Acting Dopamine Receptor Agonists Research Articles

Discriminative stimulus effects of direct‐ and indirect‐ acting dopamine receptor agonists in free‐feeding and food‐restricted mice.

In rats, the discriminative stimulus effects of direct‐ (e.g., quinpirole) and indirect‐ (e.g., cocaine) acting dopamine receptor agonists are mediated by multiple dopamine receptor subtypes and the relative contribution of D2 and D3 receptors to these effects can be altered by manipulating feeding conditions (e.g., food restriction). In these studies two‐lever discriminations were trained with either 10.0 mg/kg cocaine or 0.032 mg/kg quinpirole in free‐fed and food‐restricted mice using a fixed ratio 10 schedule of reinforcement for 50% sweetened condensed milk. Although free‐fed mice responded at lower rates under training conditions and were more sensitive to the rate suppressant effects of their respective training drugs, feeding condition did not affect the acquisition of either discrimination and did not alter the potencies of cocaine or quinpirole to increase cocaine‐ and quinpirole‐appropriate responding, respectively. These novel discriminations will allow for the identification of the specific receptors that mediate the interoceptive effects of cocaine and quinpirole and will serve as the basis for future studies of the influence of diet on drug effects in mice. CPF is supported by a NIDA Senior Scientist Award (K05 DA017918).

Effects of acute cocaine or dopamine receptor agonists on AMPA receptor distribution in the rat nucleus accumbens.

Changes in α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR) surface expression in the rodent nucleus accumbens (NAc) are produced by cocaine exposure and implicated in addiction-related behaviors. The direction of change depends on the animal's prior drug history. However, little is known about the effect of a single exposure to cocaine on AMPAR distribution in the NAc of untreated rats. This is essential information for interpreting the literature on AMPAR trafficking after repeated cocaine exposure. In this study, we used a protein crosslinking assay to determine the effect of a single cocaine injection on surface and intracellular AMPAR subunit levels in the rat NAc. We found increased AMPAR surface expression in the NAc 24 h, but not 30 min or 2 h, after cocaine injection. A major effect of cocaine is to increase extracellular dopamine (DA) levels, leading to DA receptor activation. Therefore, we also evaluated the effects of directly acting DA receptor agonists. In contrast to the effects of cocaine, AMPAR surface expression was significantly decreased 24 h after injection of the D2-class agonist quinpirole, whereas no significant effects were produced by the D1-class agonist SKF 81297 or the mixed DA agonist apomorphine. Our results show that the effects of a single cocaine exposure in drug- and injection-naïve rats are distinct from those previously reported after repeated cocaine administration. They further suggest that cocaine exerts these effects by influencing neuronal circuits rather than simply stimulating NAc DA transmission.

Eating high-fat chow increases the sensitivity of rats to quinpirole-induced discriminative stimulus effects and yawning

Discriminative stimulus effects of direct acting dopamine receptor agonists (e.g. quinpirole) appear to be mediated by D3 receptors in free-feeding rats. Free access to high-fat chow increases sensitivity to quinpirole-induced yawning, and this study examined whether eating high-fat chow increases sensitivity to the discriminative stimulus effects of quinpirole. Five rats discriminated between 0.032 mg/kg quinpirole and vehicle while responding under a continuous reinforcement schedule of stimulus shock termination. When rats had free access to high-fat chow (discrimination training was suspended), the quinpirole discrimination dose-response curve shifted leftward, possibly indicating enhanced sensitivity at D3 receptors. In the same rats, both the ascending (mediated by D3 receptors) and descending (mediated by D2 receptors) limbs of the dose-response curve for quinpirole-induced yawning shifted leftward. When rats had free access to a standard chow (discrimination training was suspended), the quinpirole discrimination and yawning dose-response curves did not change. Together with published data showing that the discriminative stimulus effects of quinpirole in free-feeding rats are mediated by D3 receptors and the insensitivity of this effect of quinpirole to food restriction (shown to increase sensitivity to D2 but not D3-mediated effects), these results suggest that the leftward shift of the discrimination dose-response curve when rats eat high-fat chow is likely because of enhanced sensitivity at D3 receptors. Thus, eating high-fat food enhances drug effects in a manner that might impact clinical effects of drugs or vulnerability to drug abuse.

The ‘magic’ of l-dopa: why is it the gold standard Parkinson's disease therapy?

The chronic treatment of Parkinson's disease with L-dopa is often associated with fluctuations of motor response and dyskinesias. Therefore, to overcome the adverse effects of the long-term use of L-dopa, directly acting dopamine receptor agonists have been introduced. However, L-dopa remains the most effective treatment of the slowness of movement, increased muscle tone, and tremor that are typical of Parkinson's disease. Why is this so? In this article, we discuss evidence that suggests that dopamine produced from L-dopa has a larger number of actions compared with dopamine receptor agonists. In addition to stimulating D1- and D2-like dopamine receptors, dopamine might also activate adrenoceptors, novel dopamine sites, the dopamine transporter and trace amine receptors, all of which might contribute to the superior effect of L-dopa in Parkinson's disease.

Nucleus accumbens dopamine and discriminated approach learning: interactive effects of 6-hydroxydopamine lesions and systemic apomorphine administration.

Although dopaminergic mechanisms have been implicated in incentive motivational processes, their role in appetitive conditioning remains poorly understood. To investigate the effects of dopamine (DA) depleting lesions of the nucleus accumbens and the direct acting dopamine receptor agonist apomorphine on the learning of discriminated appetitive approach behavior in a Pavlovian autoshaping paradigm. Rats received bilateral infusions of either phosphate-buffered saline (shams) or 6-hydroxydopamine (lesions) directly into the nucleus accumbens. Ten days later, rats were trained on an autoshaping task whereby a previously neutral light stimulus was paired with food reward. Presentation of another stimulus (CS-) was never followed by reward. Over 100 pairings subjects developed a conditioned response of approaching the reward-predictive stimulus (CS+). Prior to each autoshaping session subjects were administered either saline (1 ml/kg SC) or apomorphine (30 microg/kg; 100 microg/kg), in a between-subjects design. Lesioned subjects showed a delay in the acquisition of discriminated approach and were insensitive to a subsequent change in the contingency of the task whereby approaches to the CS+ now prevented food delivery. Low dose apomorphine profoundly impaired learning in both sham and lesioned subjects. Despite increasing the overall number of CS+ and CS- approaches, the higher dose of apomorphine allowed discriminated approach in sham-operated animals only. These data are compatible with the hypothesis that nucleus accumbens dopamine serves to energize rather than guide conditioned approach to appetitive cues. They also support the notion that DA inputs in this region confer flexibility of approach to cues predictive of reward.

Potential of Adenosine A2A Receptor Antagonists in the Treatment of Movement Disorders

The current pharmacological treatment of Parkinson’s disease, based largely on levodopa and directly acting dopamine receptor agonists, remains unsatisfactory for many patients if long term treatment is required. An alternative strategy may be to reduce the activity of endogenous pathways that antagonise dopaminergic systems. One such pathway is the adenosine pathway. Adenosine receptors are present throughout the CNS, but with the A2A receptor subtype being highly localised to the basal ganglia, especially intrinsic cholinergic neurons and the enkephalin-containing γ-aminobutyric acid (GABA) striopallidal projection neurons. A subtype of A2A receptors may exist in extrastriatal areas. Agonists at these receptors increase neuronal excitability and facilitate neurotransmitter release, but they also interact with dopamine receptors to suppress the effects of dopamine. Conversely, A2A receptor antagonists in general stimulate locomotor behaviour in a wide variety of experimental paradigms and show related behavioural properties consistent with their preventing the activation of adenosine receptors by the endogenous agonist purine, thereby facilitating the activation of dopamine receptors. Preliminary studies in humans with nonselective adenosine receptor antagonists have indicated that this motor stimulant activity may extend to a reduction of the hypokinesia and tremor associated with Parkinson’s disease. The development of selective antagonists of A2A receptors, recently reported by several pharmaceutical companies, may therefore herald the advent of a new pharmacological approach to the treatment of Parkinson’s disease.

Hallucinosis in idiopathic Parkinson’s disease

BACKGROUNDHallucinosis is a complication of the treatment of idiopathic Parkinson’s disease commonly thought to afflict older, chronically medicated, cognitively impaired patients. However, patients with idiopathic Parkinson’s disease of short duration...

Modification of apomorphine-induced behaviour following chronic swim exercise in rats.

Four week swim exercise schedule (45 min day-1, 6 days each week) in rats led to a significant adaptive change in functional responsiveness of dopamine receptors (auto-receptors) in the nigrostriatal and mesolimbic system that was evident from the modification of behavioural responses elicited by a low dose of apomorphine, a direct acting dopamine receptor agonist. Thus, a remarkable increase in yawning response, development of full blown stereotypy, as well as profound attenuation of locomotory and hypothermic response was observed in exercise-trained rats as compared with the non-exercise group (control), following intraperitoneal administration of 0.3 mg kg-1 of apomorphine.

An introduction to the pharmacologic properties of Dopacard (dopexamine hydrochloride)

Dopexamine hydrochloride (Dopacard) has been developed as a peripherally acting dopamine receptor agonist with afterload reducing properties for use in the acute management of low cardiac output states. Dopexamine hydrochloride is one-third as potent as dopamine in stimulating DA1 receptors but 60 times as potent as a beta 2-adrenoceptor agonist. Unlike dopamine, it is a weak beta 1-adrenoceptor agonist and does not stimulate vascular alpha adrenoceptors. Its stimulant properties at vascular DA1 receptors and at vascular beta 2 adrenoceptors endow it with the ability to improve renal blood flow and to increase cardiac output secondary to afterload reduction. In addition, mild positive inotropic activity arises from stimulation of cardiac beta 2 adrenoceptors, potentiation of endogenous norepinephrine due to uptake-1 blockade, and activation of the baroreceptor reflex. Other features of dopexamine hydrochloride that should enhance its clinical use are lack of arrhythmogenicity and rapid responsiveness to alterations in infusion rate.

Clinical pharmacokinetics of anti-parkinsonian drugs.

Of the neurological disorders, none can claim a battery of therapeutic agents based upon as rational a pharmacology as can Parkinson's disease. In this review, the clinical pharmacokinetics of the major classes of anti-Parkinsonian drugs is discussed. Although they are the oldest drugs in the anti-Parkinsonian armamentarium, little pharmacokinetic data are available regarding the anticholinergic and antihistaminic agents. Based on elimination half-lives of 10 to 18 hours, most could probably be effectively given on a twice-daily schedule. Amantadine is unique among anti-Parkinsonian agents both in lacking a clearly defined mechanism of action and in being eliminated from the body exclusively by renal excretion of unchanged drug. Thus the normal decline of renal function in the elderly Parkinsonian population becomes an important factor in avoiding potential drug toxicity. The pharmacokinetics and pharmacodynamics of levodopa are complex. Since it is an amino acid, it follows metabolic pathways and must compete for absorption and brain uptake with a number of large neutral amino acids. It has a short elimination half-life and, as Parkinson's disease progresses, the brain loses its capacity to store the drug and becomes dependent in a moment-to-moment fashion on plasma levodopa concentrations, creating therapeutic response fluctuations in over 50% of patients. Pharmacokinetic considerations in the management of these response fluctuations are discussed. The newest class of anti-Parkinsonian agents are the direct acting dopamine receptor agonists. These drugs, all derivatives of ergot, have more prolonged durations of anti-Parkinsonian action than levodopa. However, other than bromocriptine, clinical experience with members of this class of drugs is still limited.

ChemInform Abstract: A Molecular Mechanics Approach to the Understanding of Presynaptic Selectivity for Centrally Acting Dopamine Receptor Agonists of the Phenylpiperidine Series.

ChemInformVolume 18, Issue 11 Other Subjects ChemInform Abstract: A Molecular Mechanics Approach to the Understanding of Presynaptic Selectivity for Centrally Acting Dopamine Receptor Agonists of the Phenylpiperidine Series. T. LILJEFORS, T. LILJEFORS Dep. Org. Chem., Chem. Center, Univ., 22100 Lund, SwedenSearch for more papers by this authorH. + WIKSTROEM, H. + WIKSTROEM Dep. Org. Chem., Chem. Center, Univ., 22100 Lund, SwedenSearch for more papers by this author T. LILJEFORS, T. LILJEFORS Dep. Org. Chem., Chem. Center, Univ., 22100 Lund, SwedenSearch for more papers by this authorH. + WIKSTROEM, H. + WIKSTROEM Dep. Org. Chem., Chem. Center, Univ., 22100 Lund, SwedenSearch for more papers by this author First published: March 17, 1987 https://doi.org/10.1002/chin.198711340AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume18, Issue11March 17, 1987 RelatedInformation

A molecular mechanics approach to the understanding of presynaptic selectivity for centrally acting dopamine receptor agonists of the phenylpiperidine series.

Molecular mechanics (MMP2) calculated geometries and conformational energies have been employed in an attempt to elucidate the molecular basis for presynaptic dopamine receptor selectivity of centrally acting agonists of the phenylpiperidine series. A receptor interaction model based on the McDermed receptor concept, on superimpositions of calculated structures, and on conformational analysis is presented. The model focuses on the interaction between N-alkyl substituents and the receptor. From comparisons with rigid structures having either agonistic or antagonistic properties it is concluded that the presynaptically selective compound (S)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [S)-3PPP) is acting as an agonist in one rotameric form and as an antagonist in another one. The selectivity of (S)-3PPP and the nonselectivity of its enantiomer are suggested to be due to differences in the interactions between N-alkyl substituents and the receptor. The receptor model presented led to the hypothesis that the piperidine ring in the compounds studied should be equivalent to a N-methyl group in its receptor interactions. Examples are given in support of this idea. Presynaptic selectivity was predicted for an aminotetralin derivative and was also observed in subsequent testing.

Bromocriptine potentiates the behavioural effects of directly and indirectly acting dopamine receptor agonists in mice.

After an initial period of depression which lasted up to 90 min following injection, bromocriptine (BRC, 5-20 mg/kg, IP) produced dose-dependent and long lasting (7 h) locomotor stimulation in mice. The locomotor stimulation was antagonised by reserpine, alpha-methyl-p-tyrosine (AMPT) or haloperidol. The blockade by AMPT of BRC's locomotor stimulant effect was reversed by prior treatment of the mice with a low, behaviourally inactive dose of L-Dopa plus benserazide. In mice pretreated with reserpine, BRC enhanced the stimulant action of d-amphetamine. Moreover, in mice pretreated with reserpine plus AMPT, BRC significantly enhanced the locomotor stimulant effect of apomorphine. This ability of BRC to enhance the effect of apomorphine commenced as soon as 20 min after BRC administration and lasted for at least 8 h. The dopamine (DA) uptake inhibitor and DA receptor agonist nomifensine potentiated and prolonged the stimulant effect of BRC while inhibitors of the neuronal uptake of noradrenaline (desipramine) and 5-hydroxytryptamine (fluoxetine) were without marked effect. The results clearly show that BRC, in behavioural terms, has no efficacy per se at the postsynaptic DA receptor and that it requires either DA or the administration of an exogenous agonist such as apomorphine for the expression of its effects.

ADTN — a potent dopamine receptor agonist

In tccent years then: has been considerable interest in the development of potent and selective dopamine receptor agonists. Drugs which stimulate post-synaptic dopamine receptors in the striatum have proved to be remarkably effective in the treatment of Parkinson’s disease. In addii tion to the post-synaptic dopamine recep tots, there is also evidence for the presence in the CNS of dopamine autoreceptors. either located on dopaminecontaining terminals (axon terminal autoreceptor) or located on the soma or dendrites of dopaminecontaining neurones. Drugs acting as selective agonists at dopamine auto receptors, either axon terminal or soma dendritic, would be expected to inhibit the release of dopamine. Such drugs might be of potential value as antLpsychotic drugs. In the pituitary. dopamine receptors appear to be involved in regulating the release of certain hormones, for example pmlactin secretion is inhibited by dopamme receptor agonists. Such drugs may therefore be useful in the treatment of certain endocrinological disorders such as hyperpmlactinaemia. Dopamine receptor agonists may also be of value for their peripheral catdio~vascular and renal actions, for example in the treatment of congestive heart failure and shock. The demonstration that there are present on sympathetic nerve terminals presynaptic dopamine receptors, the activation of which leads to inhibition of notadrenaline release, has led to the realization that peripherally acting dopamine receptor agonists might also be of value as antihypertensive drugs. Thus, there is considerable interest in the development of potent and selective dopamine receptor agonists. The present article is concerned with the actions of ADTN (2 amino 6.7 dihydmxy I .2.3.4 tetrdhydronaphthalener). one of the most potent knowa dopamine receptor agonists. The dopamine molecule is. a flexible structure which can adopt a number of different conformations. The kquinoline norsalsolinol and 6,7 and S,Sdihydmxy derivatives of 2-aminotetralin contain the dopamine skeleton in a fixed semi-rigid structure. These compounds have been used in an attempt to obtain informati ,n about the active conformation of dopaminc when is acting at it receptor’ z. Thus. norsalsolinol correspon& to the folded form of dopamine in which the phenol group iscir to the amino group. ADTN errresponds to an extended, rrons . confomra tion @-mtamer) whereas 2 amino 5.6 dihydroxy 1.2.3.4 tetrahydio naphthalene corresponds to the extended form (a-mtamer) (Pig. I ). The molecult of ADTN contains an asymetric carbon aerm and thusexhibits stereoisomerism. The two enantiomers have recently been resolved by Dr John McDermed and his colleagues’ aho have shown that (+ )_ADTN HBr has the R absolute contiguration. A number of methods are available for evaluating the activity of dopamine recep tor agonists. In a few cases, the tests are direct and consist of comparing the physiological response evoked by dopamine with that evoked by thr corn pound under test. Examples of tests in this category ate studies in which dopamine has been shown to act on receptors on inverts brate neumnes. on neurones in the nummalian CNS andh viva orin vitro studies on the peripheral vasculatulr. Care has to be taken, even in these socalled duect measurements. to ensure that the corn pound und::r study is not acting indirectly by releasing an endogenous substance cr by activating some other receptor system. Other less direct tests have also been used to

Dopamine receptor alteration in schizophrenia: neuroendocrine evidence.

Growth hormone (hGH) responses to centrally acting dopamine agonists were used as indices of CNS dopaminergic function in order to test hypotheses implicating dopaminergic alteration in the etiopathology of schizophrenia. Apomorphine, a direct acting dopamine receptor agonist, and L-Dopa, an indirect agonist dependent upon presynaptic conversion to dopamine for its action, both elicited elevations in plasma hGH in most young male schizophrenic- and control-subjects. A highly significant difference was seen between the distribution of hGH responses to apomorphine for schizophrenics and that for controls. Unusually high hGH response to apomorphine was seen in schizophrenics who subsequently failed to respond to neuroleptic therapy; intermediate hGH response was seen in controls; and low hGH response was seen in subsequent neuroleptic responders; differences in hGH response were statistically significant for all intergroup comparisons. No such differences were seen between responses of individuals to L-Dopa and to apomorphine. The findings suggest that the variability of hGH response to apomorphine is a reflection of dopamine receptor sensitivity, and that this variability may be an index of non-endocrine related dopaminergic sensitivity. They are consistent with hypotheses relating schizophrenia to alteration in dopamine receptors, although the type of receptor and the direction of alteration may be complex.