Dopamine D3 receptor agonists produce similar decreases in body temperature and locomotor activity in D3 knock-out and wild-type mice

The function of the dopamine (DA) D3 receptor, a member of the D2-like family, has not been firmly established. It has been reported that the potency of DA receptor agonists in producing hypothermia and hypolocomotion in rodents correlates more strongly with the in vitro affinity for, or potency (mitogenesis test) at the D3 than the D2 subtype. In order to investigate further the role of D3 receptors in hypothermia and hypolocomotion, we tested the effects of ip administration of three DA receptor agonists reported to be selective for the D3 receptor subtype (7-OH-DPAT, quinelorane and PD 128907) on core temperature and spontaneous locomotor activity in homozygous (D3-/-), heterozygous (D3+/-) mutant and wild-type (D3+/+) mice. Quinelorane (0.003-0.3 mg/kg), PD 128907 (1-10 mg/kg) and 7-OH-DPAT (0.1-3 mg/kg) induced hypothermia and decreased locomotion to a similar extent in the three genotypes. Additionally, the putatively selective DA D3 receptor antagonist PNU 99194A (3-20 mg/kg i.p.) increased locomotor activity in habituated mice and reversed the hypothermia induced by 30 microg/kg of quinelorane, with no apparent difference between D3-/-, D3+/- and D3+/+ genotypes. The spontaneous level of locomotor activity of mutants (D3-/- or D3+/-) was found to be either at, below, or above that of controls, with no consistent trend between different batches of mice. These results show that the presence of DA D3 receptors is not necessary for the expression of these effects induced by the three agonists or the antagonist supposedly selective for the D3 receptor subtype. This raises the question of the involvement of the D3 receptor in these behavioural effects and the issue of the in vivo selectivity of these four compounds for the D3 receptor subtype. Alternatively, possible adaptive mechanisms taking place in D3-/- mice might have compensated for the absence of DA D3 receptors.     

Dopamine receptor agonists: selectivity and dopamine D1 receptor efficacy

Dopamine receptor selectivity was investigated for a number of dopamine receptor agonists. In vitro, the benzazepine derivatives, e.g., SKF 38393 and SKF 75670 as well as the isoquinoline derivatives, SKF 89626 and SKF 89615, were D1 receptor-selective. All other compounds like apomorphine, CY 208-243, 6,7-ADTN and 3-PPP were either D2-selective or did not discriminate between subtypes. In general, the same receptor profile seen in vitro was observed in vivo. The exceptions to this pattern were: compounds which did not cross the blood-brain barrier, like 6,7-ADTN and SKF 89626, and compounds which appeared nonselective in vitro but demonstrated D2 selectivity in vivo like apomorphine, CI 201-678 and CY 208-243. A number of compounds were characterized in detail with respect to a GTP-induced affinity shift in inhibition of [3H]SCH 23390 binding, and potency and efficacy in stimulating adenylate cyclase from rat striatum. Inhibition of specific [3H]SCH 23390 binding by these agonists in the absence of GTP occurred with Hill slopes below unity and could best be explained by a two-site model with a high (KH)- and low-affinity (KL) component. Inhibition of [3H]SCH 23390 binding in the presence of 15 microM GTP occurred with Hill slopes of unity. The KI values obtained in the presence of 15 microM GTP were similar to the KL values, the low-affinity component observed in the absence of GTP. The capability of the agonists to stimulate the adenylate cyclase was analyzed in relation to dopamine (efficacy = 100%). The efficacy of the benzazepine derivatives varied from 24 (SKF 75670) to 100% (SKF 83189), dependent on the substituents on the benzazepine core. The isoquinolines, SKF 89626 and SKF 89615 had full efficacy, whereas most other agonists tested appeared to have only partial efficacy. In summary, the present paper presents data on dopamine receptor selectivity and efficacy in stimulating adenylate cyclase for a number of dopaminergic agonists. These data may create a basis for selection of agonists in future characterizations of dopaminergic-mediated events.     

Behavioral effects of dopamine agonists and antagonists in MPTP-lesioned D3 receptor knockout mice

To test the modulatory role of D(3) receptors in normal and dopamine-depleted mice, D(3) receptor KO mice and wild-type (WT) littermates were administered saline, L-dopa/carbidopa (20/2 mg/kg ip), a preferential D(3)>D(2) agonist S32504, a D1+D(2)/D(3) agonist apomorphine, a selective D(3) antagonist S33084, or apomorphine with S33084 prior to and after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We monitored lines crossed in a 55-min session, average number of rears, and average number of grooming bouts. MPTP treatment produced equivalent 70% losses of dopamine fibers in the caudate putamen (CPu) and nucleus accumbens (NAC) of WT and D(3) KO mice as compared to their control (vehicle injected) counterparts. D(3) receptors were absent in KO mice, and the number of D(3) receptors was unaffected by MPTP-induced loss of DA terminals in WT mice. The results support a lack of involvement of the D(3) receptor for D1:D2 receptor-mediated behavioral activity (synergy). First, S32504 inhibited all behaviors and to a similar degree in D(3) KO and WT mice. Second, S33084 at the higher concentration increased number of lines crossed in response to high dose apomorphine in both D(3) KO and WT mice. Third, in nonlesioned mice, apomorphine-induced gnawing stereotypies were inhibited by S33084 in both D(3) KO and WT mice. Interestingly, the inhibition of apomorphine-induced gnawing was not apparent in MPTP-lesioned mice, and this stereotypy was elevated in D(3) KO-MPTP-lesioned mice. Thus, the suppressive effects of S32504 could be via D2 autoreceptor inhibition of DA release, and D2 receptor blockade by S33084 leads to release of that inhibition. This may be more apparent in MPTP-lesioned partially DA denervated mice.     

Synergistic behavioural effects of dopamine D1 and D2 receptor agonists are determined by circadian rhythms.

The effects of continuous subcutaneous infusions of rats for 336 h with vehicle, SKF 38393 (a dopamine D1 receptor agonist), (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, a dopamine D2 receptor agonist) or both D1 and D2 receptor agonists, on locomotor activity were investigated. Rats were maintained under constant lighting conditions, either continuous dark (dark:dark) or continuous light (light:light), before and during drug treatments in order to determine the influence of free-running circadian rhythms on drug responses. The D2 receptor agonist initially increased locomotion in rats kept under dark:dark during both subjective night (period of maximum locomotion) and day (period of minimum locomotion), but had no effect in rats maintained in light:light throughout the 336 h of treatment. The motor stimulant effects of the D2 receptor agonist on rats kept in dark:dark increase during the course of treatment during subjective night (sensitization), but decreased during the rats' subjective day (tolerance). The D1 receptor agonist, SKF 38393, had no effect on its own regardless of the lighting conditions and the duration of treatment. However, the D1 receptor agonist interacted synergistically with the D2 receptor agonist in rats maintained under light:light, depending on the duration of treatment. Synergistic effects were also observed on initiation of treatment in rats under dark:dark but only during subjective day. Tolerance to the synergistic effects of the receptor agonists occurred as a function of treatment duration, but only during subjective day. The D1 receptor agonist blocked the effects of the D2 receptor agonist during the rats' subjective night after 100 h of treatment, but not after 25 or 325 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of dopamine D3/D2 receptor agonists on intracranial self stimulation in the rat

The effects of the dopamine D₃/D₂ receptor agonists quinpirole, quinelorane and (±)7-OH-DPAT [(±) 7-hydroxy-2(N,N-di-n-propylamino) tetralin] on intracranial self-stimulation (ICSS) were investigated. Rats implanted with bipolar electrodes into the lateral hypothalamus were trained to lever press on a continuous reinforcement schedule for positively reinforcing trains of electrical stimulation. Three measures of responding were calculated; the frequency at which responding was 50% of the maximum (M50), the asymptotic response rate and the total area under the curve (AUC) for each frequency sweep. Quinpirole (2.2–66.0 μg/kg SC) significantly increased M50 and reduced both asymptote and AUC. Quinelorane (0.25–79.0 μg/kg SC) had no significant effect on M50 values but significantly reduced both asymptote and AUC. (±)7-OH-DPAT (2.5–74.0 μg/kg) did not significantly affect any of the measures. The data show that low doses of quinpirole and quinelorane, but not (±)7–OH–DPAT, inhibit ICSS maintained by electrodes in the lateral hypothalamus. Either dopamine D₂ or dopamine D₃ receptor stimulation may play a role in mediating ICSS inhibition, but studies with more selective receptor agonists and antagonists are required to define the role of each receptor. Received: 18 August 1997/Final version: 17 April 1998     

Reinforcing effects of D2 dopamine receptor agonists and partial agonists in rhesus monkeys.

Dopamine (DA) receptors play a role in the reinforcing effects of psychomotor stimulants and other drugs. Both D1 and D2 DA receptor agonists have been reported to function as positive reinforcers in maintaining self-administration in non-human subjects. The purpose of the present study was to evaluate, in monkeys, the reinforcing effects of DA D2 receptor agonists that vary in their efficacy as D2 agonists. Rhesus monkeys were prepared with venous catheters and lever pressing was maintained by i.v. cocaine (n=5, 0.03 mg/kg/inj) in daily baseline sessions (2 h/day, fixed ratio 25). Various doses of cocaine or D2 agonists were then made available for at least four to seven sessions, and until responding was stable. At least one dose of the higher-efficacy D2 agonists, R(-)-propylnorapomorphine (NPA) (n=4, 0.001-0.01 mg/kg/inj), R(-)-apomorphine (APO) (n=4, 0.003-0.1 mg/kg/inj) and R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine HCl [R(+)-3-PPP] (n=4, 0.03-0.3 mg/kg/inj), functioned as a positive reinforcer in all the monkeys tested. In contrast, no dose of the lower-efficacy D2 agonists, R(+)-terguride (n=4, 0.001-0.3 mg/kg/inj) and S(-)-3-(3-hydroxyphenyl)-N-propylpiperidine HCl [S(-)-3-PPP] (n=4, 0.001-0.3 mg/kg/inj), maintained self-administration. In in vitro binding studies with monkey brain tissue NPA and terguride had high affinities for the D2 receptor, while APO had intermediate affinity, and the 3-PPPs had low affinity. Among the compounds that were reinforcers potency as a reinforcer was directly related to D2 affinity in three of the four monkeys, consistent with D2 receptor involvement in the reinforcing effect of these compounds. The data suggest that the efficacy at D2 receptors is directly related to the reinforcing effect.     

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.     

Haloperidol-induced catalepsy is absent in dopamine D(2), but maintained in dopamine D(3) receptor knock-out mice

We have previously found that mice homozygous for the deletion of the dopamine D(2) receptor gene (D(2)(-/-) mice) do not present spontaneous catalepsy when tested in a "bar test". In the present study, we sought to analyse the reactivity of D(2) receptor mutant mice to the cataleptogenic effects of dopamine D(2)-like or D(1)-like receptor antagonists. In parallel, we assessed the cataleptogenic effects of these antagonists in dopamine D(3) receptor mutant mice. D(2)(-/-) mice were totally unresponsive to the cataleptogenic effects of the dopamine D(2)-like receptor antagonist haloperidol (0.125-2 mg/kg i.p.), while D(2)(+/-) mice, at the highest haloperidol doses tested, showed a level of catalepsy about half that of wild-type controls. The degree of haloperidol-induced catalepsy was thus proportional to the level of striatal dopamine D(2) receptor expression (0.50, 0.30 and 0.08 pmol/mg protein as measured at 0.25 nM [3H]spiperone for D(2)(+/+), D(2)(+/-) and D(2)(-/-) mice, respectively). However, D(2)(-/-) and D(2)(+/-) mice were as sensitive as their wild-type counterparts to the cataleptogenic effects of the dopamine D(1)-like receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390: 0.03-0.6 mg/kg s.c.). Striatal dopamine D(1) receptor expression (as measured using [3H]SCH 23390 binding) was not significantly affected by the genotype. The ability of SCH 23390 to induce catalepsy in D(2)(-/-) mice suggests that their resistance to haloperidol-induced catalepsy is due to the absence of dopamine D(2) receptors, and not to the abnormal striatal synaptic plasticity that has been shown by others to occur in these mice. In agreement with the observation that dopamine D(2) and dopamine D(1) receptor expression was essentially identical in D(3)(+/+), D(3)(+/-) and D(3)(-/-) mice, dopamine D(3) receptor homozygous and heterozygous mutant mice, on the whole, did not differ from their controls in the time spent in a cataleptic position following administration of either haloperidol (0.5-2 mg/kg i.p.) or SCH 23390 (0.03-0.6 mg/kg s.c.). Also, dopamine D(3) receptor mutant mice were no more responsive than wild-type controls when co-administered subthreshold doses of haloperidol (0.125 mg/kg) and SCH 23390 (0.03 mg/kg), suggesting that dopamine D(3) receptor knock-out mice are not more sensitive than wild-types to the synergistic effects of concurrent blockade of dopamine D(2) and dopamine D(1) receptors in this model. These results suggest that the dopamine D(2) receptor subtype is necessary for haloperidol to produce catalepsy, and that the dopamine D(3) receptor subtype appears to exert no observable control over the catalepsy produced by dopamine D(2)-like, D(1)-like and the combination of D(1)-like and D(2)-like receptor antagonists.     

Dopamine uptake by the human platelet: effects of dopamine receptor agonists

The uptake of dopamine by human platelets has been shown to be temperature- and energy-dependent and not to occur as a result of dopamine binding to and then being internalised with the dopamine D-1 or D-2 receptor. However, occupancy of these receptors could affect dopamine uptake by platelets through their second messenger systems. We have therefore studied the effect of dopamine receptor agonists, which stimulate receptor second messenger systems, on dopamine uptake by platelets. Uptake of [3H]dopamine by human platelets was not affected by the dopamine D-1 receptor agonist SKF 38393 or the dopamine D-2 receptor agonists, quinpirole and bromocriptine. In contrast, the uptake of [3H]dopamine was decreased by the mixed dopamine receptor agonists dopamine and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN). Furthermore, [3H]ADTN, like [3H]dopamine, was taken up by platelets. In conclusion ADTN, a compound structurally similar to dopamine appears to complete for the dopamine uptake system on the human platelet. Thus, our data further support the hypothesis that a selective dopamine uptake system is present on the human platelet and that this system is not influenced by the dopamine D-1 or D-2 receptor.     

Dopamine D3 receptor knockout mice and the motivational effects of ethanol

Dopamine D3 receptors have been implicated in the behavioral effects of abused drugs including ethanol. The present experiments characterized the acquisition of ethanol-induced place conditioning and ethanol self-administration in D3 knockout (D3 KO) mice compared with C57BL/6J (C57) mice. For place conditioning, D3 KO and C57 mice received six pairings of a tactile stimulus with ethanol (3 g/kg i.p.). D3 KO mice showed higher basal locomotor activity levels in comparison with the C57 mice during conditioning. Ethanol produced similar magnitudes of conditioned place preference in both genotypes. In a two-bottle drinking procedure, mice of each genotype received 24 h access to water and either 3% or 10% v/v ethanol. No difference was noted between D3 KO and C57 mice in either consumption or preference. In an operant self-administration procedure using 23 h sessions, D3 KO and C57 mice received access to 10% v/v ethanol on an FR4 schedule of reinforcement, food on an FR1 schedule of reinforcement and water from a sipper tube. D3 KO and C57 mice had similar response rates of ethanol and food as well as similar water intakes. Overall, these results indicate that elimination of D3 receptor function has little influence on ethanol reward or intake.     

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.     

Dopamine D2, but not D4, receptor agonists are emetogenic in ferrets

Agents that activate the dopamine D2-like family of receptors elicit emesis in humans and other species with a vomiting/emetic reflex; however, the lack of dopamine receptor subtype selective agonists has hampered an understanding of which dopamine D2-like receptor subtype(s) contributes to the emetic response. In this study, stable cell lines expressing the ferret dopamine D2-long (D2L) and D4 receptors were used to characterize known dopamine agonists via radioligand binding and calcium ion flux assays, while emetic activity of these dopamine receptor agonists was determined in male ferrets. Latencies to first emetic event, average number of emetic episodes, and stereotypical behaviors which may be indicative of nausea were also determined. Agonists at dopamine D1-like and D4 receptors had no emetic effect in ferrets. Conversely, stimulation of dopamine D2 and/or D3 receptors resulted in a robust emetic response characterized by a relatively short latency (<15 min) and multiple emetic events. Competitive antagonists of dopamine D2-like receptors (domperidone, haloperidol) dose-dependently blocked the emetic response to PNU95666E, a dopamine D2 receptor selective agonist. Thus, dopamine D2 and/or D3 receptor agonists elicit emesis, while dopamine D1/D5 or D4 receptor-selective agonists are devoid of emetic properties.     

Discriminative stimulus effects of putative D3 dopamine receptor agonists in rats

Three separate groups of rats were trained to discriminate the putative D3 dopamine receptor agonists (+/-)-7-hydroxydipropylaminotetralin (7-OH-DPAT) (0.03 mg/kg), PD 128,907 (1.0 mg/kg) and quinpirole (0.03 mg/kg) from saline. Food was presented after each 10 (7-OH-DPAT and PD 128,907) or 20 (quinpirole) consecutive responses on one lever after administration of the training drug, and the other lever after the administration of saline. Once stable performances were obtained, the effects of various doses of several dopaminergic agonists were assessed during test sessions in which responses on either lever were reinforced. The substitution tests were conducted to determine if differences in potencies would be obtained, which would be suggestive of differences in the mechanisms underlying the discriminative effects of the training drugs. Non-selective agonists with activity at both D2 and D3 dopamine receptors (D2-like agonists) substituted for each of the three training drugs. In addition, the selective D2 dopamine receptor agonist U91356A also generalized to both 7-OH-DPAT and PD 128,907. The potencies of the D2-like agonists in substituting for each training drug were highly correlated with potencies in substituting for the others. SKF 82958 and SKF 81297, agonists with selectivity for D1 and D5 dopamine receptors (D1-like agonists), partially substituted for 7-OH-DPAT but not PD 128,907. The D1-like partial agonist SKF 38393 did not substitute for any of the training drugs for which it was tested. Cocaine produced intermediate substitution in 7-OH-DPAT- and PD 128,907-trained subjects and did not substitute at all in quinpirole-trained subjects. The dopamine D1-like antagonist SCH 39166 (0.001-0.03 mg/kg) did not alter the discriminative stimulus effects of PD 128,907, whereas the D2-like dopamine antagonist spiperone (0.001-0.1 mg/kg) produced at the highest dose an insurmountable antagonism of the discriminative effects of PD 128,907. In contrast, there was no appreciable antagonism of the effects of PD 128,907 on response rates. The data collected are consistent with a distinction between the effects of each of these training drugs and the indirectly acting agonist cocaine. Further, these data indicate that there are differences in the mechanisms underlying the discriminative effects of PD 128,907 and its effects on response rates. Moreover, these data indicate that each of the training drugs is distinct from drugs acting through D1 dopaminergic mechanisms. However, there were no data that clearly distinguished these training drugs from each other or from drugs acting through D2 dopaminergic mechanisms.     

Dopamine D3 receptor knock-out mice exhibit increased behavioral sensitivity to the anxiolytic drug diazepam

Dopamine D₃ receptors (DRsD3) seem to have a pivotal role in mood disorders. Using the elevated plus maze (EPM) and the novelty-induced grooming test (NGT), we assessed the responses of DRD3-deficient (D₃^−/−) mice to the acute treatment (different testing time) with the anxiolytic drug, diazepam. D₃^−/− mice treated with diazepam (0.1 or 0.5 mg/kg) exhibited a better behavioral response in the EPM than their wild type (WT). Furthermore, in D₃^−/− mice, but not in WT, 1 mg/kg diazepam induced anxiolytic effects at all testing times. The contribution of DRsD3 in the anxiolytic effects of diazepam was confirmed by similar results obtained in EPM by using the selective DRD3 antagonist U99194A (10 mg/kg) in combination with diazepam, in WT animals. D₃^−/− mice treated with diazepam (all doses), also showed a decrease in grooming behavior. However, the [³H]flunitrazepam autoradiographic analysis revealed no significant changes in D₃^−/− mice compared to WT, suggesting that if γ-aminobutyric acid receptor GABA_A changes are involved, they do not occur at the level of binding to benzodiazepine site. These data suggest that D₃^−/− mice exhibit low baseline anxiety levels and provide the evidence that the DRD3 is involved in the modulation of benzodiazepine anxiolytic effects.     

The dopamine D2 agonists RU 24213 and RU 24926 are also kappa-opioid receptor antagonists.

The di-(phenethyl)-amine derivatives, RU 24213 and RU 24926 are widely used as selective dopamine D2-receptor agonists. Binding studies now show that they also have affinity for the kappa-opioid receptor. Their affinity is not greatly reduced in the presence of NaCl/GTP, suggesting an antagonist action. This is confirmed for RU 24926, the more active of the two, using the field-stimulated rabbit vas-deferens. With respect to the mu-receptor, RU 24926 shows low binding affinity and also an antagonist effect. These results demonstrate kappa- as well as mu-antagonist activity in a novel chemical series. Moreover, since the kappa-receptor may regulate dopamine release, the results of experiments using these compounds as dopamine D2 agonists should be interpreted with caution.     

Hypotensive and bradycardic effects elicited by spinal dopamine receptor stimulation: effects of D1 and D2 receptor agonists and antagonists.

In anesthetized rats, intrathecal (i.t.) administration, at the upper thoracic level of the spinal cord of fenoldopam (a selective dopamine D1-receptor agonist) or quinpirole (a selective D2-receptor agonist) decreased blood pressure (BP) and heart rate (HR) in a dose-dependent manner. Apomorphine, a nonselective DA receptor agonist, produced similar effects. Apomorphine-induced hypotension was competitively antagonized by either SCH 23390 or remoxipride, selective D1- and D2-receptor antagonists, respectively, but only remoxipride antagonized the bradycardia. Furthermore, SCH 23390 antagonized the hypotensive effect of fenoldopam but did not change that induced by quinpirole. Remoxipride antagonized the hypotensive effect of quinpirole but did not alter the hypotensive effect of fenoldopam. Quinpirole-induced bradycardia was antagonized only by remoxipride. Bradycardia elicited by fenoldopam did not appear to be generated by dopamine receptor stimulation, as suggested by the lack of blocking effects of SCH 23390 and remoxipride. Data obtained with fenoldopam were corroborated with use of SK&F 38393, another dopamine D1-receptor agonist. We conclude that hypotensive effects of i.t.-administered DA receptor agonists appear to result from activation of spinal D1- and D2-receptors whereas bradycardia is related only to activation of spinal D2-receptors.     

Effects of dopamine receptor agonists on passive avoidance learning in mice: interaction of dopamine D1 and D2 receptors.

The present study examined the effects of dopamine D1 and D2 receptor agonists on the acquisition stage of passive avoidance learning and on locomotor activity in mice. The D2 agonist, RU 24213 (1-10 mg/kg s.c.), and the non-selective agonist, apomorphine (0.3-3 mg/kg s.c.), but not the D1 agonist, SKF 38393 (1-10 mg/kg s.c.), impaired learning and activated locomotion. RU 24213 (1 mg/kg s.c.) was more effective in impairing learning than in activating locomotion. The concurrent administration of SKF 38393 (10 mg/kg i.p.) and RU 24213 (1 and 3 mg/kg s.c.) produced a synergistic effect in both behavioral situations. The D1 antagonist, SCH 23390 (0.025 mg/kg i.p.), slightly inhibited the effects of apomorphine and of the combination of SKF 38393 and RU 24213 on learning but not on locomotion. The D2 antagonist, (-)-sulpiride (40 mg/kg i.p.), completely blocked these effects in both situations. These results suggest that dopamine receptor agonists impair passive avoidance learning through the D2 receptor, and that D1 and D2 receptors act synergistically in this impairment, as they do in their effects on locomotion. The involvement of D1 and D2 receptors is qualitatively similar in each of these behaviors, although some small differences may exist.     

Anxiolytic-like effects of preferential dopamine D3 receptor agonists in an animal model

The aim of the present study was to examine a potential anxiolytic-like action of (+)-7-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (7-OH-DPAT), a preferential dopamine D(3) receptor agonist, and (N-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-2-naphthylcarboxamide (BP 897), partial dopamine D(3) receptor agonist. Diazepam was used as a reference compound. The anxiolytic-like effect of those drugs was tested in the conflict drinking test (Vogel test) in male Wistar rats. The obtained results showed that 7-OH-DPAT and BP 897 (like diazepam) induced anxiolytic-like effects in the conflict drinking test. 7-OH-DPAT (0.05 and 0.1 mg/kg), BP 897 (0.5 mg/kg) and diazepam (5 and 10 mg/kg), tested at the effective doses in an animal model, did not affect motor coordination but produced significant reduction in exploratory activity in the open field test. These data suggest that preferential dopamine D(3) agonists may play a role in the therapy of anxiety, however, further studies are necessary to elucidate the mechanism of these actions.     

The modulatory actions of dopamine D2/3 agonists and antagonists on the locomotor-activating effects of morphine and caffeine in mice

Morphine produces robust increases in locomotor activity in mice. Recent data indicate that dopamine (DA) D2/3 agonists attenuate the discriminative stimulus and antinociceptive effects of mu opioid agonists such as morphine. The present study was designed to determine the extent to which D2/3 receptor activation and blockade can modulate morphine-induced locomotion using a novel cumulative dosing procedure in Swiss-Webster mice. The results indicate that morphine-induced locomotion is nonsignificantly attenuated by the D2/3 agonists quinelorane and quinpirole, whereas the D2/3 antagonists eticlopride and nafadotride, as well as the partial D2/3 agonist BP897, significantly reduced morphine-induced locomotion. To determine the specificity of this modulation, these agonists and antagonists were examined in combination with caffeine, a drug that also indirectly alters DAergic activity. Unlike the effects on morphine, caffeine-induced locomotion was unaltered by eticlopride, nafadotride and BP897, but was attenuated by quinelorane and quinpirole. These results indicate that modulation of D2/3 receptors can, in turn, alter the locomotor-activating effects of morphine.     

Inhibitory effects of partial D2 dopamine receptor agonists on the d-amphetamine discriminative cue

The ability of partial dopamine (DA) receptor agonists with low relative efficacy to inhibit the d-amphetamine discriminative cue has been determined in rats trained to discriminate 0.5mg/kg d-amphetamine from saline. The classical neuroleptic haloperidol and selective D1 antagonist SCH 23390 potently blocked the cueing properties of d-amphetamine. A complete blockade of d-amphetamine discrimination was also observed with the partial DA agonist terguride. In contrast, preclamol [(-)-3-PPP] and SDZ 208-911 produced only a partial inhibition which was characterized by an asymptotic drug effect across a wide dose range. Clear variations in the sensitivity of individual rats to the inhibitory effects of preclamol on the d-amphetamine cue were observed. Some rats were sensitive to even low doses of preclamol, while others were minimally affected across the dose range. Variations in individual response were also observed with SDZ 208-911 and terguride, but not with haloperidol or SCH 23390. The present findings are discussed in relation to the partial agonist profile of preclamol, SDZ 208-911 and terguride and to possible underlying differences in DA receptor sensitivity between individual rats.