Comparison of the functional potencies of ropinirole and other dopamine receptor agonists at human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells.

1. The aim of the present study was to characterize functional responses to ropinirole, its major metabolites in man (SKF-104557 (4-[2-(propylamino)ethyl]-2-(3H) indolone), SKF-97930 (4-carboxy-2-(3H) indolone)) and other dopamine receptor agonists at human dopamine D2(long) (hD2), D3 (hD3) and D4.4 (hD4) receptors separately expressed in Chinese hamster ovary cells using microphysiometry. 2. All the receptor agonists tested (ropinirole, SKF-104557, SKF-97930, bromocriptine, lisuride, pergolide, pramipexole, talipexole, dopamine) increased extracellular acidification rate in Chinese hamster ovary clones expressing the human D2, D3 or D4 receptor. The pEC50s of ropinirole at hD2, hD3 and hD4 receptors were 7.4, 8.4 and 6.8, respectively. Ropinirole is therefore at least 10 fold selective for the human dopamine D3 receptor over the other D2 receptor family members. 3. At the hD2 and hD3 dopamine receptors all the compounds tested were full agonists as compared to quinpirole. Talipexole and the ropinirole metabolite, SKF-104557, were partial agonists at the hD4 receptor. 4. Bromocriptine and lisuride had a slow onset of agonist action which precluded determination of EC50s. 5. The rank order of agonist potencies was dissimilar to the rank order of radioligand binding affinities at each of the dopamine receptor subtypes. Functional selectivities of the dopamine receptor agonists, as measured in the microphysiometer, were less than radioligand binding selectivities. 6. The results show that ropinirole is a full agonist at human D2, D3 and D4 dopamine receptors. SKF-104557 the major human metabolite of ropinirole, had similar radioligand binding affinities to, but lower functional potencies than, the parent compound.     

Identification and characterization of postsynaptic D1- and D2-dopamine receptors in the cardiovascular system

Measuring adenylate cyclase activity (AC) as a biochemical index of dopamine (DA) receptor function, we obtained evidence for the presence in rabbit vasculature of both D1 receptors associated with stimulation of AC and of D2 receptors coupled with AC in an inhibitory way. The cAMP generating system in rabbit mesenteric artery was stimulated by DA and several DA agonists, an effect antagonized by the D1-receptor blocker SCH 23390 and by other neuroleptic drugs. When activation of D1 sites was impeded by SCH 23390, DA, (-)apomorphine, and (-)NPA inhibited cAMP formation. In addition, selective D2 agonists inhibited basal AC activity even when there was no D1-receptor blockade. The relative order of potency of various neuroleptics in antagonizing bromocriptine-induced inhibition of AC confirmed the D2 nature of these binding sites. Inhibition of AC activity elicited by bromocriptine remained unchanged after chemical sympathectomy, suggesting that vascular D2 receptors inhibiting AC activity are located postsynaptically in the arterial wall.     

Dopamine D2/D3 receptors modulate cocaine's reinforcing and discriminative stimulus effects in rhesus monkeys

Numerous studies have suggested that dopamine (DA) D2 and D3 receptors are involved in the behavioral effects of cocaine. The present experiments evaluated the reinforcing and cocaine-like discriminative stimulus effects of several D2/D3 agonists in rhesus monkeys. In the first experiment, animals (n = 4) were trained to self-administer 0.03 mg/kg/inj cocaine under a fixed-interval (FI) 5-min schedule. When substituted for cocaine, the D2/D3 agonist quinpirole (0.003-0.03 mg/kg/inj) functioned as a reinforcer in all monkeys. In two cocaine-naive monkeys trained to respond under an FI 3-min schedule of food presentation, quinpirole maintained low rates of responding in one subject, while at the highest dose (0.03 mg/kg/inj) it functioned as a reinforcer in the second monkey. In this animal, increased activity was observed at this dose, which may have contributed to the overall rate of responding. In the second experiment, monkeys (n = 4) were trained to discriminate cocaine from saline using a two-lever, food-reinforced, drug discrimination procedure. The D2/D3 agonists quinpirole, (+/-)-7-OH-DPAT, and R-( + )-7-OH-DPAT fully substituted for cocaine. However, the time-course of substitution differed between quinpirole, which substituted for cocaine 10 min after administration, and (+/-)- and R-(+)-7-OH-DPAT, which required 60-min pretreatments. The behavioral potencies, as determined from ED50, values, correlated with previously reported in vitro binding affinity and functional activity at the D3 receptor [R-(+ )-7-OH-DPAT > (+/-)-7-OH-DPAT > quinpirole]. These results further indicate that direct-acting D2/D3 agonists can function as reinforcers and produce cocaine-like discriminative stimulus effects, and support the idea that D3 receptors should continue to be a valuable target for future behavioral studies evaluating cocaine's mechanisms of action.     

Role of dopamine D1 and D2 receptors in mediating the d-amphetamine discriminative cue.

The role of D1 and D2 dopamine (DA) receptors in mediating the discriminative cue produced by d-amphetamine (0.5 mg/kg) in rats has been assessed by using compounds which exert strong selectivity for each of these DA receptor subtypes. The D2 agonists quinpirole and RU 24213 substituted completely for d-amphetamine, while the D1 agonists SKF 38393 and SKF 81297 failed to exert such effects. On the other hand, the D2 antagonists raclopride and YM 09151-2, and D1 antagonists SCH 23390 and SKF 83566, all completely blocked d-amphetamine discrimination. The D2 antagonists produced more pronounced inhibitory effects on response rate than did D1 antagonists. Quinpirole substitution for d-amphetamine was blocked by YM 09151-2, but not by SCH 23390, while the locomotor stimulatory effect of quinpirole was inhibited by both drugs. The present findings confirm that D2 receptors play a primary role in the d-amphetamine discriminative cue, while the precise role of D1 receptors remains to be disclosed.     

Hypothermia in mice: D2 dopamine receptor mediation and absence of spare receptors

The nonselective dopamine (DA) receptor agonists R(-)apomorphine (APO) and R(-)-N-n-propylnorapomorphine (NPA) elicited dose- and time-dependent hypothermia in mice with ED50 values of 300 and 18 micrograms/kg, respectively. The selective D2 agonist quinpirole (LY 171555) also elicited dose-dependent hypothermia, whereas the selective D1 agonist SKF 38393 had no effect. The selective D1 and D2 antagonists SCH 23390 (1 mg/kg) and sulpiride (200 mg/kg), respectively, did not significantly alter body temperature. The hypothermic effect of a maximal dose of NPA (0.2 mg/kg) was not blocked by SCH 23390 (1 mg/kg) but was significantly attenuated (p less than 0.001) by pretreatment with sulpiride (200 mg/kg). Pretreatment with sulpiride (200 mg/kg) produced a parallel, 40-fold shift to the right of the dose-response curve for NPA. Partial, irreversible DA receptor inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (2 mg/kg) reduced the maximal hypothermic effect of NPA (to 49% of control) without altering its ED50. Analysis of the data indicated a linear relationship between DA receptor occupancy and hypothermic response. The results demonstrate that DA agonist-induced hypothermia in mice is mediated by D2 receptors and that there is no receptor reserved for this response.     

Mapping dopamine D2/D3 receptor function using pharmacological magnetic resonance imaging

Rationale Regulation of dopamine release and synthesis occurs via pre-synaptic dopamine (DA) D2/D3 autoreceptors (DARs). Mapping of DAR function in vivo is difficult and is usually best assessed using invasive measures of DA release, such as microdialysis at discrete sites. We wished to show that pharmacological magnetic resonance imaging (phMRI) may prove useful for this purpose. Objective To demonstrate that the relative cerebral blood volume (rCBV) changes induced by amphetamine can be modulated by DA D2 receptor antagonists and agonists in a manner consistent with modulation of DAR function and to compare these effects with microdialysis. Methods We used phMRI with iron oxide contrast agents to map changes in rCBV in response to an amphetamine challenge, pre-treatment and post-treatment with varying doses of the D2 antagonist eticlopride and the D2 agonist quinpirole. We also compared the effects of D2 antagonism using microdialysis measurements of DA release. Results Antagonism of D2 receptors with eticlopride potentiated rCBV changes induced by amphetamine in the nucleus accumbens and caudate putamen in a dose-dependent manner. The amphetamine-induced increase in rCBV in the accumbens in animals pre-treated with eticlopride was paralleled by a similar percentage increase in DA release measured by means of microdialysis. Conversely, agonism of D2 receptors using quinpirole reduced amphetamine-induced rCBV changes in the caudate putamen and nucleus accumbens. The effects of both quinpirole and eticlopride on amphetamine-induced rCBV changes were largest in the nucleus accumbens. Conclusions These results suggest that phMRI may potentially prove useful to map DAR function non-invasively in multiple brain regions simultaneously.     

Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function

The striatum contains a high density of histamine H(3) receptors, but their role in striatal function is poorly understood. Previous studies have demonstrated antagonistic interactions between striatal H(3) and dopamine D(1) receptors at the biochemical level, while contradictory results have been reported about interactions between striatal H(3) and dopamine D(2) receptors. In this study, by using reserpinized mice, we demonstrate the existence of behaviorally significant antagonistic postsynaptic interactions between H(3) and D(1) and also between H(3) and dopamine D(2) receptors. The selective H(3) receptor agonist imetit inhibited, while the H(3) receptor antagonist thioperamide potentiated locomotor activation induced by either the D(1) receptor agonist SKF 38393 or the D(2) receptor agonist quinpirole. High scores of locomotor activity were obtained with H(3) receptor blockade plus D(1) and D(2) receptor co-activation, i.e., when thioperamide was co-administered with both SKF 38393 and quinpirole. Radioligand binding experiments in striatal membrane preparations showed the existence of a strong and selective H(3)-D(2) receptor interaction at the membrane level. In agonist/antagonist competition experiments, stimulation of H(3) receptors with several H(3) receptor agonists significantly decreased the affinity of D(2) receptors for the agonist. This kind of intramembrane receptor-receptor interactions are a common biochemical property of receptor heteromers. In fact, by using Bioluminescence Resonance Energy Transfer techniques in co-transfected HEK-293 cells, H(3) (but not H(4)) receptors were found to form heteromers with D(2) receptors. This study demonstrates an important role of postsynaptic H(3) receptors in the modulation of dopaminergic transmission by means of a negative modulation of D(2) receptor function.     

Dopamine D2 receptor knock-out mice are insensitive to the hypolocomotor and hypothermic effects of dopamine D2/D3 receptor agonists.

The dopamine (DA) D2-like family of receptors is comprised of three subtypes, the D2, D3, and D4 receptors. It has been suggested that the potency of DA receptor agonists to produce hypothermia and hypolocomotion in rodents correlates more strongly with the in vitro affinity for, or potency (mitogenesis test) at the D3 than at the D2 subtype. However, it has recently been reported that when tested in DA D3 receptor knock-out mice, several DA D2/D3 receptor agonists (7-OH-DPAT, PD 128907 and quinelorane) induced levels of hypothermia and decreases of locomotor activity similar to those obtained in control (wild-type) mice. These results do not argue in favour of an implication of DA D3 receptors in these in vivo effects. In order to investigate whether the DA D2 receptor is the subtype that mediates hypothermia and hypolocomotion produced by DA D2/D3 receptor agonists, we tested the effects of ip administration of the DA D2/D3 receptor agonists 7-OH-DPAT and PD 128907, on core temperature and locomotor activity in DA D2 receptor knock-out mice (homozygotes: D2(-/-) and heterozygotes: D2(+/-)), and in wild-type (D2(+/+)) mice. 7-OH-DPAT (0.1-3 mg/kg) and PD 128907 (1-10 mg/kg) induced hypothermia and decreased locomotion in D2(+/+) mice, but had no effects in D2(-/-) mice; the magnitude of the hypothermic and locomotor-reducing effects of these two agonists in D2(+/+) mutants was approximately half that of D2(+/+) mice. During the first 10 min in the activity chambers, the level of spontaneous locomotor activity of D2(-/-) individuals was almost 50% below that of D2(+/+) mice; basal locomotor activity of D2(+/-) mice was between that of D2(-/-) and D2(+/+) individuals. Neither type of mutant showed spontaneous catalepsy or deficits in forelimb muscle strength (grip-strength test). These results show that the presence of DA D2 receptors is necessary for the expression of the locomotor- and core temperature-decreasing effects of DA D2/D3 receptor agonists such as 7-OH-DPAT and PD 128907.     

Is stimulation of both D1 and D2 receptors necessary for the expression of dopamine-mediated behaviors?

Recent electrophysiological findings have indicated that D1 dopamine (DA) receptor stimulation by SKF 38393 enables the inhibitory effects of the D2 receptor agonist quinpirole on nucleus accumbens neurons. In the present study, a similar interaction was shown for quinpirole-induced stereotyped behaviors. In control rats, SKF 38393 enhanced the stereotyped responses induced by quinpirole, converting lower-level stereotypies (sniffing and rearing) to more intense oral behaviors (licking and gnawing). In rats depleted of DA (79% reduction) by the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT), the behavioral effects of quinpirole were abolished. However, quinpirole-induced stereotyped responses were reinstated by SKF 38393 suggesting that D1 receptor stimulation by endogenous DA is necessary for D2 receptor-mediated stereotyped responses (sniffing, rearing). In support of this suggestion, stereotyped behaviors produced by the non-selective D1/D2 agonist apomorphine were not affected by AMPT pretreatment. In contrast to the effects of quinpirole, the ability of SKF 38393 to induce grooming responses was not abolished by AMPT pretreatment or by combined pretreatment with AMPT and reserpine (greater than 99% DA depletion). These results indicate that D1 receptor stimulation enables D2 receptor-mediated stereotyped responses, but that this relationship is not reciprocal since D2 receptor stimulation is not necessary for the grooming response elicited by SKF 38393.     

Functional potencies of new antiparkinsonian drugs at recombinant human dopamine D1, D2 and D3 receptors

We measured the affinities of bromocriptine, pramipexole, pergolide and ropinirole at human recombinant dopamine D1, D2 and D3 receptors in binding and functional tests. All four compounds bound with high affinity at the dopamine D3 receptor; bromocriptine and pergolide also had high affinity for the dopamine D2 receptor, while only pergolide had significant, although moderate, affinity for the dopamine D1 receptor. Only pergolide had high potency and intrinsic activity at the dopamine D1 receptor for stimulating cyclic AMP accumulation. In addition, the potencies and efficacies of pergolide and bromocriptine, as well as that of dopamine, at the dopamine D1 receptor were increased in the presence of forskolin, an adenylate cyclase activator. All four compounds were highly potent agonists at dopamine D2 and D3 receptors, as measured in a mitogenesis assay. Bromocriptine was ten times more potent and pramipexole and ropinirole ten times less potent at the dopamine D2 than at the dopamine D3 receptor, whereas pergolide was equipotent at the two receptors. These results suggest that the activity of recently developed antiparkinsonian drugs at either the dopamine D1 or the dopamine D3 and not only the dopamine D2 receptors should be taken into account in analyses of their mechanisms of action in therapeutics.     

Dopamine D1 rather than D2 receptor agonists disrupt prepulse inhibition of startle in mice.

Although substantial literature describes the modulation of prepulse inhibition (PPI) by dopamine (DA) in rats, few reports address the effects of dopaminergic manipulations on PPI in mice. We characterized the effects of subtype-specific DA agonists in the PPI paradigm to further delineate the specific influences of each DA receptor subtype on sensorimotor gating in mice. The mixed D1/D2 agonist apomorphine and the preferential D1-family agonists SKF82958 and dihydrexidine significantly disrupted PPI, with differing or no effects on startle. In contrast to findings in rats, the D2/D3 agonist quinpirole reduced startle but had no effect on PPI. Pergolide, which has affinity for D2/D3 and D1-like receptors, reduced both startle and PPI, but only at the higher, nonspecific doses. In addition, the D1-family receptor antagonist SCH23390 blocked the PPI-disruptive effects of apomorphine on PPI, but the D2-family receptor antagonist raclopride failed to alter the disruptive effect of apomorphine. These studies reveal potential species differences in the DA receptor modulation of PPI between rats and mice, where D1-family receptors may play a more prominent and independent role in the modulation of PPI in mice than in rats. Nevertheless, due to the limited selectivity of DA receptor agonists, further studies using specific receptor knockout mice are warranted to clarify the respective roles of specific DA receptor subtypes in modulating PPI in mice.     

Alpha 1 (but not alpha 2)-adrenoceptor agonists in combination with the dopamine D2 agonist quinpirole produce locomotor stimulation in dopamine-depleted mice

Mice were premedicated with reserpine and alpha-methyl-p-tyrosine to deplete stores of dopamine (DA) (and other neurotransmitters) and to stop DA (and noradrenaline (NA] synthesis. In DA-depleted mice, the mixed alpha 1/alpha 2 agonist clonidine potentiated locomotor stimulation induced by a low dose of apomorphine as measured in automated activity cages. Clonidine and the slightly alpha 1-selective agonist ST587, but not ST91, an alpha-agonist which does not readily cross the blood brain barrier, produced marked stimulation when combined with the selective D2 agonist quinpirole. The D1 -selective agonist SKF38393 also produced marked excitation when combined with quinpirole. All the selective agonists, bar quinpirole which in some cases produced a significant locomotor stimulation, were relatively inactive when given alone. A "blind" observational analysis of the animals challenged with clonidine plus quinpirole indicated an increase in sniffing, rearing and shaking behaviour. In contrast, observation of the animals challenged with SKF38393 plus quinpirole indicated increased sniffing, rearing and biting and, in one case, increased grooming behaviour. Clonidine did not produce excitation (in automated cages) when combined with the selective D1 agonist SKF38393. The excitation produced by clonidine plus quinpirole was blocked by the selective D2 antagonist raclopride but not by the selective D1 antagonist SCH23390. The stimulation was also blocked by the alpha 1 antagonist prazosin but not by the alpha 2 antagonists idazoxan or yohimbine. Biochemical analysis in the striata of mice challenged with clonidine plus quinpirole did not provide any obvious biochemical basis for the behavioural interaction. It is concluded that alpha 1 receptor agonists in combination with D2 DA agonists can produce marked stimulation in DA depleted mice.     

Dopamine D3 receptor antisense oligodeoxynucleotide potentiates imipramine-induced dopaminergic behavioural supersensitivity

Chronic antidepressant treatments result in the potentiation of dopaminergic transmission in the mesolimbic dopamine system revealed as an increased motor response to dopamine D2-like agonists. On the basis of the involvement of this system in the control of motivation and reward-related behaviour, which are impaired in depression, it has been suggested that such supersensitivity might play an important role in the mechanism of action of these drugs. Several studies have provided evidence suggesting a role of dopamine D3 receptors in mediating antidepressant-induced increased motor response to dopamine agonists. To test this hypothesis, we studied the effect of the intracerebroventricular infusion of a dopamine D3 receptor antisense oligodeoxynucleotide (10 microg/3 microl, 2-3 daily injections) on the expression of imipramine-induced supersensitivity (20 mg/kg daily intraperitoneal injections for 21 days) to the motor effect of the dopamine D2-like receptor agonist quinpirole (a single 0.3 mg/kg subcutaneous injection 24-48 h after imipramine withdrawal). The results show that a treatment previously shown to reduce the synthesis of dopamine D3 receptors, rather than resulting in an inhibitory effect, potentiated the ability of imipramine to induce dopaminergic motor supersensitivity. The present results suggest that increased dopamine D3 receptor expression following antidepressant treatments is not involved in the mechanism of dopaminergic supersensitivity, and are consistent with evidence supporting an inhibitory role for dopamine D3 receptors in motor activity, both in normal and in sensitized subjects.     

Antidepressant-like effect of D(2/3) receptor-, but not D(4) receptor-activation in the rat forced swim test.

Dopamine plays a role in the pathophysiology of depression and therapeutic effects of antidepressants but the contribution of individual D(2)-like receptor subtypes (D(2), D(3), D(4)) to depression is not known. We present evidence that activation of D(2)/D(3), but not D(4) receptors, can affect the outcome in the rat forced swim test (FST). Nomifensine, a dopamine uptake inhibitor (7, 14, and 28 micromol/kg); quinpirole, a D(2)-like receptor and agonist (0.4, 1.0, and 2.0 micromol/kg); PD 12,8907, a preferential D(3) receptor agonist (0.17, 0.35, and 0.7 micromol/kg); PD 168077 (0.1, 0.3, and 1.0 micromol/kg) and CP 226269 (0.3, 1.0, and 3.0 micromol/kg), both selective D(4) receptor agonists, were administered s.c. 24, 5, and 0.5/1 h before testing. Nomifensine, quinpirole at all doses and PD 128907 at the highest dose decreased immobility time in FST. PD 168077 and CP 226269 had no effect on the model. To further clarify what type of dopamine receptors were involved in the anti-immobility effect of quinpirole, we tested different antagonists. Haloperidol, a D(2)-like receptor antagonist (0.27 micromol/kg), completely blocked the effect of quinpirole; A-437203 (LU-201640), a selective D(3) receptor antagonist (17.46 micromol/kg), showed a nonsignificant trend to attenuate the effect of the low dose of quinpirole, and L-745,870, a selective D(4) receptor antagonist (1.15 micromol/kg), had no effect. The pharmacological selectivity of the compounds tested suggests that the antidepressant-like effects of quinpirole are most likely mediated mainly by D(2) and to a lesser extent by D(3) but not D(4) receptors.     

The role of D1 and D2 dopamine receptors in the acquisition and expression of cocaine-induced conditioned increases in locomotor behavior

Certain motoric effects of cocaine increase in intensity with repetitive administration. Conditioned drug effects are among primary determinants of such sensitization. The purpose of these experiments was to evaluate the role of D1 and D2 dopamine (DA) receptor mechanisms in the acquisition and expression of cocaine conditioning. On Day 1, rats were injected with cocaine (40mg/kg) either before (PAIRED) or after (UNPAIRED) exposure to a locomotor activity chamber. On Day 2, all animals were injected with a low dose of cocaine (10mg/kg) prior to placement in the locomotor chambers. Conditioning on Day 2 was evidenced by significantly higher activity levels in the PAIRED group relative to the UNPAIRED or saline-treated groups. Pretreatment with D1 (SCH 23390) or D2 (raclopride, sulpiride, haloperidol) DA antagonists on Day 1 prevented the development of conditioning as assessed on Day 2, indicating that both receptor subtypes are involved in acquisition. However, pretreatment with raclopride or SCH 23390 on Day 2, prior to cocaine injections, did not eliminate the differences in behavior between the conditioned and non-conditioned groups. Neither D1 (SKF 82958, SKF 38393) nor D2 (quinpirole) agonists administered alone were effective in establishing conditioning, while a combination of SKF 82958 and quinpirole was effective, suggesting that conditioning in this experimental paradigm requires the concurrent activation of both receptor subtypes. In the final study it was found that conditioned cocaine effects could be revealed only in the presence of quinpirole or apomorphine on Day 2. The D1 agonists (SKF 38393 and SKF 82958) were ineffective. This would suggest either that only quinpirole and apomorphine are effective in amplifying the conditioned effects of cocaine on Day 2 or that the cues produced by these drugs are more similar to those produced by cocaine than those produced by D1 agonists.     

Modulation of the locomotor activating effects of the noncompetitive NMDA receptor antagonist MK801 by dopamine D2/3 receptor agonists in mice

The noncompetitive NMDA receptor antagonist MK801 (dizocilpine) produces behavioral stimulation mediated, in part, through indirect activation of the dopamine (DA) system. Previous reports indicate that D2/3 agonists inhibit MK801-induced stereotypies; however, it is unclear if these agonists also attenuate MK801-induced locomotion. As such, the ability of the D2/3 agonists, quinelorane and quinpirole, and the partial D3 agonist, BP897, to attenuate the locomotor activating effects of MK801 was examined in mice. MK801 (0.1-1.0 mg/kg) produced a biphasic effect on total distance traveled with the intermediate dose of 0.3 mg/kg producing the greatest stimulation. The increase in MK801-induced total distance traveled was attenuated by the coadministration of quinelorane and quinpirole at doses that alone had no effect on activity. Similarly, the partial D3 agonist, BP897, blocked the effects of MK801. The D3-preferring antagonist, nafadotride, reversed the attenuation of quinelorane and partially reversed the attenuation of quinpirole. The D2-preferring antagonist, eticlopride, reversed the attenuating effects of quinelorane, but was not effective against quinpirole. Nafadotride and eticlopride were ineffective against the attenuating effects of BP897 on MK801-induced locomotion. Because BP897 is a partial agonist it was tested against quinelorane/MK801 and quinpirole/MK801 combinations. BP897 reversed the attenuating effects of quinelorane, but not those of quinpirole on MK801's effects. These results demonstrate that the DA system, through D2/3 receptor activation, modulates the locomotor activating effects produced by noncompetitive NMDA receptor blockade.     

Relative dopamine D1 and D2 receptor affinity and efficacy determine whether dopamine agonists induce hyperactivity or oral stereotypy in rats

The effects of a range of dopamine (DA) agonists on stereotyped behaviour in rats were analysed and compared both with the affinity of the compounds for D1 and D2 receptor binding sites in vitro and their ability to stimulate the adenylate cyclase activity in rat striatal homogenates. Full and partial agonists at the D1 receptor coupled to adenylate cyclase do not induce sterotypies when given alone, whereas full D2 agonists (e.g. quinpirole) induce hyperactivity but not oral sterotypies. Partial D2 agonists (e.g. (-)-3-PPP) only induce sedation. Mixed D1/D2 agonists (e.g. apomorphine) induce both hyperactivity and oral stereotypies. Maximum stereotypies were induced by combination of SK & F 38393 and a series of D2 agonists, including full agonists and the partial D2 agonist B-HT 920, whereas partial agonists with low intrinsic activity (e.g. (-)-3-PPP, EMD 23448) did not induce stereotypies when given together with SK & F 38393. However, these partial agonists reduced the maximum effect of apomorphine, whereas the full agonists (e.g. quinpirole, (-)-NPA) and B-HT 920 had no apomorphine antagonistic activity. The mixed D1/D2 agonists apomorphine and N,N-dipropyl-5,6-ADTN were only weakly influenced by SK & F 38393, or not at all. D1 agonists with central effects, including SK & F 38393, SK & F 81297 (with relatively high efficacies), and the partial agonist SK & F 75670 with low efficacy, changed the hyperactivity induced by quinpirole into maximum oral stereotypy, whereas the peripheral D1 agonist fenoldopam had no such effect. Inhibition of DA and NA synthesis with alpha-methyl-p-tyrosine depleted striatal DA levels by 72 per cent and antagonized the hyperactivity induced by the D2 agonists quinpirole and (-)-NPA, but not that of apomorphine. Combination of SK & F 38393 and quinpirole induced maximum stereotypy in DA-depleted animals. These results suggest that D1 receptor tonus is a necessary prerequisite for the expression of a DA agonist's effect. The hyperactivity induced by full D2 agonists appears to be mediated by D1 tonus provided by endogenous DA activity, but stronger D1 stimulation is necessary to induce oral stereotypy. A high degree of D1 receptor activation increases the ability of partial D2 agonists to induce hyperactivity or oral stereotypies since treatment with both SK & F 38393 and B-HT 920 had marked effects while B-HT 920 was ineffective.(ABSTRACT TRUNCATED AT 400 WORDS)     

Subchronic intermittent caffeine administration to unilaterally 6-hydroxydopamine-lesioned rats sensitizes turning behaviour in response to dopamine D(1) but not D(2) receptor agonists

The effects of caffeine, an antagonist of adenosine A(1) and A(2A) receptors, are significantly influenced by modifications in dopamine transmission. Administration of caffeine to unilaterally 6-hydroxydopamine-lesioned rats induces ipsilateral turning behaviour in rats never exposed to a dopamine receptor agonist, whereas contralateral turning is elicited if rats are repeatedly primed with a dopamine receptor agonist. In this study, rats unilaterally lesioned with 6-hydroxydopamine and subchronically treated with an intermittent administration of caffeine (15 mg/kg) or vehicle, were administered, 3 days after discontinuations of the treatment, with the dopamine D(1) receptor agonist 1-phenyl 1,2,3,4,5-tetrahydro(1H)-3-benzazepine-7,8-diolhydrochloride (SKF 38393), the D(2)/D(3) receptor agonist quinpirole, the D(2) receptor agonist R(-)-propylnorapomorphine or the dopamine precursor L-3,4-dihydroxyphenyl-alanine. Administration of SKF 38393 (1.5 mg/kg) or L-3,4-dihydroxyphenyl-alanine (6 mg/kg), but not quinpirole (0.15 mg/kg) or R(-)-propylnorapomorphine (0.01 mg/kg), induced a significantly higher contralateral turning behaviour in rats subchronically treated with caffeine than in vehicle-pretreated rats. The results show that repeated intermittent caffeine exposure enhances the motor stimulant effects elicited by dopamine agonists by a preferential sensitization of dopamine D(1) receptors.     

Recruitment of beta-arrestin2 to the dopamine D2 receptor: insights into anti-psychotic and anti-parkinsonian drug receptor signaling

Drugs acting at dopamine D2-like receptors play a pivotal role in the treatment of both schizophrenia and Parkinson's disease. Recent studies have demonstrated a role for G-protein independent D2 receptor signaling pathways acting through beta-arrestin. In this study we describe the establishment of a Bioluminescence Resonance Energy Transfer (BRET) assay for measuring dopamine induced recruitment of human beta-arrestin2 to the human dopamine D2 receptor. Dopamine, as well as the dopamine receptor agonists pramipexole and quinpirole, acted as full agonists in the assay as reflected by their ability to elicit marked concentration dependent increases in the BRET signal signifying beta-arrestin2 recruitment to the D2 receptor. As expected from their effect on G-protein coupling and cAMP levels mediated through the D2 receptor RNPA, pergolide, apomorphine, ropinirole, bromocriptine, 3PPP, terguride, aripiprazole, SNPA all acted as partial agonists with decreasing efficacy in the BRET assay. In contrast, a wide selection of typical and atypical anti-psychotics was incapable of stimulating beta-arrestin2 recruitment to the D2 receptor. Moreover, we observed that haloperidol, sertindole, olanzapine, clozapine and ziprasidone all fully inhibited the dopamine induced beta-arrestin2 recruitment to D2 receptor (short variant) in a concentration dependent manner. We conclude that most anti-psychotics are incapable of stimulating beta-arrestin2 recruitment to the dopamine D2 receptor, in accordance with their antagonistic properties at the level of G-protein coupling.     

Modulation of the discriminative stimulus effects of mu opioid agonists in rats: II. Effects of dopamine D2/3 agonists

Dopamine (DA) D2/3 receptor agonists have been shown to attenuate the behavioral effects of mu opioid agonists. This study was designed to examine the modulatory actions of the D2/3 agonists quinelorane, quinpirole and (+/-)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (7-OH-DPAT) on the discriminative stimulus effects of the higher-efficacy mu agonists heroin, methadone and morphine, as well as the lower-efficacy agonist nalbuphine, in rats trained to discriminate heroin from water. All three D2/3 agonists attenuated the heroin-like discriminative stimulus effects of morphine, methadone and nalbuphine, whereas quinpirole and 7-OH-DPAT, but not quinelorane, effectively attenuated the discriminative stimulus effects of heroin. Each D2/3 agonist administered alone occasioned water-appropriate responding and decreased rates of responding. These results extend previous findings, which demonstrated that activation of D2/3 receptors attenuates the antinociceptive effects of mu agonists, to now include their discriminative stimulus effects as well. The exact nature of this modulation of opioid effects by dopamine agonists is unclear, and may include neurochemical interactions as well as psychological mechanisms such as perceptual masking.