Differential actions of dopamine agonists and antagonists on the γ-butyrolactone-induced increase in mouse brain dopamine

-Butyrolactone (GBL) increased the dopamine concentration in the forebrain of the mouse. Apomorphine dose-dependently antagonized the GBL effect, while piribedil was less effective. Haloperidol prevented the antagonism of GBL by apomorphine but pimozide was ineffective in blocking apomorphine. After chronic treatment with haloperidol or pimozide, there was no alteration of the maximum GBL-induced increase in dopamine nor was there any significant change in the antagonism by apomorphine, although a trend toward increased sensitivity to apomorphine was noted in the group withdrawn from haloperidol. These results suggest that in the mouse, haloperidol is a more effective antagonist of presynaptic dopamine autoreceptors than pimozide, while apomorphine is a better presynaptic agonist than piribedil.     

Do neuroleptics prevent the penetration of dopamine agonists into the brain?

A new, specific and highly sensitive method for the determination of apomorphine based on high performance liquid chromatography on a C18 reverse-phase column, coupled with electrochemical detection has been developed. The limit of detection of the assay is approximately 0.5 ng/sample (2 pmol). Haloperidol, cis-flupenthixol, metoclopramide and reserpine prevented the accumulation of apomorphine equally in "dopaminergic" as well as in "non-dopaminergic" brain areas. The non-neuroleptic trans-isomer of flupenthixol was without effect. Suppression of the accumulation of the dopamine agonist 6,7-ADTN (administered as the prodrug dibenzoyl-6,7-ADTN) was seen after combined treatment with haloperidol or reserpine, whereas cis- and trans-flupenthixol were without effect. The results imply that certain behavioural, biochemical and neuropharmacological studies, based on apomorphine in combination with other drugs, may need reinterpretation.     

Selective dopamine antagonist pretreatment on the antiparkinsonian effects of benzazepine D1 dopamine agonists in rodent and primate models of parkinson's disease — the differential effects of D1 dopamine antagonists in the primate

In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle, pretreatment with the D₁ DA antagonists, SCH 23390 (7-chloro-8-hydroxy-2,3,4,5-tetrahydro-3-methyl-1-phenyl-1H-3-benzazepine) and A66359 (1-[2-bromo-4, 5-dimethoxybenzyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4 tetrahydroisoquinoline), but not the D₂ DA antagonist raclopride inhibited the contralateral circling induced by the benzazepine D₁ DA agonists SKF 38393 (7-H, 3-H analogue of SCH 23390), SKF 80723 (7-H, 3-H, 6-Br analogue) and SKF 83959 (7-H, 6-Cl, 3-CH₃ analogue). In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated common marmosets, administration of SKF 80723 and SKF 83959 increased locomotor activity and reversed the motor disability. Grooming and oral activities were also increased. Pretreatment with SCH 23390 and A66359 inhibited all the behavioural changes induced by both D₁ DA agonists. In general, higher doses of A66359 and more especially SCH 23390 were needed to inhibit SKF 83959 and SKF 80723 induced increases in oral activity and grooming than locomotor activity. Raclopride pretreatment did not affect SKF 83959 and SKF 80723 induced oral activity and grooming, though it reduced the duration of the locomotor changes induced by the D₁ DA agonists. These findings demonstrate that the behavioural effects of benzazepine D₁ DA agonists in the 6-OHDA lesioned rat and MPTP-treated marmoset are mediated by D₁ DA receptor sites, although in the primate, stimulation of D₂ DA receptors by endogenous DA may be necessary in facilitating the antiparkinsonian effects of D₁ DA agonists. The differential sensitivities of locomotor/motor disability and oral/grooming behaviours to antagonism by D₁ DA antagonists may indicate the involvement of multiple D₁ DA receptor subtypes in mediating benzazepine D₁ DA agonist induced behaviours in the MPTP-treated marmoset.     

A double-blind, randomized, placebo-controlled study of the dopamine D₃ receptor antagonist ABT-925 in patients with acute schizophrenia

There is substantial preclinical and clinical evidence to suggest a potential role for the dopamine D? receptor in the treatment of schizophrenia. ABT-925 is a selective dopamine D? receptor antagonist with an approximately 100-fold higher in vitro affinity for dopamine D? versus D? receptors. This double-blind, randomized, placebo-controlled, escalating-dose, parallel-group study assessed the efficacy and safety of ABT-925 in the treatment of patients with acute exacerbation of schizophrenia. One hundred fifty-five patients were assessed over a 6-week double-blind treatment period (placebo: n = 48; ABT-925 50 mg once daily [QD]: n = 53; ABT-925 150 mg QD: n = 54). The primary efficacy measure was mean change from baseline to final evaluation on the Positive and Negative Syndrome Scale total score. Secondary measures of efficacy and pharmacokinetic parameters were also assessed. Safety assessments included adverse event monitoring, laboratory tests, vital signs, movement rating scales, and electrocardiogram measures. No statistically significant treatment effect was observed with ABT-925 50 mg QD or 150 mg QD compared with placebo on primary or secondary efficacy end points. Pharmacokinetic parameter estimates increased with dose in a linear fashion. ABT-925 50 mg QD and 150 mg QD were generally well tolerated, with adverse event profiles similar to that of placebo. Findings from a concurrent positron emission tomography study among healthy volunteers suggest that the ABT-925 doses used in this study may not have been sufficient to adequately occupy D? receptors, thereby underscoring the importance of pharmacodynamic markers, such as PET, in determining appropriate compound doses before embarking on studies in a target population.     

The GABAB antagonist,CGP 35348, antagonizes the effects of baclofen, γ-butyrolactone and HA 966 on rat striatal dopamine synthesis

Summary The effects of the new GABA_B antagonist, CGP 35348 (3-aminopropane-diethoxymethylphosphinic acid), on rat striatal dopamine synthesis and the increases thereof, caused by (–)-baclofen, -butyrolactone (GBL), and HA 966 (3-amino-l-hydroxypyrrolid-2-one), were investigated. CGP 35348 did not alter dopamine synthesis on its own up to the highest dose tested (500 mg/kg i.p.). However, it antagonized the increase elicited by 50 mg/kg s. c. (–)-baclofen at doses above 100 mg/kg i. p.; at 500 mg/kg i. p. this antagonism disappeared within about 6 h of interval between the administration of the compound and (–)-baclofen. CGP 35348 also clearly and significantly attenuated the effects of graded doses of GBL and HA 966 at 500 mg/kg i. p., but was unable to alter the responses elicited by 0.3 mg/kg i. p. haloperidol or 10 mg/kg i. p. tetrabenazine. This indicates that the compound did not generally attenuate increases of dopamine synthesis. It is likely that its GABA_B antagonistic properties are responsible for the attenuation of the effect of (–)-baclofen, and our results suggest that this compound is useful for the characterization of the role of GABAB receptors in vivo, e.g. in behaviour. On the other hand, they also suggest the possibility that GBL and HA 966 elicit their effects on dopamine synthesis by means of an interaction with GABA_B receptors; a weak in vitro interaction with the latter in radioligand binding experiments has been found for GBL, but not for HA 966.     

Comparison of the effects of haloperidol,remoxipride and raclopride on “pre”- and postsynaptic dopamine receptors in the rat brain

Summary The ability of the dopamine receptor antagonists haloperidol, raclopride and remoxipride to prevent the B-HT 920-induced decrease in striatal and limbic L-DOPA accumulation in gamma-butyrolactone (GBL)- and NSD 1015-treated rats (termed GBL-reversal) was used to define the effects of these compounds on presynaptic dopamine receptors. The doses of the dopamine antagonists producing antagonism of GBL-reversal were in each case roughly similar to the doses required to increase dopamine turnover in striatal and limbic areas. The potencies of haloperidol, raclopride and remoxipride in the GBL model were compared with their potencies in behavioural models for postsynaptic dopamine receptors. Haloperidol produced antagonism of GBL-reversal over a similar dose range to that required for antagonism of apomorphine-induced hyperactivity and stereotypy syndromes. Raclopride was effective in the order of potency: antagonism of apomorphine-induced hyperactivity > antagonism of GBL-reversal > antagonism of apomorphine-induced stereotypy. For remoxipride, the dose-response curve for antagonism of GBL-reversal was superimposable over that for antagonism of apomorphine-induced stereotypies, with an ED₅₀ value about 12 times higher than that for antagonism of apomorphine-induced hyperactivity. Thus, the relative potencies of dopamine receptor antagonists at pre- and postsynaptic dopamine receptors vary considerably from compound to compound. Send offprint requests to O. Magnusson     

The effect of the dopamine agonist pergolide on tyrosine hydroxylase activity in rat striatal and limbic miniprisms in vitro: A model for the dopamine autoreceptor?

Summary A method for the assay of tyrosine hydroxylase activity in rat striatal and limbic (nucleus accumbens + olfactory tubercle) brain miniprisms is described. The dopamine agonists apomorphine (1 mol/l) and pergolide (0.01–100 mol/l) inhibited the tyrosine hydroxylase activity in both regions. The inhibition produced by 1 mol/l pergolide was antagonised partially in striatal miniprisms and completely in limbic miniprisms by 1 mol/l haloperidol. The dopamine D₂-selective antagonist raclopride, at concentrations up to 300 nmol/l, did not antagonise the inhibition produced by pergolide in striatal miniprisms, but appeared partially to antagonise the inhibition in limbic miniprisms. It is concluded that whilst pergolide potently inhibits tyrosine hydroxylase activity in striatal and limbic miniprisms, the inhibition is of doubtful value as a predictive model of dopamine autoreceptor function in striatal miniprisms, but may be useful when limbic miniprisms are used.     

Rapid regulation of the dopamine transporter: role in stimulant addiction?

Dopamine (DA) and the DA transporter (DAT) play important roles in psychomotor stimulant behavioral activation and reward. By understanding how DAT activity is regulated, we will better appreciate its contribution to normal neurotransmission and to brain diseases like drug addiction. DAT is regulated long-term by chronic drug administration. It is also regulated in a rapid, dynamic fashion by many factors--including brief exposure to DAT substrates, e.g. DA and amphetamine, and inhibitors, e.g. cocaine. We found that individual differences in the initial and sensitized locomotor responsiveness of rats to cocaine reflect differences in in vivo DAT function. Our ex vivo studies have further suggested that differences in basal and/or rapid cocaine-induced expression of functional DATs in striatum contribute to the differences in initial responsiveness. Studies in model systems have demonstrated that short-term DAT regulation occurs by altered transporter trafficking, and thereby cell surface expression. For example, a rapid, complex regulation of DAT by DA is suggested. Amphetamine causes DAT internalization into early endosomal compartments whereas cocaine appears to up-regulate surface expression of DAT. Future studies are needed to confirm these observations in neurons, as well as to elucidate the mechanisms of rapid DAT endocytic trafficking at neuronal synapses.     

Effects of the histamine H₁ receptor antagonist and benztropine analog diphenylpyraline on dopamine uptake, locomotion and reward

Diphenylpyraline hydrochloride (DPP) is an internationally available antihistamine that produces therapeutic antiallergic effects by binding to histamine H? receptors. The complete neuropharmacological and behavioral profile of DPP, however, remains uncharacterized. Here we describe studies that suggest DPP may fit the profile of a potential agonist replacement medication for cocaine addiction. Aside from producing the desired histamine reducing effects, many antihistamines can also elicit psychomotor activation and reward, both of which are associated with increased dopamine concentrations in the nucleus accumbens (NAc). The primary aim of this study was to investigate the potential ability of DPP to inhibit the dopamine transporter, thereby leading to elevated dopamine concentrations in the NAc in a manner similar to cocaine and other psychostimulants. The psychomotor activating and rewarding effects of DPP were also investigated. For comparative purposes cocaine, a known dopamine transporter inhibitor, psychostimulant and drug of abuse, was used as a positive control. As predicted, both cocaine (15 mg/kg) and an equimolar dose of DPP (14 mg/kg) significantly inhibited dopamine uptake in the NAc in vivo and produced locomotor activation, although the time-course of pharmacological effects of the two drugs was different. In comparison to cocaine, DPP showed a prolonged effect on dopamine uptake and locomotion. Furthermore, cocaine, but not DPP, produced significant conditioned place preference, a measure of drug reward. The finding that DPP functions as a potent dopamine uptake inhibitor without producing significant rewarding effects suggests that DPP merits further study as a potential candidate as an agonist pharmacotherapy for cocaine addiction.     

Is dopamine neurotransmission altered in prodromal schizophrenia? A review of the evidence

It is known that early treatment improves the outcome in patients with schizophrenia. Treatment interventions prior to the onset of frank psychosis hold the promise of even better outcomes. Since schizophrenia typically has a year long prodromal phase before becoming clinically manifest, the field has made increasing efforts to define reliable criteria for subjects who are at high risk for psychosis (at-risk mental state, ARMS subjects). Still, no single test exists that would be sensitive and specific enough to justify individual treatment decisions in ARMS subjects. The most prominent theory on the pathogenesis of schizophrenia, the dopamine hypothesis, has undergone several modifications since its formulation more than half a century ago. Although there is nearly indisputable evidence for increased dopamine neurotransmission in schizophrenia, recent theories suggest that increased dopamine function is not causal, but can be seen as a final common pathway mediating psychosis in schizophrenia. Dopaminergic and glutamatergic neurons interact at striatal interneurons to control striatal output and information processing in fast glutamatergic networks. Both, glutamatergic and dopaminergic neurotransmission, are believed to be already altered in prodromal phases of schizophrenia. Results from neuroimaging studies indicate that dopamine transmission is altered before the outbreak of psychosis, and recent findings also suggest alterations in dopamine-glutamate coupling in ARMS subjects. Improved methods for imaging dopamine and glutamate function in the living brain have thus the potential to identify young people at ultra-high risk who would most likely benefit from early psychological and pharmacological interventions.     

Novel δ1-receptor agonist KNT-127 increases the release of dopamine and L-glutamate in the striatum, nucleus accumbens and median pre-frontal cortex

The effects of systemic δ1-agonist on neurotransmission remains obscure, since no selective δ1-agonist exists that can penetrate the blood-brain barrier. Recently, we succeeded in synthesizing a putative δ1-receptor agonist, KNT-127, which has been demonstrated the effectiveness of systemic administration against anxiety and depressive-like behavior. To clarify the functional selectivity of KNT-127 and neurotransmission regulating system of δ1-receptor, the present study investigated the interaction between KNT-127 and δ-receptor antagonists on the release of dopamine, L-glutamate and GABA in nucleus accumbens (NAc), striatum and median pre-frontal cortex (mPFC) using multi-probe microdialysis. Intraperitoneal administration of KNT-127 increased the release of dopamine and L-glutamate in three regions, but decreased and increased GABA releases in respective NAc and mPFC without affecting that in striatum. The effects of KNT-127 in the three regions were abrogated by δ1-antagonist but not by δ2-antagonist. MK801 inhibited KNT-127-induced dopamine release in striatum and NAc, but enhanced that in mPFC, inhibited KNT-127-induced mPFC GABA release without affecting KNT-127-induced GABA reduction in NAc. Muscimol enhanced KNT-127-induced dopamine release in mPFC. Sulpiride inhibited KNT-127-induced reduction of GABA release in NAc. The results indicated that KNT-127 is a selective δ1-agonist, and suggested that δ1-receptor directly activates the release of dopamine and L-glutamate in the striatum, NAc and mPFC, but not that of GABA in the three regions. δ1-receptor indirectly inhibited GABA release in NAc via activated dopaminergic transmission, while δ1-receptor indirectly enhanced GABA release in mPFC via activated glutamatergic transmission.     

Probing the steric space at the floor of the D1 dopamine receptor orthosteric binding domain: 7α-, 7β-, 8α-, and 8β-methyl substituted dihydrexidine analogues

To probe the space at the floor of the orthosteric ligand binding site in the dopamine D(1) receptor, four methylated analogues of dihydrexidine (DHX) were synthesized with substitutions at the 7 and 8 positions. The 8α-axial, 8β-equatorial, and 7α-equatorial were synthesized by photochemical cyclization of appropriately substituted N-benzoyl enamines, and the 7β-axial analogue was prepared by an intramolecular Henry reaction. All of the methylated analogues displayed losses in affinity when compared to DHX (20 nM): 8β-Me(ax)-DHX (270 nM), 8α-Me(eq)-DHX (920 nM), 7β-Me(eq)-DHX (6540 nM), and 7α-Me(ax)-DHX (>10000 nM). Molecular modeling studies suggest that although the disruption of an aromatic interaction between Phe203(5.47) and Phe288(6.51) is the cause for the 14-fold loss in affinity associated with 8β-axial substitution, unfavorable steric interactions with Ser107(3.36) result in the more dramatic decreases in binding affinity suffered by the rest of the analogues.     

Imaging the high-affinity state of the dopamine D2 receptor in vivo: Fact or fiction?

Positron Emission Tomography (PET) has been used for more than three decades to image and quantify dopamine D2 receptors (D2R) in vivo with antagonist radioligands but in the recent years agonist radioligands have also been employed. In vitro competition studies have demonstrated that agonists bind to both a high and a low-affinity state of the D2Rs, of which the high affinity state reflects receptors that are coupled to G-proteins and the low-affinity state reflects receptors uncoupled from G-proteins. In contrast, antagonists bind with uniform affinity to the total pool of receptors. Results of these studies led to the proposal that D2Rs exist in high and low-affinity states for agonists in vivo and sparked the development and use of agonist radioligands for PET imaging with the primary purpose of measuring the proportion of receptors in the high-affinity (activating) state. Although several lines of research support the presence of high and low-affinity states of D2Rs and their detection by in vivo imaging paradigms, a growing body of controversial data has now called this into question. These include both in vivo and ex vivo studies of anesthesia effects, rodent models with increased proportions of high-affinity state D2Rs as well as the molecular evidence for stable receptor-G-protein complexes. In this commentary we review these data and discuss the evidence for the in vivo existence of D2Rs configured in high and low-affinity states and whether or not the high-affinity state of the D2R can, in fact, be imaged in vivo with agonist radioligands.     

Advances in dopamine receptor agonists for the treatment of Parkinson’s disease

Introduction: Dopamine agonists (DA) are a class of agents which directly stimulate dopamine receptors mimicking the endogenous neurotransmitter dopamine. At first used as adjunctive therapy in the advanced phases of the disease, over the years a significant role was found for DA monotherapy as a first approach in the initial stage of Parkinson’s disease (PD). Several reviews have already reported efficacy and safety of DA in PD and differences between DA and levodopa. Therefore the objective of this review is to gather recent updates in DA therapy. A thorough knowledge of recent literature evidences, would help clinician in the management of treatment with DA.

Areas covered: Our review investigates recent updates on DA therapy, the role of these compounds in controlling non-motor symptoms (NMS) as well as new formulations under clinical evaluation and newly emerged post-marketing safety considerations. A literature search has been performed using Medline and reviewing the bibliographies of selected articles.

Expert opinion: DA represents a very important option in the treatment of PD, even though there are still some criticisms and unmet needs. A better knowledge of dopamine receptors could lead to identification of new compounds able to better balance clinical efficacy and side effects.     

ADHD and the dopamine transporter: are there reasons to pay attention?

The catecholamine dopamine (DA) plays an important role as a neurotransmitter in the brain in circuits linked to motor function, reward, and cognition. The presynaptic DA transporter (DAT) inactivates DA following release and provides a route for non-exocytotic DA release (efflux) triggered by amphetamines. The synaptic role of DATs first established through antagonist studies and more recently validated through mouse gene-knockout experiments, raises questions as to whether altered DAT structure or regulation support clinical disorders linked to compromised DA signaling, including drug abuse, schizophrenia, and attention deficit hyperactivity disorder (ADHD). As ADHD appears to have highly heritable components and the most commonly prescribed therapeutics for ADHD target DAT, studies ranging from brain imaging to genomic and genetic analyses have begun to probe the DAT gene and its protein for possible contributions to the disorder and/or its treatment. In this review, after a brief overview of ADHD prevalence and diagnostic criteria, we examine the rationale and experimental findings surrounding a role for human DAT in ADHD. Based on the available evidence from our lab and labs of workers in the field, we suggest that although a common variant within the human DAT (hDAT) gene (SLC6A3) is unlikely to play a major role in the ADHD, contributions of hDAT to risk maybe most evident in phenotypic subgroups. The in vitro and in vivo validation of functional variants, pursued for contributions to endophenotypes in a within family approach, may help elucidate DAT and DA contributions to ADHD and its treatment.     

Comparing the influence of dopamine D₂ polymorphisms and plasma drug concentrations on the clinical response to risperidone

Although several studies have reported that dopamine D? receptor (DRD2) polymorphisms affect the therapeutic efficacy of antipsychotics, other studies have suggested that the plasma drug concentration is related to the clinical response. Currently, there are no definitive data regarding which factor has greater clinical significance. Sixty patients with acute exacerbations of schizophrenia received 6 mg/d of risperidone for 4 weeks. Clinical evaluations using the Brief Psychiatric Rating Scale and the Udvalg for Klinicke Unders?gelser Side Effect Rating Scale were performed before and after administration of risperidone. TaqI A and -141C Ins/Del polymorphisms were determined, and the plasma concentrations of risperidone and 9-hydroxyrisperidone were measured. The TaqI A polymorphism had no effect on therapeutic efficacy, but the -141C Ins/Del polymorphism was associated with an improvement in positive symptoms. In addition, the plasma concentration of the active moiety (risperidone plus 9-hydroxyrisperidone) correlated with the improvement in the total Brief Psychiatric Rating Scale score as well as with positive symptoms. Although there were no associations between DRD2 polymorphisms and psychic adverse effects, the plasma drug concentration was associated with psychic adverse effects. These findings suggest that DRD2 polymorphisms are associated with the therapeutic effects of risperidone as they relate to positive symptoms and that plasma drug concentrations are associated with overall symptoms as well as excitement and cognitive symptoms. Both the genotyping of DRD2 and the monitoring of plasma drug concentrations may be useful for improving clinically dominant symptoms. Further work involving replication in a larger sample is required to support our findings.     

Human disposition,metabolism and excretion of etamicastat,a reversible,peripherally selective dopamine β-hydroxylase inhibitor

Aims

Etamicastat is a reversible dopamine-β-hydroxylase inhibitor that decreases noradrenaline levels in sympathetically innervated tissues and slows down sympathetic nervous system drive. In this study, the disposition, metabolism and excretion of etamicastat were evaluated following [¹⁴C]-etamicastat dosing.

Methods

Healthy Caucasian males (n = 4) were enrolled in this single-dose, open-label study. Subjects were administered 600 mg of unlabelled etamicastat and 98 µCi weighing 0.623 mg [¹⁴C]-etamicastat. Blood samples, urine and faeces were collected to characterize the disposition, excretion and metabolites of etamicastat.

Results

Eleven days after administration, 94.0% of the administered radioactivity had been excreted; 33.3 and 58.5% of the administered dose was found in the faeces and urine, respectively. Renal excretion of unchanged etamicastat and its N-acetylated metabolite (BIA 5-961) accounted for 20.0 and 10.7% of the dose, respectively. Etamicastat and BIA 5-961 accounted for most of the circulating radioactivity, with a BIA 5-961/etamicastat ratio that was highly variable both for the maximal plasma concentration (19.68–226.28%) and for the area under the plasma concentration–time curve from time zero to the last sampling time at which the concentration was above the limit of quantification (15.82– 281.71%). Alongside N-acetylation, metabolism of etamicastat also occurs through oxidative deamination of the aminoethyl moiety, alkyl oxidation, desulfation and glucuronidation.

Conclusions

Etamicastat is rapidly absorbed, primarily excreted via urine, and its biotransformation occurs mainly via N-acetylation (N-acetyltransferase type 2), although glucuronidation, oxidation, oxidative deamination and desulfation also take place.