Evidence for postsynaptic dopamine agonist effects of B-HT 920 in the presence of the dopamine D-1 agonist SKF 38393

The ability of B-HT 920, a selective dopamine (DA) D-2 agonist, to stimulate postsynaptic DA receptors in brain was evaluated by assessing its ability to induce stereotypy and to increase locomotor activity in rats. When administered alone, B-HT 920 (0.03–3.0 mg/kg) did not induce stereotypy and produced only inhibition of locomotor activity, suggesting a lack of postsynaptic DA agonist actions. However, a different pattern of effects emerged when B-HT 920 was administered in combination with the selective DA D-1 agonist SKF 38393 (10 mg/kg): stereotypies (sniffing, licking, and gnawing) were induced and there was an inverted U-shaped function for locomotor activity. These data are consistent with the hypothesis that B-HT 920 has postsynaptic DA D-2 receptor agonist effects in normal rats that are revealed when D-1 receptor stimulation is also increased. Offprint requests to: L.T. Meltzer     

D1/D2 dopamine and N-methyl-d-aspartate (NMDA) receptor participation in experimental catalepsy in rats

Mixed D₁/D₂ dopamine (DA) antagonists, perphenazine (5 mg/kg) and haloperidol (2 mg/kg) induced catalepsy in rats. SCH 23390 (1 mg/kg), a D₁ DA antagonist, also produced catalepsy. Co-administration of perphenazine (0.5 mg/kg) and SCH 23390 (0.1 mg/kg), at low doses, produced a marked increase in cataleptic response. B-HT 920, a D₂ agonist, reversed the cataleptogenic effects of perphenazine, haloperidol and SCH 23390. SKF 38893 (5 mg/kg) reduced the cataleptogenic effect of SCH 23390 but failed to reverse haloperidol- or perphenazine-induced catalepsy. SKF 38393 (10 mg/kg), however, protected the animals against perphenazine- induced catalepsy. Combined administration of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) enhanced the protective effect of B-HT 920 in SCH 23390-treated animals but not in animals treated with haloperidol or perphenazine. MK-801 (0.025–0.5 mg/kg), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reduced the cataleptogenic effects of perphenazine, haloperidol as well as SCH 23390. The anticataleptic action of MK-801 was enhanced by scopolamine (0.1 mg/kg) but not by bromocriptine (1 mg/kg) or clonidine (0.05 mg/kg) in perphenazine-treated rats. Unlike B-HT 920 (0.1 mg/kg), SKF 38393 (5 mg/kg) potentiated the anticataleptic effect of MK-801 (0.01 mg/kg) against SCH 23390-induced catalepsy. The above data suggests D₁/D₂ interdependence in catalepsy and a modulatory role of D₁ and D₂ DA receptor stimulation on the anticataleptic effect of MK-801.     

Potentiation by serotonergic inhibition of yawning induced by dopamine receptor agonists in rats

Low doses of the dopamine D2-receptor agonist, B-HT 920 (25 micrograms/kg, SC), and the dopamine D1/D2-receptor agonists, apomorphine (50 micrograms/kg, SC) and piribedil (1 mg/kg, SC), evoked yawning. However, the dopamine D1-receptor agonist, SK&F 38393 (2 mg/kg, SC), failed to induce yawning. The yawning responses induced by B-HT 920, apomorphine or piribedil were markedly increased without eliciting stereotypy by pretreatment with reserpine (5 mg/kg, IP, 24 hr). These yawning responses were also enhanced by p-chlorophenylalanine (PCPA) (300 mg/kg, IP, 72 hr), but not by alpha-methyl-p-tyrosine (300 mg/kg, IP, 6 hr). The yawning induced by B-HT 920 given alone and in combination with reserpine or PCPA was inhibited by spiperone (0.5 mg/kg, IP) or scopolamine (0.5 mg/kg, IP), but not by SCH 23390 (0.5 mg/kg, IP). The present results suggest that yawning is evoked by stimulation of dopamine D2-receptors having a high affinity and consequent muscarinic activation, and that the yawning induced by dopamine receptor agonists is potentiated by decreases in serotonergic neuron activity.     

Modulatory role of D-1 and D-2 dopamine receptor subtypes in nociception in mice

The role of D-1 and D-2 dopamine (DA) receptors in nociception in naive as well as reserpinized mice and the modulation of the nociceptive action of morphine or naloxone by the selective D-1 and D-2 DA agonists, was investigated in mice. The D-2 DA agonists, B-HT 920 and bromocriptine produced an anti-nociceptive effect in naive mice and reversed the hyperalgesic effect of reserpine (2 mg/kg, 4 h prior) pre-treatment. The D-1 DA agonist, SKF 38393 (5 mg/kg) failed to alter the nociceptive responsiveness of naive and reserpinized mice. Apomorphine, a mixed D-1/D-2 DA agonist, produced significant analgesia in naive mice and also reversed reserpine-induced hyperalgesia. SKF 38393 (5 mg/kg) enhanced the anti-nociceptive effect of B-HT 920 (0.1 mg/kg) in naive and reserpine-pre-treated mice. The anti-nociceptive response of morphine (5 mg/kg) was enhanced by B-HT 920 while SKF 38393 reduced the same. Apomorphine (0.5 mg/kg) or the combination of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) failed to enhance the anti-nociceptive effect of morphine. Reserpine (2 mg/kg, 4 h prior) pre-treatment significantly reduced the anti-nociceptive effect of morphine. Similarly, the hyperalgesic action of naloxone (20 mg/kg) was reversed by B-HT 920, bromocriptine and apomorphine but not by SKF 38393. The reversal of the hyperalgesic action of naloxone by B-HT 920 was blocked by pre-treatment with haloperidol (0.5 mg/kg) and sulpiride (100 mg/kg). SKF 38393 (5 mg/kg) failed to potentiate the reversal action of B-HT 920 against naloxone. These data suggest a predominant role of D-2 DA receptors in anti-nociception and the possibility of the existence of an interlink between the DAergic and opioid systems.     

Modulation of MK-801 response by dopaminergic agents in mice

Various doses of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists, MK-801 (0.1–0.5 mg/kg) and ketamine (2.5–10 mg/kg), produced a dose-dependent increase in stereotypic behaviour in naive mice. MK-801 (0.1 mg/kg) and ketamine (2.5 mg/kg) potentiated the stereotypic response of apomorphine (0.1–0.5 mg/kg) in mice pretreated with reserpine (5 mg/kg, 24 h prior) and alpha-methyl-p-tyrosine (150 mg/kg, 1 h prior) but not in naive mice. SKF 38393, a D₁ dopamine agonist, enhanced whereas B-HT 920, a D₂ dopamine agonist, reduced the stereotypic response of MK-801 in naive mice. The response of MK-801 was blocked by pretreatment with haloperidol (0.5 mg/kg), molindone (2.5 mg/kg), clozapine (7.5 mg/kg) and SCH 23390 (0.1 mg/kg). The present data suggest involvement of endogenous DA transmission in the stimulant action of non-competitive NMDA antagonists in mice. Dopamine D₁ and D₂ receptor stimulation, respectively, exert opposing effects on the behavioural expression of MK-801 in mice.     

Effects of daily SKF 38393, quinpirole,and SCH 23390 treatments on locomotor activity and subsequent sensitivity to apomorphine

In three experiments, male Wistar rats (250–350 g) were injected (SC) daily with the D₁-type dopamine receptor agonist, SKF 38393 (0.0, 4.0, 8.0, or 16.0 mg/kg), the D₂-type dopamine receptor agonist, quinpirole (0.0, 0.3, or 3.0 mg/kg), and/or the D₁-type dopamine receptor antagonist, SCH 23390 (0.0 or 0.5 mg/kg) for 8–10 days. After each daily injection, the rats were tested for locomotor activity in photocell arenas for 20 min. Following this subchronic pretreatment, all rats were challenged with the mixed dopamine receptor agonist apomorphine (1.0 mg/kg, SC) and tested for locomotor activity. SKF 38393 treatments produced a dose-dependent decrease in locomotor activity which did not significantly change across days. Quinpirole also depressed locomotor activity when first injected, but this quinpirole-induced inhibition of activity progressively decreased across days. When subsequently challenged with apomorphine, rats in both the SKF 38393 and the quinpirole pretreatment groups displayed greater locomotor activity than rats pretreated with only vehicle. Although SCH 23390 pretreatments did not affect subsequent sensitivity to apomorphine, SCH 23390 completely blocked the effect of quinpirole. These results suggest that although repeated D₁ receptor stimulation may be sufficient to induce behavioral sensitization to apomorphine, D₂ receptor stimulation also contributes to the effect.Portions of this paper were presented at the 1991 Society for Neuroscience meetings, New Orleans, La, USA.     

Evidence that the enhancement of dopamine function by repeated electroconvulsive shock requires concomitant activation of D1-like and D2-like dopamine receptors

In this study, the behavioural response to dopamine D₁-like receptor agonists (SKF 38393, SKF 81297 and SKF 77434) and D₂-like receptor agonists (quinpirole and RU 24213), administered alone and in combination to rats treated repeatedly with electroconvulsive shock (five ECS over 10 days) or sham, was tested. Agonist-induced behaviour was monitored by automated activity meters and direct observation using a checklist scoring method. Repeated ECS (compared to sham controls) had no significant effect on the behavioural response to SKF 38393 (7.5 mg/kg SC), SKF 81297 (0.2 mg/kg SC), SKF 77434 (0.1 mg/kg SC), quinpirole (0.1 and 0.25 mg/kg SC) or RU 24213 (0.3 mg/kg SC), when administered alone. In contrast, repeated ECS markedly increased locomotion (activity counts and scores) induced by the non-selective dopamine agonist apomorphine (0.5 mg/kg SC) and by co-administration of a D₁-like agonist plus a D₂-like agonist [SKF 38393 (7.5 mg/kg SC) plus quinpirole (0.25 mg/kg SC), SKF 81297 (0.2 mg/kg SC) plus quinpirole (0.1 mg/kg SC), and SKF 77434 (0.1 mg/ kg SC) plus RU 24213 (0.3 mg/kg SC)]. This ECS-induced enhancement of dopamine-mediated behaviour was observed for up to 3 weeks after cessation of ECS treatment. In addition, ECS also enhanced the locomotor response to intra-accumbens SKF 38393 plus quinpirole (0.4 and 1.0 μg/side, respectively). These results provide evidence that the enhancement of dopamine function by repeated ECS requires concomitant stimulation of both D₁-like and D₂-like receptors, and that this effect is long-lasting. Received: 24 January 1997 /Final version: 5 March 1997     

Locomotor Behaviour of Selective Dopamine Agonists in Mice: Is Endogenous Dopamine the Only Catecholamine Involved?

The purpose of the study was to determine the effect alone and in combination of the selective dopamine (DA) agonists SKF 38393 (D1-) and B-HT 920 (D2-) on the locomotor activity of reserpine pretreated mice (5 mg kg-1 i.p.). After 4 h, reserpine-B-HT 920 (up to 20 mg kg-1 s.c.) did not induce locomotor activity whereas SKF 38393 was markedly effective at high doses (greater than or equal to 30 mg kg-1 s.c.). In contrast, at 24 h, reserpine-B-HT 920 (0.2-6 mg kg-1 s.c.) elicited considerable locomotor activity and SKF 38393 (1-100 mg kg-1 s.c.) was effective at lower doses when compared with the corresponding 4 h reserpine experiments. When, however, these animals additionally received alpha-methyl-p-tyrosine (alpha MPT; 300 mg kg-1 i.p., at 4 h before the DA agonists) neither B-HT 920 (0.2-20 mg kg-1 s.c.) nor SKF 38393 (1-100 mg kg-1 s.c.) had an effect of their own. When B-HT 920 was tested in the presence of a fixed-dose of SKF 38393 (10 or 3 mg kg-1 s.c., combination experiments) B-HT 920 (0.6-20 mg kg-1 s.c.) induced considerable locomotor activity at 4 h post reserpine. At 24 h post reserpine the dose-response curve of B-HT 920 (0.06-20 20 mg kg-1 s.c.) was shifted to the left and the maximum effect was greatly increased. When additional alpha MPT was given, the dose response curve was the same but the maximum effect was markedly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biphasic locomotor effects of the dopamine D1 agonist SKF 38393 and their attenuation in non-habituated mice

The locomotor stimulatory effects of the dopamine D₁ receptor partial agonist SKF 38393 were examined in male C57B1/6J mice. Non-habituated mice showed marked dose-related (3–300 mg/kg, SC) locomotor stimulation. The time-course effect was biphasic at very high doses (100–300 mg/kg), with dose-related locomotor depression followed by dose-related long-term hyperlocomotion. For all doses, locomotor effects were detectable throughout the 4-h test period. To determine whether these effects were mediated by D₁ receptor stimulation, effects of SKF 38393 were assessed in combination with behaviorally inactive and active doses (0.1 and 0.2 mg/kg, respectively) of the selective D₁ receptor antagonist SCH 39166. Both doses of SCH 39166 attenuated the hyperlocomotion induced by 30 mg/kg of the agonist to a similar degree. However, neither dose was able to reverse either the depressant or the stimulatory effects of 300 mg/kg SKF 38393. These results demonstrate effects of the prototypical D₁ agonist previously unobserved, and raise questions concerning the nature of agonist/antagonist interactions at the D₁ receptor subtype.     

Individual differences in behavior following amphetamine,GBR-12909, or apomorphine but not SKF-38393 or quinpirole

Subjects that respond more to a novel environment show a greater locomotor response to drugs of abuse such as cocaine and amphetamine. The current study was performed to examine differences between high (HR) and low (LR) responding rats to a novel environment following administration of amphetamine, a selective dopamine uptake blocker (GBR-12909), a nonselective dopamine agonist (apomorphine), and selective dopamine D₁ and D₂/D₃ agonists. A behavioral checklist and a rating scale were used to determine the behavioral arousal caused by administration of amphetamine (0, 0.5, 2.0, and 8.0 mg/kg), GBR-12909 (0, 1.25, 5.0, and 20.0 mg/kg), apomorphine (0, 0.1, 0.3, and 1 mg/kg), SKF 38393 (0, 2.5, 10, and 40 mg/kg), or quinpirole (0, 0.05, 0.5, and 5.0 mg/kg). The five drugs produced behavioral activation profiles distinct from each other. Following amphetamine administration, both HR and LR subjects showed dose dependent increases in behavioral arousal. The behaviors primarily affected were sniffing, locomotor activity, rearing, and oral activity. HR rats showed a greater overall behavioral response to amphetamine administration compared with LR rats and there were differences in specific behaviors between the two groups. Following GBR-12909 administration, all subjects showed dose dependent increases in sniffing, locomotor activity, and rearing. Differences between HR and LR were observed in sniffing, locomotor activity, and rearing behaviors. HR and LR both showed dose dependent increases in behavior following apomorphine administration. HR showed greater behavioral activation after apomorphine than LR. SKF 38393 produced pronounced increases in the amount of sniffing, grooming, and intense grooming, in addition to increasing the overall behavioral rating of all subjects, while quinpirole produced increases in sniffing, locomotor activity, and oral movements. However, the behavioral effects of SKF 38393 and quinpirole did not differ between HR and LR. These results suggest that activation of the dopamine system but probably not only one type of dopamine receptor is sufficient to produce behavioral differences between high and low responding subjects.     

The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment

B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepine), an agonist at alpha 2-adrenoceptors and at dopamine autoreceptors, was tested with respect to stimulation of postsynaptic brain dopamine receptors in mice, rats and rhesus monkeys. In mice B-HT 920 (0.2-20 mg/kg s.c.) injected 4 h after reserpine did not stimulate locomotor activity; this was in contrast to apomorphine (0.1-10 mg/kg s.c.) which elicited locomotor activity in a dose-dependent manner. However, B-HT 920 was effective in inducing locomotor activity when injected 12, 24 and 48 h after reserpine. This effect was dose-dependent and increased with the duration of reserpine pretreatment. In naive rats, B-HT 920 (0.02-2.0 mg/kg s.c.) only decreased exploratory activity and did not elicit stereotyped activity in doses up to 4 mg/kg s.c. This was in contrast to the stereotypy-inducing effect of apomorphine (2.0 and 4.0 mg/kg s.c.). In rats with unilateral striatal ibotenic acid lesion, B-HT 920 (0.2-2.0 mg/kg s.c.) was ineffective in producing significant ipsilateral rotation, whereas apomorphine (0.5-10.0 mg/kg s.c.) was very potent in this model. In rats with unilateral 6-OH-dopamine lesions of the medial forebrain bundle B-HT 920 elicited strong contralateral rotation in a dose-dependent manner (0.02-1.0 mg/kg s.c.). In this model B-HT 920 was equi-effective but long acting when compared with apomorphine. The contralateral rotation produced by B-HT 920 was antagonized by the D2-antagonist sulpiride but not by the D1-antagonist SCH 23390. In rhesus monkeys with severe parkinson-like symptoms induced by MPTP, B-HT 920 in doses of 10 micrograms/kg i.m. and higher restored normal behavior, resulting in complete relief of parkinson symptoms in all animals with 100 micrograms/kg i.m. It is concluded that the property of B-HT 920 to stimulate the 'denervated' supersensitive (reserpine, 6-OH-dopamine, MPTP) but not the normosensitive postsynaptic dopamine receptor in the striatum may represent a novel principle for a specific approach to dopamine substitution treatment of Parkinson's disease.     

Dopamine D-2 receptor agonist-induced behavioural depression: critical dependence upon postsynaptic dopamine D-1 function

Summary The dopamine (DA) D-2 receptor agonists quinpirole (threshold dose, 0.01 mg/kg IP), pergolide (0.025 mg/kg), B-HT 920 (0.003 mg/kg) and (–)-3-PPP (4 mg/kg) produced dose-dependent locomotor depression (immobility) in mice as assessed by a subjective scoring system, with the immobility being characterized by a frozen posture. The animals were still but had their eyes open. The immobility was accompanied by reductions in sniffing, rearing and grooming. The depression (and the associated reduction in the various behaviours) produced by quinpirole (0.1 mg/kg), pergolide (0.1 mg/kg) and B-HT 920 (0.1 mg/kg) was substantially (but not always completely) reversed by the selective D-1 receptor agonist SKF38393 (up to 12 mg/kg) and the non-selective D-1 receptor agonist CY208243 (up to 3 mg/kg). The immobility induced by (–)-3-PPP (16 mg/kg) was also reversed by CY208243 and SKF38393, but the reversal was due to an increase in grooming behaviour in mice challenged with the D-1 receptor agonists, whether or not the animals had also received (–)-3-PPP. There was no reversal of the depression of rearing or sniffing. In contrast, CY208243 and SKF38393 also antagonized the immobility induced by B-HT 920, but the reversal was accompanied by at least partial reversals of the depression of sniffing, rearing and grooming. The reversal of quinpirole-induced immobility by SKF38393 and CY208243 was antagonized by SCH23390 (0.1 mg/kg). The selective D-2 receptor antagonist raclopride (0.025 to 0.4 mg/kg) could not reverse quinpirole-induced immobility. High doses of either raclopride (0.4 mg/kg) or SCH23390 (> 0.1 mg/kg) significantly increased immobility. Although raclopride itself (0.2 mg/kg) produced a substantial increase in DOPAC and homovanillic acid (HVA) levels in the striatum, it did not antagonize the autoreceptor mediated effects of quinpirole (0.1 mg/kg) in reducing the striatal dihydroxyphenylacetic acid (DOPAC) to DA ratio. However, the same dose of raclopride was partly effective in reducing the effects of lower doses of quinpirole (0.01 and 0.03 mg/kg) on the striatal DOPAC to DA ratio. Raclopride (0.2 mg/kg) also partially but significantly reduced the locomotor stimulant effects of d-amphetamine in reserpinized mice. Biochemical analyses in the striata indicated that CY208243 slightly retarded DA turnover (as assessed by the DOPAC/DA ratio). SKF38393 itself also slightly reduced DA turnover. In automated activity cages, using mice depleted of DA with reserpine and a-methyltyrosine, all the D-2 receptor agonists tested, in combination with SKF38393, produced an increase in activity. It is concluded that the depression induced by D-2 receptor agonists is due substantially to a deprivation of DA at postsynaptic D-1 receptors and that, at the doses tested, the D-2 receptor agonists were able to exert measurable stimulation of the postsynaptic receptors. The ability of D-1 receptor agonists to reverse the D-2-mediated depression is due to the stimulation of the postsynaptic D-1 receptors with the injected D-1 receptor agonist (replacing the endogenous transmitter) and the stimulation of the postsynaptic D-2 receptors by the injected D-2 receptor agonist.     

Comparison of the effects of NMDA and AMPA antagonists on the locomotor activity induced by selective D1 and D2 dopamine agonists in reserpine-treated mice

This study examined the interaction between various glutamate antagonists and selective D₁ (SKF 38393) and D₂ (RU 24213) dopamine agonists in the production of locomotion in the reserpine-treated mouse. Firstly, in normal mice, the NMDA channel blocker MK 801 (0.1–1.6 mg/kg) caused a biphasic stimulation/depression of locomotor activity, whereas the competitive NMDA antagonists CGP 40116 (0.25–8 mg/kg) and CPP (0.2–20 mg/kg), and the NMDA glycine site antagonist HA 966 (0.4–10 mg/kg) inhibited locomotion monophasically. These compounds caused varying degrees of muscle weakness and impairment of posture and gait, whilst the AMPA receptor blocker NBQX (0.2–25 mg/kg) had no significant effect on unconditioned mouse motor behaviour. None of the antagonists reversed reserpine-induced akinesia by themselves, but they all potentiated the locomotor movements induced by 30 mg/kg SKF 38393. Movements remained fluent with low doses of CPP, HA 966 and NBQX, but became ataxic with MK 801 and CGP 40116, with sedation prevailing at high doses of all the antagonists, as in normal mice. CPP and NBQX also combined synergistically with SKF 38393 to promote tonic convulsions. By contrast, RU 24213-induced locomotion was dose-dependently depressed by MK 801, CGP 40116 and HA 966, but was unaffected by CPP or NBQX. These differential effects of NMDA and AMPA antagonists on D₁ and D₂ motor responding in the monoamine-depleted mouse are discussed in terms of possible mechanisms and sites of action within the brain, and the implications for their putative use as adjuvants tol-dopa in antiparkinson therapy.     

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)     

The D1 dopamine agonist SKF 38393 functions as a discriminative stimulus in rats

Rats (N=11) were trained to discriminate SKF 38393 (8.0 mg/kg, IP), a D₁ dopamine receptor agonist, from saline in a two-lever, food-reinforced (FR 30) drug discrimination paradigm. The discrimination was acquired by nine rats within an average of 77±6 (SEM) sessions. Subsequently, various doses of SKF 38393 as well as SKF 82526, a potent, selective D₁ agonist that does not readily penetrate the blood-brain barrier, were injected prior to test sessions. SKF 38393 (2–16 mg/kg) produced a dose-related increase in the percent of responses that occurred on the drug lever during test sessions. On the other hand, SKF 82526 (0.125 and 1.0 mg/kg) induced no drugappropriate responding. This experiment establishes that SKF 38393 can serve as a discriminative stimulus in rats. Furthermore, the observation that SKF 82526 did not substitute for SKF 38393 in this paradigm makes it unlikely that this effect involves a peripheral site of action. The results suggest the existence of a functional, behaviorally relevant D₁ dopamine receptor in the CNS of rats.     

Parametric and pharmacological analyses of the enhanced grooming response elicited by the D1 dopamine receptor agonist SKF 38393 in the rat

The present report investigated several parametric and pharmacological aspects of the enhanced self-grooming behavior of rats following systemic administration of the selective D₁ dopamine (DA) receptor agonist SKF 38393. The amount of time that rats spent grooming themselves was measured continuously for 30 min following drug administration to provide a quantitative measure of the drug-induced behavior. SKF 38393 increased the amount of grooming in a dose-dependent manner (0.5–16 mg/kg, SC). The onset of this effect required at least 5 min and it persisted for at least 60 min. The ability of SKF 38393 to enhance grooming was shared by R-SKF 38393, but not S-SKF 38393, consistent with the affinities of these enantiomers for the D₁ DA receptor. Unlike SKF 38393, the peripheral D₁ agonist fenoldopam (SKF 82526) failed to cause an increased grooming response, suggesting a central site of action for elicitation of this behavior. The SKF 38393-induced increase in grooming was competitively antagonized by the D₁ selective antagonist SCH 23390 (0.5 mg/kg, SC). Although the D₂ DA receptor-selective antagonist eticlopride reduced SKF 38393-elicited grooming, this antagonism appeared to be of a physiological rather than pharmacological nature. When eticlopride was coadministered with the non-selective (mixed) D₁/D₂ agonist apomorphine, an increase in grooming behavior similar to that produced by SKF 38393 was observed. Inactivation of D₁ and D₂ DA receptors produced by pretreatment with the irreversible antagonistN-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ), at a dose which reduces D₁ and D₂ receptor density by 50% (8.0 mg/kg, IP), reduced SKF 38393-induced grooming by approximately 50%. Prior protection of D₁ receptors by SCH 23390 completely prevented the effect of EEDQ whereas prior protection of D₂ receptors by eticlopride did not. These results demonstrate that enhanced grooming behavior elicited by dopamine agonists in rats, when measured as the amount of time spent grooming, provides a reliable, quantifiable index of selective D₁ DA receptor activation in the CNS. In addition, this behavior does not appear to require concurrent stimulation of D₂ DA receptors by endogenous DA.     

Comparison of dopamine receptor antagonists on hyperlocomotion induced by cocaine, amphetamine, MK-801 and the dopamine D1 agonist C-APB in mice

Rationale: Direct or indirect stimulation of dopamine receptors increases locomotor activity in mice. Determining the role played by D₁ and D₂ dopamine receptors in the mediation of this activity can be difficult due to the wide variety of experimental paradigms used to investigate these phenomena. Objectives: This study set out to compare the role of selective antagonism of dopamine D₁ and D₂ receptors on the hyperactivity induced by a range of stimulants. Methods: Mice were habituated to perspex locomotor activity boxes (30×30× 30 cm) and activity was measured via photobeam interrupts. Results: Haloperidol and clozapine both reduced the hyperactivity induced by MK-801. Haloperidol did so only at a dose that also decreased spontaneous activity (0.1 mg/kg), whereas clozapine reduced MK-801-induced hyperactivity at a dose that had no effect on spontaneous activity (1.25 mg/kg). The D₁ antagonist SCH23390 (0.01 mg/kg) reduced hyperlocomotion induced by amphetamine (2.5 mg/kg), cocaine (10 mg/kg) and C-APB (1.0 mg/kg) at doses that did not consistently alter spontaneous activity, whereas the selective D₂ antagonist raclopride only attenuated the hyperlocomotion induced by amphetamine, cocaine and C-APB at doses in excess of the minimum dose required to attenuate spontaneous locomotor activity significantly. The latency to peak levels of hyperlocomotion induced by MK-801 (0.3 mg/kg) was delayed by SCH23390 (0.1 mg/kg) but peak levels of activity were not reduced. Conclusions: The results of the present study suggest that selective blockade of D₁ receptors suppresses amphetamine and cocaine-induced hyperactivity in mice but not MK-801-induced locomotor activity. Received: 1 January 1998 / Final version: 4 March 1999     

Alpha 2-adrenoceptor- and D2-dopamine receptor-mediated analgesic response of B-HT 920.

The involvement of D2-dopamine receptors in the antinociceptive action of B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-(4H) thiazolo-(4,5d)-azepine) has been investigated in mice. B-HT 920 (0.1-2.0 mg kg-1) and apomorphine (0.1-2.0 mg kg-1) produced a dose-dependent increase in tail flick latency. Analgesia induced by apomorphine was blocked by the D2-antagonist, haloperidol (1 mg kg-1) but not by the opioid antagonist, naloxone (1 mg kg-1). The antinociceptive action of B-HT 920 was potentiated by the D1-agonist SKF 38393 (5 mg kg-1), an action antagonized by haloperidol. The selective alpha 2-adrenoceptor blocking drug yohimbine (1 mg kg-1) and naloxone (1 mg kg-1) blocked the antinociceptive action of B-HT 920 (1 mg kg-1). Haloperidol, however, failed to modify the B-HT 920-induced increase in tail flick latency. B-HT 920 and apomorphine reversed reserpine (2 mg kg-1) 4 h-induced hyperalgesia. The reversing action of apomorphine was blocked by haloperidol but not by yohimbine. Thus, a role of alpha 2-adrenoceptors and D2-dopamine receptors is postulated in the antinociceptive action of B-HT 920.     

Effect of NMDA receptor antagonists on D1, D2 and D1/D2 mediated behaviors in intact rats

The effect of treatment with the competitive (CGP 43487) and non-competitive (MK-801) NMDA antagonists on behaviors induced by the stimulation of D₁ (SKF 38393 induced grooming), D₂ (LY 171555 elicited hypermotility) or D₁/D₂ (apomorphine induced locomotion and stereotypies) was observed in intact rats. The administration of low doses of MK-801 (0.03 and 0.06 mg/kg) or CGP 43487 (0.375 and 0.75 mg/kg), which were without effect by themselves on animal locomotion, reduced the hyperactivity induced by LY 171555 (0.15 mg/kg) and did not change the stimulating motor effect of a low dose of apomorphine (0.15 mg/kg). Spontaneous grooming behavior was inhibited by both NMDA antagonists, whereas the administration of CGP 43487 but not of MK-801 potentiated grooming response to SKF 38393 (10 mg/kg). Both antagonists increased stereotyped behavior induced by 0.25 mg/kg apomorphine. The results, according to those obtained by other authors in DA depleted/lesioned animals, support the view of interaction between NMDA/D₁,D₂ receptors in intact rats.     

Dopamine receptor mediated hypothermic action of B-HT 920 in rats.

The hypothermic action of the thiazoloazepine derivative B-HT 920, an alpha 2-adrenoceptor agonist has been investigated in rats. B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d)-azepine dihydrochloride) (0.25-1.0 mg kg-1 i.p.) induced a dose-dependent hypothermia. This peak effect was seen within 60-90 min and lasted up to 120 min. Its action was potentiated by the selective D1-dopamine agonist SKF 38393 and inhibited by the D2-antagonists haloperidol (1 mg kg-1) and sulpiride (100 mg kg-1). The hypothermic action of B-HT 920 was centrally mediated; i.c.v. administration of 10 micrograms produced a significant fall in rectal temperature which was sensitive to blockade by haloperidol. B-HT 920 also potentiated the hypothermic action of apomorphine (0.1 and 0.5 mg kg-1) in a haloperidol sensitive manner. Reserpine (5 mg kg-1 i.p.) pretreatment reduced the hypothermic response of B-HT 920 (0.5 mg kg-1) but sensitized the response due to the combination of B-HT 920 (0.5 mg kg-1) and apomorphine (0.1 mg kg-1). Neither the selective alpha 2-adrenoceptor antagonists, yohimbine (1 mg kg-1) or idazoxan (1 mg kg-1), the histamine antagonist mepyramine (10 mg kg-1) nor the 5-HT antagonist cyproheptadine (5 mg kg-1) inhibited B-HT 920-induced hypothermia. Similarly, the selective alpha 1-antagonist prazosin (1 mg kg-1) and the beta-antagonist propranolol (10 mg kg-1) failed to modify the hypothermic action of B-HT 920. These observations demonstrated hypothermia induced by B-HT 920 is mediated by postsynaptic D2-receptors and D1- and D2-receptor interplay is essential for the full expression of hypothermia in rats.