonists can lead to improvements in memory and cognitive function, and review the current status of drug discovery and development for these uses.

Cocaine or Selective Block of Dopamine Transporters Influences Multisecond Oscillations in Firing Rate in the Globus Pallidus

Previous studies have shown that direct-acting dopamine agonists modulate the multisecond oscillations which are present in globus pallidus spike trains in vivo in awake rats. To investigate possible modulation by endogenous dopamine and by other monoamines, and by drugs with abuse potential, cocaine or selective monoamine uptake blockers were injected systemically during extracellular recording of single globus pallidus neurons and the results analyzed with spectral and wavelet methods. Both cocaine and the selective dopamine uptake blocker GBR-12909 significantly shortened the period of multisecond oscillations, as well as increasing overall firing rate. Cocaine effects were blocked by dopamine antagonist pretreatment, as well as by N-methyl-d-aspartate receptor antagonist (MK-801) pretreatment. Desipramine and fluoxetine (blockers of norepinephrine and serotonin uptake, respectively) had no significant effects on multisecond oscillations. The results suggest that dopamine has a primary role among monoamines in modulating multisecond oscillations in globus pallidus activity, and that tonic dopaminergic and glutamatergic transmission is necessary for normal slow oscillatory function.

Neuroprotective effects of D3 dopamine receptor agonists

The effects of D 3 receptor activation are unresolved at this time, but may have practical implications in the treatment of Parkinson's disease (PD). As a result of assessing the neuroprotective effects of the direct-acting D 3 preferring dopamine (DA) agonist pramipexole (PPX), we have observed that drugs which psossess D 3 affinity increase the production of a DA neurotrophic factor in tissue culture. This molecule is increased by treatment with PPX, is constitutively produced by DA neurons in culture, and possesses a molecular weight of approximately 35 kDa. It is hypothesized that this molecule may be the so-called DA autotrophic factor referred to by many authors over the past two decades. Interestingly, the protein is oxidant-labile and, therefore, D 3 agonists which increase its production and also possess antioxidant capacity would provide unique neuroprotective benefits to patients with PD. However, many questions remain. Although the data supporting this notion are strong, it is clear that other unknown characteristics of DA agonists, including increased production of anti-apoptotic proteins, are also involved. This manuscript will review this concept in the context of tissue culture strategies of neuroprotection. Although no conclusion can be made at this time, it is clear that direct comparisons of the neuroprotective effects of direct-acting DA agonists in mesencephalic culture can provide considerable insight into the mechanistic actions of anti-dopaminergic drugs.

Attenuation of levodopa-induced toxicity in mesencephalic cultures by pramipexole.

The direct-acting dopamine (DA) agonist pramipexole (2 amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydrochlori de) was evaluated for its ability to attenuate levodopa-induced loss of tyrosine hydroxylase immunoreactive (THir, a marker for dopamine neurons) cells in mesencephalic cultures. Pramipexole reduced levodopa-induced THir cell loss in a dose-dependent and saturable fashion (ED50 = 500 pM), its inactive stereoisomer was significantly less potent in this regard and pergolide and bromocriptine had negligible cytoprotective effects. Culture media from mesencephalic cultures incubated with pramipexole for 6 days increased THir cell counts in freshly harvested recipient cultures. The magnitude of this effect was directly proportional to the amount of pramipexole in the donor cultures and heat-inactivation of the media abolished the growth promoting effect. The results from this exploratory set of experiments suggest that pramipexole may be cytoprotective to dopamine neurons in tissue culture. Pramipexole's affinity for DA receptors, its antioxidant action or its ability to enhance mesencephalic trophic activity could be responsible for this effect.

Management of Motor Fluctuations in Parkinson’s Disease

A complication of chronic levodopa therapy is a shortening of benefit of each dose. Peripheral pharmacokinetics, central pharmacokinetics, and central pharmacodynamics are involved in the pathophysiology of motor fluctuations. Strategies to improve 'wearing-off' fluctuations attempt to provide more constant plasma levodopa levels or more continuous stimulation of dopamine receptors. Controlled-release levodopa preparations are very effective for mild to moderate fluctuations. The addition of direct-acting dopamine agonists or the MAO-B inhibitor selegiline is helpful for short-term improvement. Liquid levodopa is beneficial for some patients with severe fluctuations. Apomorphine injections will provide immediate 'rescue' from 'off' states. Catechol-O-methyl transferase inhibitors are a new class of drugs which appear to improve motor fluctuations. Manipulations of dieting protein may reduce fluctuations in some patients. It is possible that motor fluctuations may be delayed by the early use of sustained release levodopa preparations or early combinations of levodopa with a dopamine agonist.

Influence of the estrous cycle and estradiol on the behavioral effects of amphetamine and apomorphine in rats

This experiment was designed to investigate the influence of hormonal status of the rat on the effects of two doses of an indirect-acting dopamine agonist (amphetamine 0.25 and 1.0 mg/kg, IP) and a direct-acting dopamine agonist (apomorphine 62.5 and 250 μg/kg, SC) on the acquisition of conditioning avoidance responses (CARs) and the performance of some spontaneous behaviors. Active conditioned avoidance was improved by amphetamine in all the groups except in females at diestrus; apomorphine improved this response only in females at estrus and in ovariectomized rats after estradiol replacement, but the avoidance response was deteriorated in males and females at diestrus and after ovariectomy without estradiol replacement. Both dopaminergic drugs had contrasting effects on motor activity, number of rearings, and number of head shakes according to the hormonal status of the rat. Only the time spent in grooming behavior decreased after the treatment with both dopamine agonists in all of the five groups studied. These results provided behavioral evidence for the hypothesis that dopaminergic activity in the CNS is affected distinctively by modifications in the sexual hormone status (gender, estrous cycle, ovariectomy, and estradiol replacement). Relationships between ovarian hormones and dopaminergic system are discussed.

The Effect of Apomorphine, MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine) and Placebo on Smooth Pursuit Gain and Corrective Saccades in Normal Subjects

The effects of apomorphine (0.01 mg/kg SC) a direct-acting dopamine (DA) agonist, MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine) (20 mg PO), a direct-acting serotonin (5-HT) agonist, and placebo on smooth pursuit eye movements were evaluated in 10 to 12 normal volunteers. Smooth pursuit was tested just prior to administration of either apomorphine, MK-212, or placebo (on separate days), and then repeatedly tested at 30 min intervals for two hours after dose administration. The smooth pursuit targets were a series of predictable, constant velocity ramps with velocities of 5 degrees/sec (slow target) and 20 degrees/sec (fast target). Eye movements were recorded with infrared oculography, and the following six measures were obtained; steady-state gain (slow-target-gain; fast-target-gain), corrective catch-up saccade (CUS) rate (slow-target-CUS-rate; fast-target-CUS-rate), and CUS amplitude (slow-target-CUS-amplitude; fast-target-CUS-amplitude). The placebo test yielded a statistically significant monotonic decrease over time in slow-target-gain and corresponding increase in slow-target-CUS-rate, but no effects of placebo were noted for the fast target. Apomorphine injection produced a marked reduction in both slow-target-gain and fast-target-gain at 30 min, returning to baseline thereafter. Apomorphine injection also produced a statistically significant increase in slow-target-CUS-amplitude. Ingestion of MK-212 produced a statistically significant increase in slow-target-gain and fast-target-gain as well as a corresponding decrease in slow-target-CUS-rate and fast-target-CUS-rate at 90 min or 120 min. There was evidence that the decline in slow-target-gain after apomorphine was associated with side-effects such as sleepiness, but the decline in fast-target-gain was not related to side-effects. The improved smooth pursuit performance after MK-212 was not related to side-effects. The data suggest that serotoninergic stimulation can improve smooth pursuit performance, whereas dopaminergic stimulation worsens this performance.

Apomorphine and amphetamine produce differential effects on the speed and success of reaction time responding in the rat

Apomorphine, a nonselective, direct-acting dopamine agonist, and amphetamine, a nonselective indirect-acting dopamine agonist, were compared for their effects on the reaction time response in rats. Animals were shaped to release a lever in response to an auditory/visual stimulus to avoid mild foot shock. The characteristics of the reaction time response of primary interest were percent successful avoidance and response latency. Apomorphine (0, 1, and 5 mg/kg, IP) significantly decreased successful avoidance, but had no effect on response latencies. Thus, the decrease in successful avoidance was not a direct result of longer latencies. Amphetamine (0, 0.5, and 1 mg/kg, IP) produced a different pattern of effects on the reaction time response. Successful avoidance was not affected by amphetamine treatment. However, response latencies were dose-dependently decreased in response to amphetamine. These results demonstrate that dopamine receptor stimulation by different dopamine agonists produces a different pattern of effects on the characteristics of the reaction time response. In addition, these results demonstrate that successful avoidance can be modulated independently of response latencies.

Comparison of the clinical pharmacology of (-)NPA and levodopa in Parkinson's disease.

Direct acting dopamine agonists are generally less effective than levodopa in relieving symptoms of Parkinson's disease. In an attempt to quantitate and explain this situation, the acute motor responses to intravenous injections of the dopamine agonist, (-)-N-n-propyl-norapomorphine hydrochloride (NPA), were compared with those of the dopamine precursor, levodopa. At optimum dose levels, the acute anti-Parkinsonian efficacy of NPA averaged only about 50% of maximum, while essentially total symptom suppression was obtained with levodopa in patients previously treated with the amine precursor. Dyskinesia severity, however, was similar with the two drugs. These differences in anti-Parkinsonian efficacy may reflect the fact that while NPA acts mainly on D-2 dopamine receptors, levodopa results in stimulation of both the D-1 and D-2 subsets of receptors at a more physiological ratio. Future efforts to develop dopamine agonists for the treatment of Parkinsonian symptoms may thus have to consider focusing on drugs having pharmacological profile more similar to that of dopamine.

Pergolide: A dopamine agonist at both D 1 and D 2 receptors

Pergolide is a potent, direct-acting dopamine agonist used in treating Parkinson's disease. It is an agonist found recently to have high affinity for D 3 receptors. The affinity of pergolide for D 1 receptors is lower than for D 2 receptors, and there have been some reports that it may not interact with D 1 receptors in vivo at doses used to activate D 2 receptors. A growing body of evidence suggests that pergolide does occupy and activate D 1 receptors in vivo , although the relevance to therapeutic efficacy in Parkinson's disease needs further study.

Neuroendocrine measures of dopaminergic function in chronic cocaine users

Plasma prolactin (PRL) and growth hormone (GH) levels are determined, in part, by the effects of dopamine (DA) at pituitary and hypothalamic DA receptors, respectively. To determine if chronic cocaine abuse alters dopaminergic activity, basal PRL and GH concentrations were measured in 16 male patients meeting DSM-III-R criteria for cocaine dependence (8 cocaine users and 8 cocaine + alcohol users) and 8 normal controls. In addition, the functional responsivity of DA receptors was assessed in the same group of patients by measuring the change in plasma PRL and GH concentration following the administration of the direct-acting DA agonist, apomorphine (0.01 mg/kg, s.c.) or saline. No difference in basal plasma PRL and GH levels or plasma PRL and GH responses to apomorphine administration was found between the entire group of cocaine patients and normal controls. However, three of the cocaine patients had basal plasma PRL levels that were more than 2.5 SD greater than that of the normal controls, suggesting that some interference of dopaminergic inhibition of PRL secretion might be present in at least some cocaine users. Although baseline plasma PRL levels were elevated in a subgroup of cocaine users, these data do not support the hypothesis that chronic cocaine abuse produces consistent abnormalities in dopaminergic function at the pituitary or hypothalamus.

Antiparkinsonian effects of caffeine depend upon pavlovian drug conditioning processes

Caffeine induces the antiparkinsonian response of contralateral rotation in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions following exposure to the direct-acting dopamine agonist apomorphine. This effect of caffeine has been attributed to a ‘priming’ effect of apomorphine which enables the supersensitive dopamine receptors to respond to caffeine and other methylxanthines. These studies, however, did not differentiate between conditioning and pharmacological variables. To resolve this issue, a Pavlovian conditioning procedure was employed in which separate groups of 6-OHDA rats were given 0.05 mg/kg (s.c.) apomorphine treatments paired or unpaired with a test environment. The animals in the paired or conditioning treatment groups subsequently exhibited contralateral rotation when tested with caffeine (10 mg/kg, i.p.), whereas animals in the unpaired or ‘priming’ treatment groups displayed only enhanced ipsilateral rotation. The activation of the conditioned contralateral rotation by caffeine in the paired group occurred even after the response was suppressed by extinction. This preferential activation following extinction of a previously conditioned drug response by caffeine implicates caffeine mechanisms (e.g. adenosine antagonism) in drug conditioning processes.

Effect of direct and indirect dopamine agonists on brain extracellular ascorbate levels in the striatum and nucleus accumbens of awake rats

Systemic administration of direct and indirect dopamine agonists resulted in increased extracellular ascorbic acid levels in the striatum and, to a lesser degree, in the nucleus accumbens as measured by in vivo voltammetry. Intraperitoneal d-amphetamine sulfate (5mg/kg) increased ascorbate concentrations in striatal extracellular fluid. Amphetamine also increased extracellular ascorbate levels in the nucleus accumbens although more gradually and to a lesser extent. Intraperitoneal phenethylamine hydrochloride (20 mg/kg) following pargyline hydrochloride pretreatment (20 mg/kg) increased extracellular ascorbate levels in the striatum significantly above the small increase seen in the nucleus accumbens. The direct acting dopamine agonists Ly-141865 and Ly-163502 when given i.p. at 1 mg/kg, resulted in increased extracellular ascorbate concentrations in both brain areas, again with a significantly greater effect in the striatum. These results indicate that brain extracellular ascorbate levels can be modulated by dopaminergic neuro-transmission and that this modulation is quantitatively different in different dopamine-containing brain structures.

D-1 dopamine receptor stimulation potentiates neurophysiological effects of bromocriptine in rats with lesions of the nigrostriatal dopamine pathway

Neurophysiological techniques were used to examine the possibility that the effects of bromocriptine, a direct acting dopamine agonist, can be potentiated by D-1 receptor stimulation in an animal model of parkinsonism. Single unit activity of substantia nigra pars reticulata neurons was recorded in rats with 6-hydroxydopamine induced lesions of the nigrostriatal pathway. The results showed that the coadministration of bromocriptine with the selective D-1 agonist SKF 38393 greatly attenuated pars reticulata neuronal activity at doses that did not produce significant effects when administered alone. Thus, processes elicited by D-1 receptor stimulation and bromocriptine exert synergistic effects in these 6-hydroxydopamine lesioned rats. This observation may be relevant to the mechanism underlying I-DOPA's ability to potentiate the therapeutic effects of bromocriptine in parkinsonian patients.

PHNO, a novel dopamine agonist, in animal models of parkinsonism.

PHNO, a naphthoxazine compound, was investigated in animal models of central dopaminergic activity. The drug in doses of 5-300 micrograms/kg when administered subcutaneously, or transdermally, induced stereotypic behavior in rats which was blocked by haloperidol but not by reserpine pretreatment. In rats with unilateral 6-hydroxydopamine lesions of the substantia nigra PHNO induced dose-dependent contralateral turnings. The drug caused emesis in dogs and hypothermia in mice. PHNO bound to D-2 dopamine receptors in the rat striatum. Chronic injection with PHNO did not induce behavioral supersensitivity or increase dopamine receptor density. These data indicate that PHNO is a direct acting dopamine agonist that is highly potent. PHNO differs from other dopaminergic drugs and may be useful in the treatment of Parkinson's disease.

Chronically administered morphine increases dopamine receptor sensitivity in mice

Chronic morphine treatment has been suggested to cause the development of supersensitive dopamine receptors. This increase in sensitivity was detected as a hypersensitivity in direct-acting dopamine agonists and as an increase in the affinity of dopamine receptors. However, these binding studies were performed in animals which had been withdrawn from morphine for a period of 24–48 h prior to killing. In the present study mice were implanted with pellets containing 75 mg of morphine free base. The pellets were left in situ in all experiments. One group of mice exhibited an increased sensitivity to apomorphine 72 h following pellet implantation as evidenced by a decrease in the ED 50 of apomorphine for inducing cage climbing behavior. A second matched group of mice was found to have a significant increase in whole brain [ 3H]spiroperidol binding sites. These results suggest that chronic morphine treatment can cause the development of central supersensitive dopamine receptors. Lithium administered concurrently with the morphine attenuated the increased sensitivity to apomorphine and the increase in the number of [ 3H]spiroperidol binding sites. Concurrent lithium treatment also facilitated the degree of analgesic tolerance, and naloxone-induced withdrawal hypothermia. The ability of lithium to enhance analgesic tolerance while simultaneously attenuating the increase in dopamine receptors suggests that alterations in dopamine receptors might modify the degree of analgesic tolerance which develops to chronic morphine administration, or might modify the animal's response to thermal stimuli. The mechanism by which lithium enhanced naloxone-induced hypothermia is presently unknown.

Differential effects of selected dopaminergic agents on locomotor activity in normotensive and spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) exhibit a significantly higher level of spontaneous locomotor activity than age-matched normotensive controls (WKY). The direct-acting dopamine agonists, apomorphine and pergolide, produced a biphasic effect on locomotor activity levels in normotensive controls. Low doses of these agonists decreased activity levels, while higher doses of these agonists dramatically stimulated activity. In marked contrast to these results was the effect observed in the SHR, in which these agonists at all doses tested decreased activity. Amphetamine, a dopamine releaser, stimulated activity levels in both the WKY and SHR; however, the magnitude of the increase was somewhat attenuated in the SHR.