Dopamine D1 receptor agonists induce penile erections in rats

The dopamine receptor agonist apomorphine has been recently introduced in the treatment of erectile dysfunction. While it is well established that dopamine D2-like receptors play a crucial role in this effect, conflicting result are reported in the literature as for the role of dopamine D1-like receptors. The aim of this study was to determine the effect of systemic administration of dopamine D1-like receptor agonists on penile erection in rats. Male Wistar rats were treated with three different, and not structurally related, dopamine D1-like receptor agonists: the partial agonists SKF38393 ((+) 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine) and CY 208-243 ((-)-4,6,6a,7,8,12b-exahydro-7-methylindole [4,3-ab]fenantridine), and the full agonist A 77636 ((-)-(1R,3S)-3-Adamantyl-1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran hydrochloride). All three compounds dose-dependently increased the number of penile erections, with the full agonist A77636 showing a more pronounced effect with respect to the other two. Moreover, the dopamine D1-like receptor antagonist SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) dose-dependently antagonised A77636 effect. These results show that systemic administration of dopamine D1-like receptor agonists induce penile erection in rats. This observation suggests that dopamine D1-like receptor agonists might be considered as a possible alternative to apomorphine in the treatment of erectile dysfunction, thus avoiding the typical side effects related to the stimulation of dopamine D2-like receptors such as nausea.     

Multiple cytochrome P450 enzymes responsible for the oxidative metabolism of the substituted (S)-3-phenylpiperidine, (S,S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride, in human liver microsomes.

(S,S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride [(-)-OSU6162] is a weak dopamine D2 receptor modulator that possesses potential for the treatment of levodopa (L-DOPA)-induced dyskinesias in patients with Parkinson's disease. In this report, incubations with human liver microsomes revealed that (-)-OSU6162 is selectively metabolized via N-dealkylation to yield N-depropyl (-)-OSU6162. Kinetics evidence is presented that the N-depropylation of (-)-OSU6162 in human hepatic microsomes is mediated by multiple cytochrome p450 (p450) enzymes, in particular CYP2D6. This hypothesis is borne out by several lines of in vitro evidence; 1). incubations of (-)-OSU6162 (5 micro M) with hepatic microsomes from a panel of human donors showed that (-)-OSU6162 N-depropylase activity correlated well with CYP2D6-catalyzed dextromethorphan O-demethylase activity but not with other p450 enzyme-specific activities; 2). quinidine, a CYP2D6-specific inhibitor, inhibited (-)-OSU6162 N-depropylation, whereas other p450 enzyme-specific substrates/inhibitors did not significantly inhibit this activity; 3). CYP2D6 possessed highest intrinsic (-)-OSU6162 N-depropylase activity when compared with a battery of recombinant heterologously expressed human p450 enzymes. In addition, the selectivity of (-)-OSU6162 to inhibit six human p450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2E1, CYP2D6 and CYP3A4) was evaluated using an in vitro inhibition screen. Of the enzymes examined, only the activity of CYP2D6 was inhibited by coincubation with (-)-OSU6162. Thus, it is concluded that (-)-OSU6162 is metabolized by several p450 enzymes and that CYP2D6 accounts for the majority of the observed p450 N-depropylase activity in vitro.     

Effects of acute and repeated treatment with a novel dopamine D2 receptor ligand on L-DOPA-induced dyskinesias in MPTP monkeys

(S)-(-)-3-(3-(methylsulfonyl)phenyl)-1-propylpiperidine ((-)-OSU6162) is a phenylpiperidine derivative which exhibits low affinity to the dopamine D2 receptor in vitro. However, in vivo, positron emission tomography scanning studies show that the compound displaces the selective dopamine D2 receptor antagonist, raclopride. We have evaluated, in this study, the effect of (-)-OSU6162, on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in a primate model of Parkinson's disease. Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-DOPA were used in this study. The monkeys were housed in observation cages equipped with an electronic motility monitoring system. They were injected subcutaneously (s.c.) with L-DOPA methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-DOPA/benserazide) alone or in combination with (-)-OSU6162 (1.0, 3.0, 6.0 or 10 mg/kg, s.c.). Subcutaneous injection of sterile saline was used as control. L-DOPA/benserazide increased locomotion and improved parkinsonism but also induced dyskinesias. Co-administration of (-)-OSU6162 with L-DOPA/benserazide produced a significant reduction in L-DOPA-induced dyskinesias. This improvement in L-DOPA-induced dyskinesias occurred mainly at the onset of the L-DOPA/benserazide effect as reflected by an increase in the duration of the "ON" state without dyskinesias up to 3.4 fold after (-)-OSU6162 co-administration as compared to L-DOPA/benserazide alone. The anti-dyskinetic effect of (-)-OSU6162 was maintained during 14 days and no tolerance to this effect was observed. Our data suggests that (-)-OSU6162 could be of significant clinical value to reduce L-DOPA-induced dyskinesias in fluctuating advanced Parkinson's disease patients.     

Effects of the substituted (S)-3-phenylpiperidine (-)-OSU6162 on PET measurements of [11C]SCH23390 and [11C]raclopride binding in primate brains

The substituted (S)-3-phenylpiperidine (-)-OSU6162 belongs to a novel class of functional modulators of dopaminergic systems. In vivo, (-)-OSU6162 has a unique stabilising profile on dopaminergic functions. In vitro this compound exhibits low affinity for the dopamine D2 receptor, but due to its similarity to neuroleptics on brain dopaminergic neurochemistry and different postsynaptic effects it has been characterised as a preferential dopamine autoreceptor antagonist. To further clarify the effects of (-)-OSU6162 on the postjunctional nigrostriatal dopaminergic system, dopamine receptor binding was measured in rhesus monkeys (Macaca mulatta) by positron emission tomography (PET) using the D1 and D2 dopamine receptor radioligands [11C]SCH23390 and [11C]raclopride respectively, before and during continuous intravenous infusions of(-)-OSU6162. Additionally, the test-retest variability of sequential [11C]SCH23390 scans was estimated. Following the administration of (-)-OSU6162, [11C]raclopride binding in striatum was dose-dependently decreased with a 76% reduction occurring after 3.0 mg/kg per h continuous infusion. Whereas (-)-OSU6162 in the lower doses had no effect on [11C]SCH23390 binding, the highest dose, 3.0 mg/kg per h, increased [11C]SCH23390 binding, which may indicate a potentiating effect on D1 dopamine receptor mediated functions. Thus, in contrast to the conditions in vitro, (-)-OSU6162 produces a high displacement of raclopride from D2 receptors in vivo.     

Dopamine partial agonist action of (-)OSU6162 is consistent with dopamine hyperactivity in psychosis

Although the Van Rossum hypothesis of dopamine receptor overactivity in schizophrenia is supported by the antagonism of, or reduced dopamine neurotransmission at, dopamine D2 receptors by antipsychotics, it has been claimed that the antipsychotic (-)-OSU6162 has a very low affinity for the dopamine D2 receptor, and has only autoreceptor dopamine D2 receptor-stimulating action, and, therefore, in order to explain its clinical action, the drug must stimulate dopamine D2 receptors that are defective or underactive in schizophrenia. Because the mode of action of (-)-OSU6162 is critical in determining whether psychosis is associated with dopamine D2 receptor overactivity or deficit activity, we measured the potency of (-)-OSU6162 on the binding of [3H]domperidone and on the incorporation of [35S]-GTP-gamma-S into human cloned dopamine D2 receptor-containing cells. We found that (-)-OSU6162 had a dissociation constant of 35 nM at the functional high-affinity site of the dopamine D2 receptor, stimulated the incorporation of [35S]-GTP-gamma-S above 100 nM, and inhibited the incorporating action of 1 microM dopamine with an inhibitory dissociation constant, Ki, of 27 nM, all being properties of a dopamine partial agonist. While not excluding the possibility that dopamine underactivity may exist in the mesocortical system in psychosis, the antipsychotic action of (-)-OSU6162 is consistent with dopamine overactivity in psychosis.     

Differential activation of adenylate cyclase and receptor internalization by novel dopamine D1 receptor agonists

Structurally dissimilar dopamine D(1) receptor agonists were compared with dopamine in their ability to activate adenylate cyclase and to internalize hemagglutinin-tagged human D(1) receptors in a stably transfected human embryonic kidney cell line. Thirteen dopamine D(1) receptor agonists were selected rationally from three different structural classes: rigid fused ring compounds [dihydrexidine, dinapsoline, dinoxyline, apomorphine, and (5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena[c]-phenanthrene-9,10-diol (A86929)]; isochromans [(1R,3S)-3-(1'adamantyl)-1-aminomethyl-3,4-dihydo-5,6-dihydroxy-1H-2-benzopyran (A77636) and (1R,3S)-3-phenyl-1-aminomethyl-3,4-dihydo-5,6-dihydroxy-1H-2-benzopyran (A68930)]; and benzazepines [7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF38393), (+/-)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF77434), 6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF82958), 3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-]H-3-benzazepine (SKF83959), R(+)-6-chloro-7,8,-dihydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF82957), and R(+)-6-chloro-7,8,-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF81297)]. The working hypothesis was that some agonists have differential effects on adenylate cyclase versus receptor internalization that could be correlated to the structural class of the agonist. First, the affinity for the hemagglutinin-hD(1) receptor and the intrinsic activity and potency of adenylate cyclase activation were determined for each compound. The internalization time course and internalization efficacy were then determined for each agonist. It was surprising that internalization efficacy was found to be independent of either agonist structural class or affinity. Only agonists that had both high adenylate cyclase functional potency and high intrinsic activity caused internalization. In addition, four agonists from two structural classes were identified that were capable of fully activating adenylate cyclase without eliciting an internalization response. This study provides the first extensive characterization of D(1) receptor internalization in response to structurally diverse agonists and, at least for the D(1) receptor, shows that functional selectivity is not predictable by simple structural examination. These data are consistent with the hypothesis that functional selectivity reflects subtle ligand-induced conformational changes as opposed to simple agonist trafficking among discrete receptor active states.     

Effects of the dopamine stabilizers (<Emphasis Type="Italic">S</Emphasis>)-(-)-OSU6162 and ACR16 on prolactin secretion in drug-naive and monoamine-depleted rats

Dopaminergic stabilizers may be conceptualized as drugs with normalizing effects on dopamine-mediated behaviours and neurochemical events. (S)-(-)-OSU6162 (OSU6162) and ACR16 are two structurally related compounds ascribed such properties, principally because of their stabilizing effects on motor activity in rodents. Reports in the literature indicate possible partial D2 receptor agonist effects using various in vitro systems. This study aimed to measure D2 receptor antagonist and agonist effects of OSU6162 and ACR16 in vivo. To address this, we have studied the effects of both compounds on prolactin secretion in drug-naive and dopamine-depleted rats; dopamine depletion was induced by pretreatment with reserpine plus α-methyl-dl-p-tyrosine. We find that OSU6162 and ACR16 both stimulate prolactin secretion in drug-naive rats with OSU6162 being considerably more potent and efficacious. Both compounds show a non-significant trend towards reversal of the increased secretion caused by dopamine depletion, whereas the D2 receptor antagonist haloperidol further increased prolactin secretion. Thus, this study suggests that OSU6162 and ACR16 act as D2 receptor antagonists under normal conditions in vivo, possibly with minor agonist effects in a state of dopamine depletion.     

Effects of dopaminergic agents on carrageenan hyperalgesia after intrathecal administration to rats

The present study explored the role of dopaminergic transmission in spinal cord in a model of carrageenan-induced inflammatory pain by examining the effects of selective agonists and antagonists of dopamine receptors. The results were as follows: (1) trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g] quinoline hydrochloride (LY171555), a dopamine D(2) receptor agonist, produced anti-hyperalgesia (150 and 300 nmol) or hypoalgesia (300 nmol) in the inflamed hindpaws and non-inflamed hindpaws, respectively; spiperone hydrochloride (8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one hydrochloride), a dopamine D(2) receptor antagonist, decreased the pain threshold of non-inflamed hindpaws (300 nmol). (2) (+/-)-SKF38393 hydrochloride ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride), a dopamine D(1) receptor agonist, had no effect on either hindpaw, even at a higher dose (300 nmol); R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (R(+)-SCH23390 hydrochloride), a dopamine D(1) receptor antagonist, induced anti-hyperalgesia in the inflamed hindpaws (300 nmol). The present results suggest that the dopaminergic system in the spinal cord is involved in the central modulation of inflammatory hyperalgesia, and that the different effects are probably induced by different receptors.     

Threshold of dopamine content and D1 receptor stimulation necessary for the expression of rotational behavior induced by D2 receptor stimulation under normo and supersensitive conditions

We measured the minimum amount of endogenous dopamine (EDA), necessary for the expression of rotational behavior induced by D₂ receptor stimulation in striatal or medial forebrain bundle (MFB) lesioned rats. We correlated these results with the minimum dose of D₁ receptor agonists needed to substitute EDA in its permissive role for D₂ motor effects to take place. Rats with unilateral quinolinic acid (QA) striatal or 6-hydroxydopamine (6-OHDA) MFB lesions were given increasing doses of the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT) in combination with a fixed dose of the D₂ receptor agonist quinpirole (trans-(–)-4aR-4,4a,5,6,7,8,8a,9-Octahydro-5-propyl-1H-pyrazolo(3,4-g)quinoline hydrochloride) and tested for rotational behavior. The animals were later sacrificed and striata removed; EDA was measured by high performance liquid chromatography (HPLC). Rotational responses were abolished by increasing doses of AMPT inducing a stepwise depletion of EDA. EDA content and rotational behavior to D₂ stimulation showed a high degree of correlation. There was an abrupt reduction in rotational behavior at dopamine levels of 50–60% of controls in both animal models. In addition, striatal or MFB lesioned rats which were maximally depleted of dopamine by AMPT pretreatment received a fixed dose of quinpirole and then challenged with increasing doses of a D₁ receptor agonist SKF 38393 ((±)-1-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride). Rotational behavior was restored by SKF 38393 in both animal models in a dose-dependent fashion. Our results confirm the need for simultaneous D₁/D₂ stimulation in the generation of rotational behavior in both animal models. Moreover, they demonstrate the existence of a threshold level of D₁ stimulation necessary to exert its permissive role on D₂ mediated responses. Received: 21 May 1996 / Accepted: 16 September 1996     

Dopaminergic modulation of rat pup ultrasonic vocalizations.

The dopamine D(1) receptor agonist, R(+)-6-chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297), the dopamine D(2)/D(3) receptor agonist, trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3, 4-g]quinoline hydrochloride (quinpirole), and the dopamine D(3) receptor agonist, (+/-)-7-hydroxy-dipropylaminotetralin hydrobromide (7-OH-DPAT) all reduced the frequency of isolation-induced infant rat ultrasonic vocalizations and lowered body temperature when compared to saline-injected controls. Ultrasonic vocalization rate was not affected by either the dopamine D(1) receptor antagonist, R(+)-2,3,4, 5-tetrahydro-8-iodo-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hydrochloride (SCH 23390) or the dopamine D(2)/D(3) receptor antagonist, S(-)-raclopride-L-tartrate (raclopride) when given alone, nor did these antagonists block the ultrasonic vocalization reductions caused by the dopamine D(1) receptor agonist or the dopamine D(2)/D(3) receptor agonist. The dopamine D(2)/D(3) receptor antagonist but not the dopamine D(1) receptor antagonist blocked the dopamine D(3) receptor agonist's ultrasonic vocalization reduction. SKF 81297 reduced general activity while quinpirole and 7-OH-DPAT increased activity. Raclopride reversed quinpirole's reduction in body temperature, as well as 7-OH-DPAT's effects on body temperature, ultrasonic vocalizations, and activity. These results indicate that dopamine D(1), D(2)/D(3), and D(3) receptor agonists all reduce ultrasonic vocalizations by as yet undetermined mechanisms.     

Endomorphins 1 and 2 induce amnesia via selective modulation of dopamine receptors in mice

The involvement of dopamine receptors in the amnesic effects of the endogenous micro-opioid receptor agonists endomorphins 1 and 2 was investigated by observing step-down type passive avoidance learning in mice. Although the dopamine D1 receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol hydrochloride (R(+)-SKF38393) (0.05 and 0.1 mg/kg), the dopamine D1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (R(+)-SCH23390) (2.5 and 5 microg/kg) or the dopamine D2 receptor agonist N-n-phenethyl-N-propylethyl-p-(3-hydroxyphenyl)-ethylamine (RU24213) (0.3 and 1 mg/kg) had no significant effects on the endomorphin-1 (10 microg)- or endomorphin-2 (10 microg)-induced decrease in step-down latency of passive avoidance learning, (-)-sulpiride (10 mg/kg), a dopamine D2 receptor antagonist, significantly reversed the decrease in step-down latency evoked by endomorphin-2 (10 microg), but not by endomorphin-1 (10 microg). Taken together, it is likely that stimulation of dopamine D2 receptors results in the endomorphin-2-but not endomorphin-1-induced impairment of passive avoidance learning.     

Effects of dopaminergic agents on carrageenan hyperalgesia in rats

The present study explored the role of central dopaminergic transmission in a model of carrageenan-induced inflammatory pain by examining the effects of selective agonists and antagonists of dopamine receptors. The results were as follow: (1) LY171555 (trans-(-)-4aR-4,4a,5,6,7,8,8a,9-Octahydro-5-propyl-1H-pyrazolo[3, 4-g]quinoline hydrochloride), dopamine D(2) receptor agonist, produced anti-hyperalgesia or hypoalgesia in the inflamed hindpaws and non-inflamed hindpaws, respectively; spiperone hydrochloride (8-[4-(4-Fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4, 5]decan-4-one hydrochloride), dopamine D(2) receptor antagonist, decreased the pain threshold of the non-inflamed hindpaws. (2) (+/-)-SKF38393 hydrochloride ((+/-)-1-Phenyl-2,3,4, 5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride), dopamine D(1) receptor agonist, produced anti-hyperalgesia or hypoalgesia when administered in a high dose (600 nmol), and decreased the pain threshold of non-inflamed hindpaws when administered in a low dose (150 nmol); R(+)-SCH23390 hydrochloride (R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride), dopamine D(1) receptor antagonist, induced anti-hyperalgesia or hypoalgesia, respectively. The present study suggests that the dopaminergic system is involved in the central modulation of inflammatory hyperalgesia, and that the different effects are probably induced by the different receptors.     

Effect of the D1 receptor agonist SKF 38393 on some behavioural effects of apomorphine in rats

Summary The dopamine receptor agonist apomorphine in experiments on rats in low doses (0.025–0.2 mg/kg, s.c.) induced yawning which reflected a selective activation of presynaptic dopamine receptors. In high doses (0.25–1.0 mg/kg) apomorphine induced stereotyped sniffing and yawning in consequence of postsynaptic D 2 receptor activation. Dopamine D 1 receptor agonist SKF 38393 inhibited yawning induced by low doses of apomorphine. The inhibitory effect of SKF 38393 on apomorphine-induced yawning was attenuated by pretreatment with specific D I receptor antagonist SCH 23390 [2-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1 H-3-benzazepine-7-ol]. On the other hand however, SKF 38393 potentiated sniffing induced by the high doses of apomorphine without affecting gnawing. These data indicate that D 1 receptor activation modulates both pre- and postsynaptic effects of apomorphine in opposite directions.     

The Dopamine Stabilizer (?)-OSU6162 Occupies a Subpopulation of Striatal Dopamine D2/D3 Receptors: An [11C]Raclopride PET Study in Healthy Human Subjects

(−)-OSU6162 is a dopamine stabilizer that can counteract both hyperdopaminergic and hypodopaminergic states. In this study, D2/D3 receptor occupancy of (−)-OSU6162 in the human brain was investigated using positron emission tomography (PET). Twelve male healthy volunteers underwent [¹¹C]raclopride PET scanning before and 1 h after a single oral dose of (−)-OSU6162 (15–90 mg). Blood samples for determination of (−)-OSU6162 and prolactin plasma levels were collected at T_max. Parametric images of [¹¹C]raclopride binding potential relative to nondisplaceable tissue (cerebellar grey matter) uptake (BP_ND) at baseline and after (−)-OSU6162 administration were generated using the simplified reference tissue model. MRI-based regions of interest were defined for the striatum, composed of caudate nucleus and putamen, and projected onto the co-registered parametric [¹¹C]raclopride BP_ND image. Furthermore, three striatal subregions, ie, anterior dorsal caudate, anterior dorsal putamen, and ventral striatum, were defined manually and additionally analyzed. Plasma concentrations of (−)-OSU6162, ranging from 0.01 to 0.9 μM, showed a linear relationship with prolactin levels, reflecting blockade of pituitary D2 receptors. A concentration-dependent increase in striatal D2/D3 receptor occupancy was observed, reaching a value of about 20% at an (−)-OSU6162 plasma level of 0.2 μM, and which for higher concentrations leveled off to a maximal occupancy of about 40%. Findings were similar in the striatal subregions. The present data corroborate the notion that (−)-OSU6162 binds preferentially to a subpopulation of D2/D3 receptors, possibly predominantly extrasynaptic, and this may form the basis for the dopamine-stabilizing properties of (−)-OSU6162.     

Adenosine A(2A) receptor antagonists KF17837 and KW-6002 potentiate rotation induced by dopaminergic drugs in hemi-Parkinsonian rats

The effects of novel adenosine A(2A) receptor antagonists KF17837 ((E)-1,3-dipropyl-8-(3,4-dimethoxystyryl)-7-methyl-3, 7-dihydro-1H-purine-2,6-dione) and KW-6002 ((E)-1,3-diethyl-8-(3, 4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione), on rotational behavior induced by apomorphine or L-DOPA (L-3, 4-dihydroxyphenylalanine) were investigated in rats with unilateral 6-hydroxydopamine lesions. Both KF17837 and KW-6002 slightly induced rotational behavior per se. However, KF17837 and KW-6002 significantly increased the total counts of turning induced by apomorphine at doses of 3 mg/kg, p.o. and 10 mg/kg, p.o., and at doses of 1 mg/kg, p.o. and higher, respectively. KF17837 and KW-6002 also potentiated the rotational behavior induced by L-DOPA at a dose of 3 mg/kg, p.o. Furthermore, i.c.v. injection (10 microg/20 microl) of a selective adenosine A(2) receptor agonist CGS 21680 [2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoaden osine] partially prevented the rotational behavior induced by apomorphine and this inhibition was reversed by KW-6002 (1 mg/kg, p.o.).The increase in total counts of apomorphine-induced turning by the adenosine A(2A) receptor antagonists seems to be mainly attributable to prolongation of turning duration rather than enhancement of intensity. These results suggest that these adenosine A(2A) receptor antagonists may be useful to ameliorate shortening in the duration of dopaminergic drug response in patients with advanced Parkinson's disease.     

Dopamine receptors in human platelets

The expression of dopamine receptors by human platelets was investigated by Western blot analysis and immunocytochemical techniques using antibodies raised against dopamine D1-D5 receptor protein. The influence of dopamine D1-like and D2-like receptor agonists on adrenaline-induced platelet aggregation was also investigated. Western blot analysis revealed that platelet membranes bind anti-dopamine D3 or D5 receptor protein antibodies, but not anti-D1, D2 or D4 receptor protein antibodies. Cytospin centrifuged human platelets exposed to anti-dopamine D3 or D5 receptor protein antibodies developed a specific immune staining, whereas no positive staining was noticeable in platelets exposed to other antibodies tested. Both the D1-like receptor agonist 1-phenyl2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF 38393) and the D2-like receptor agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) dose-dependently inhibited adrenaline-induced platelet aggregation. These effects were decreased respectively by the D-like and D2-like receptor antagonists R(+)-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hydrochloride (SCH 23390) and (-)sulpiride. The above findings indicate that human platelets express dopamine D3 and D5 receptors probably involved in the regulation of platelet function.     

The effects of dopamine and dopamine agonists on the release of 3H-GABA and 3H-5HT from rat nigral slices

Only high micromolar concentrations of dopamine and dopamine agonists altered spontaneous and KCl-evoked release of 3H-GABA and 3H-5HT from rat nigral slices in vitro. Apomorphine (100 microM) and dopamine (100 microM) enhanced the spontaneous release of 3H-5HT but the effect of dopamine was not reversed by haloperidol (1 microM). Both apomorphine (100 microM) and dopamine (100 microM) enhanced the KCl-evoked release of 3H-5HT but these effects were not reversed by haloperidol (1 microM). Apomorphine (10-250 microM) and dopamine (10-250 microM) inhibited 3H-5HT uptake into nigral synaptosomal preparations in a concentration-dependent manner. Accordingly, a major portion of the apparent effect of these drugs on 3H-5HT release may be due to inhibition of 3H-5HT uptake. Dopamine (100 and 1000 microM), amphetamine (100 microM), apomorphine (100 microM) and 2-amino-6,7-dihydroxytetralin (ADTN; 100 microM) were without effect on the spontaneous release of 3H-GABA from nigral slices. Apomorphine (100 microM) and ADTN (100 microM) reduced the KCl-evoked release of 3H-GABA from substantia nigra, an effect antagonized by haloperidol (1 microM). However, amphetamine (100 microM) and dopamine (100-1000 microM) were without effect on KCl-evoked 3H-GABA release. These results suggest that only high concentration of some dopamine agonists can modulate 3H-5HT and 3H-GABA release in substantia nigra. However, dopamine either had no effect, or its actions were not reversed by dopamine receptor blockade, so it appears unlikely that dendritic dopamine release will influence GABA and 5HT release in substantia nigra.     

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

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

The role of dopaminergic systems in gamma-hydroxybutyrate-induced electrocorticogram hypersynchronization in the rat.

The effects of dopaminergic agonists and antagonists on the duration of hypersynchronization induced in the electrocorticogram (ecog) by gamma-hydroxybutyrate (gamma-HB) were tested in rats. Apomorphine (0-2-8 mg kg-1), piribedil (2-5-10 mg kt-1) and haloperidol (0-5-1 mg kg-1) had no influence on the duration of the hypersynchrony. Amphetamine (1-5-6 mg kg-1) inhibited the hypersynchrony, while (3,4-dihydroxyphenylamino)-2-imidazoline (DPI; 5, but not 1, mg kg-1) prolonged its duration. The lack of effect of the dopamine receptor agonists apomorphine and piribedil, and the dopamine receptor blocker haloperidol, on the gamma-HB-induced hypersynchrony might indicate that the inhibition of the impulse flow in the nigrostriatal dopamine system by gamma-HB is not involved in the generation of the hypersynchrony. DPI is thought to be an agonist at a dopamine receptor not sensitive to apomorphine, and its facilitatory effect on gamam-HB-hypersynchrony can be interpreted in terms of a possible involvement of another dopamine system in the ecog hypersynchrony induced by gamma-HB. The antagonism of gamma-HB by amphetamine is possibly due to an indirect stimulatory effect on noradrenergic receptors.     

The effects of dopamine receptor agents on naloxone-induced jumping behaviour in morphine-dependent mice

In the present study, the effects of dopamine receptor agonists and antagonists on naloxone-induced jumping in morphine-dependent mice were examined. Mice were rendered dependent as described in the methods section. Naloxone was injected to elicit jumping (as withdrawal sign). The first group received dopamine receptor drugs before naloxone injection to test the effects of the drugs on the expression of jumping. Administration of the dopamine D1/D2 receptor agonist, apomorphine (0.25, 0.5 and 1 mg/kg), decreased jumping, but not diarrhoea, induced by naloxone. The effect of apomorphine on jumping was reduced by the dopamine D2 receptor antagonist, sulpiride. The dopamine D2 receptor agonist, quinpirole (0.1, 0.3 and 0.5 mg/kg), increased jumping, while it decreased diarrhoea in mice. Different doses of sulpiride did not alter jumping, but one dose of the drug (12.5 mg/kg) decreased jumping. Neither the dopamine D1 receptor agonist, SKF38393 (1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride; 8 and 16 mg/kg), nor the dopamine D1 receptor antagonist, SCH23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-benzazepine-7-ol maleate; 5, 10 and 25 mg/kg), altered jumping, but they decreased diarrhoea. The second group of animals received the drugs during the development of dependence. Administration of quinpirole (0.1, 0.3 and 0.5 mg/kg), but not bromocriptine (4, 8 and 16 mg/kg), apomorphine (0.25, 0.5, 1 and 2 mg/kg) or sulpiride (12.5, 25 and 50 mg/kg) decreased naloxone-induced jumping and diarrhoea. A dose of SKF38393 (8 mg/kg) decreased jumping, while both SKF38393 (4 and 16 mg/kg) and SCH23390 (5 and 10 microg/kg) increased diarrhoea. It is concluded that activation of both dopamine D1 and D2 receptors may suppress naloxone-induced jumping in morphine-dependent mice, and that stimulation of dopamine D1 receptors during development of morphine dependence may increase diarrhoea through peripheral mechanism.