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.     

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     

Potentiation of licking in rats by stimulation of both D-1 and D-2 dopamine receptors

Apomorphine-induced licking in rats was assessed by recording the total number of licks by direct observation. Apomorphine induced licking dose dependently. The maximum response was obtained by 0.5 mg/kg of the drug and 30 min after drug administration. Pre-treatment with dopamine antagonists, sulpiride and SCH 23390 decreased the apomorphine effect. Pre-treatment of animals with reserpine+α-methyl-p-tyrosine (AMPT) increased apomorphine-induced licking. In normal rats the D-2 agonist quinpirole and the D-1 agonist SKF 38393 also induced significant licking. The effect of quinpirole or SKF 38393 was decreased by reserpine+AMPT pre-treatment. Combined treatment with SKF 38393 and quinpirole induced more intense licking in both reserpinized and non-reserpinized animals. It is therefore concluded that the apomorphine-induced licking is mediated through both D-1 and D-2 receptors, and that pre-treatment with reserpine hypersensitizes these receptors to the drug effect. However, for either SKF 38393- or quinpirole-induced licking, the presence of endogenous dopamine seems essential.     

Morphine stimulates locomotor activity by an indirect dopaminergic mechanism: possible D-1 and D-2 receptor involvement.

1. The effect of morphine on locomotor activity in mice and the mechanism involved were evaluated. 2. Subcutaneous (s.c.) injection of different doses of morphine (10, 20 and 40 mg kg-1) into mice induced a dose-dependent locomotor activity. 3. The response to morphine was decreased in animals pretreated by the D-1 antagonist SCH 23390, the D-2 antagonist sulpiride or the opiate receptor antagonist naloxone, but not by atropine, phenoxybenzamine, propranolol and methergoline. 4. The inhibitory effects of SCH 23390, sulpiride or naloxone were dose-dependent. 5. Pretreatment with reserpine prevented the effect of morphine. SKF 38393 (D-1 agonist) or quinpirole (D-2 agonist) also induced locomotor activity in mice. Also this effect was decreased by reserpine pretreatment. 6. Combination of SKF 38393 with quinpirole but not of morphine with SKF 38393 or quinpirole induced a high degree of locomotor activity in intact and reserpinized animals. 7. It is concluded that locomotor activity induced by morphine is mediated by opiate receptor through an indirect dopaminergic mechanism.     

Effect of dopamine D-1 and D-2 receptor selective drugs on dopamine release and metabolism in rat striatum in vivo

Summary The effect of the dopamine (DA) D-1 agonist SKF 38393, the D-2 agonist LY 171555 and the mixed D-1/D-2 agonist apomorphine on striatal DA release and metabolism was tested in vivo using an intracerebral dialysis method in halothane-anaesthetized rats. The specificity of responses to these agonists was tested using the selective DA antagonists SCH 23390 (D-1) and sulpiride (D-2).Both LY 171555, 0.01 mg/kg, and SKF 38393, 10 mg/kg, reduced levels of DA in striatal perfusates. Neither SCH 23390, 0.5 and 5 mg/kg, nor sulpiride, 10 mg/kg, affected levels of DA in striatal perfusates, but 250 mg/kg sulpiride caused a DA increase. The decrease of DA levels induced by LY 171555 (0.01 mg/kg) was prevented by pretreatment with sulpiride (10 mg/kg) but not SCH 23390 (0.5 mg/kg). In comparison, pretreatment with SCH 23390 (0.5 mg/kg) completely inhibited the reduction of DA induced by SKF 38393 (10 mg/kg) while sulpiride (10 mg/kg) was without effect. Apomorphine (0.05 mg/kg) also decreased DA in striatal perfusates and this action was partially inhibited by both SCH 23390 (0.5 mg/kg) and sulpiride (10 mg/kg).Levels of the DA metabolite DOPAC in striatal perfusates also significantly decreased following LY 171555 (0.01 mg/kg) and apomorphine (0.05 mg/kg) but not SKF 38393 (10 mg/kg). The antagonist SCH 23390, in a dose, 0.5 mg/kg, that alone did not increase levels of DOPAC, inhibited the reduction of DOPAC induced by both LY 171555 and apomorphine. Sulpiride, 10 mg/kg, caused a marked increase in striatal DOPAC and this was not affected by a subsequent injection of LY 171555, SKF 38393 or apomorphine.We conclude from these data that DA release in rat striatum is autoregulated by independent D-1 and D-2 receptor-linked mechanisms. In contrast, the level of DA metabolism is controlled by a D-2 receptor-coupled mechanism which can be influenced by the D-1 receptor. This study provides further evidence that DA release and DA synthesis/metabolism are able to change independent of each other.     

Inhibitory role of D-1 dopamine receptors for the jerks induced by B-HT 920 in rats

Jerks of the head and upper trunk produced by the dopamine agonist B-HT 920 in reserpine-treated rats were abolished by the D-1 dopamine receptor agonist SKF 38393. The combined treatment with SKF 38393 and B-HT 920 instead resulted in stereotypies and locomotion. B-HT 920 also caused jerks when given after the D-1 receptor antagonist SCH 23390 to rats not pretreated with reserpine. The results indicate that B-HT 920 induces jerks by stimulation of postsynaptic D-2-like dopamine receptors provided that the D-1 receptors are not activated.     

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.     

SKF 38393 and apomorphine modify locomotion and exploration in rats placed on a holeboard by separate actions at dopamine D-1 and D-2 receptors

Horizontal motor activity, rearing and head dipping were recorded automatically in rats placed on a holeboard and taken as indices of locomotion and exploration. Other behaviours were assessed visually using a video camera. SKF 38393, 15-30 mg/kg (D-1 agonist), suppressed all three behavioural measures more effectively in habituated than in naive rats. These actions were blocked by SCH 23390 (0.05 mg/kg, D-1 antagonist) but not by haloperidol (0.05 mg/kg, D-2 antagonist). Apomorphine modified behaviour biphasically, causing haloperidol-resistant sedation at a low, presynaptic dose (0.05 mg/kg) and haloperidol-sensitive hyperactivity and stereotyped sniffing at a larger, postsynaptic dose (0.5 mg/kg, especially after habituation). Neither action was antagonised by SCH 23390. The results support the conclusion that D-1 and D-2 dopamine recognition sites can separately influence the processes controlling locomotion and exploratory activity in normal rats.     

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)     

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.     

Bromocriptine requires D-1 receptor stimulation for the expression of sniffing behaviour in rats

The effect of the mixed D-1/D-2 dopamine agonist apomorphine, the D-2 agonist bromocriptine and the D- 1-selective dopamine agonist SKF 38393 on sniffing behaviour in rats was tested in the present experiments. Apomorphine induced a dose-dependent sniffing, which was decreased by either D-2 or D-1 dopamine antagonist pre-treatment. Atropine (antimuscarinic drug) or phenoxybenzamine and propranolol (α and β- adrenergic blockers, respectively) did not alter the apomorphine response. Apomorphine induced a significant increase in sniffing in reserpine-treated animals. Bromocriptine produced sniffing during the 3rd hour after drug injection. The effect was decreased by sulpiride or SCH 23390 pre-treatment. Phenoxybenzamine or propranolol did not change the bromocriptine effect, while atropine increased the drug response. SKF 38393 also induced a slight but significant sniffing. In rats pre-treated with reserpine, neither bromocriptine nor the D-1-selective agonist SKF 38393 produced any sniffing. However, the combination of bromocriptine with SKF 38393 produced an intense sniffing behaviour. It may be concluded that bromocriptine requires D-1 receptor stimulation for the expression of sniffing.     

Permissive role of D-1 receptor stimulation by endogenous dopamine for the expression of postsynaptic D-2-mediated behavioural responses. Yawning in rats

Low doses of BHT 920, LY 171555 and (+)3PPP, three dopamine agonists selective for D-2 receptors, induced yawning in rats. This effect was reduced by the selective D-1 antagonist SCH 23390 but the antagonism did not exceed a 50% reduction from the control values. In contrast, the selective D-2 antagonist (-)sulpiride completely abolished agonist-induced yawning. A 6 h reserpine pretreatment (5 mg/kg i.p.), which depletes brain dopamine (DA) by about 95%, reduced agonist-induced yawning by an extent similar to SCH 23390; in the reserpinized rats, SCH 23390 completely lost the property of blocking agonist-induced yawning while (-)sulpiride retained it. Two 5HT receptor antagonist, ketanserin and metergoline failed to influence agonist-induced yawning. The reportedly selective D-1 agonist, SKF 38393, failed to induce yawning in normal rats as well as in rats pretreated with reserpine 6 or 16 h earlier. If one excludes that SCH 23390 and the D-2 agonists interact with the same DA-receptors, the data are consistent with the possibility that stimulation of D-1 receptors by endogenous DA plays a permissive-facilitatory role for the behavioural expression of D-2 receptor activation.     

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.     

Synergistic interaction between dopamine D-1 and D-2 receptor agonists: circling behaviour of rats with hemitransection

Circling behaviour induced by dopamine (DA) agonists with different D-1/D-2 receptor selectivity was studied in rats with hemitransection at a level caudal to the striatum. The mixed D-1/D-2 agonist apomorphine induced ipsilateral circling behaviour after administration of doses similar to those that induced stereotyped behaviour in unlesioned rats. The effect of apomorphine was not influenced by co-treatment with SK & F 38393 or quinpirole, indicating that apomorphine induces a comparable D-1 and D-2 receptor stimulation in vivo also. Three selective D-1 agonists, SK & F 38393, SK & F 75670 and Lu 24-040 had no effects alone, while the preferential D-2 agonists quinpirole, pergolide and (-)-N-propylnorapomorphine induced ipsilateral circling of weaker intensity than did apomorphine. After co-treatment with SK & F 38393 the effects of these compounds were markedly increased. Combination of SK & F 38393, SK & F 75670 or Lu 24-040 with quinpirole induced circling with intensities similar to those seen after apomorphine. Pretreatment with the D-1 antagonist SCH 23390 or the D-2 antagonist YM 09151-2 completely antagonized the ipsilateral circling induced by either apomorphine or quinpirole + SK & F 38393. A range of partial (autoreceptor) D-2 agonists, i.e. (-)-3-PPP, (+)-3-phenethyl-PP, terguride, EMD 23448 and B-HT 920 were all ineffective as was the alpha 2-adrenoceptor agonist clonidine. However, B-HT 920 induced strong ipsilateral circling after combination with SK & F 38393, whereas (-)-3-PPP was ineffective.(ABSTRACT TRUNCATED AT 250 WORDS)     

D-1 receptor involvement in reward-related learning

A comparison of the effects of apomorphine, amphetamine and dopamine (DA) receptor subtype-specific agonists in responding for conditioned reward, self-administration and place conditioning paradigms provides insights into the possible involvement of D-1 and D-2 receptors in reward-related learning. Amphetamine and the D-2 agonists bromocriptine and quinpirole enhanced responding for conditioned reward, were self-administered and produced place preferences. Apomorphine impaired responding for conditioned reward by enhancing responding on two levers, was self-administered and produced a place preference. The D-1 agonist SKF 38393 impaired responding for condition reward, did not support self-administration and produced a place preference. The failure of SKF 38393 to support self-administration may have been related to effects of this drug, for example, peripheral aversive effects or a slow onset of action, unrelated to its action at the D-1 receptor. It was suggested that a D-1 agonist might be expected to be self-administered from the point of view of the hypothesis that it is the action at D-1 receptors of DA released in association with reward that produces reward-related learning. This hypothesis was supported by the remaining data. Thus, apomorphine and SKF 38393 may have masked the DA signal associated with reward in the conditioned reward paradigm leading to a loss of control of responding by the conditioned rewarding stimulus. In self-administration, apomorphine would have its onset of action after the performance of the response which is followed immediately by a conditioned reward. The conditioned reward may effectively maintain control of behaviour by the lever and related stimuli while the drug may maintain the effectiveness of the conditioned reward. In place conditioning, there is no specific environmental stimulus that must come to control responding; therefore, apomorphine and SKF 38393 may have been seen to produce place preferences in spite of their relatively tonic action at D-1 receptors. Finally, the finding that the D-1 antagonists SCH 23390 or SCH 39166 blocked the effects of reward in these paradigms was taken as further evidence that the D-1 receptor may be critically involved in the learning produced by rewarding stimuli.     

Postsynaptic dopamine (DA) receptor stimulator properties of the putative DA autoreceptor-selective agonist B-HT 920 uncovered by co-treatment with the D-1 agonist SK&F 38393

Postsynaptic dopaminergic behavioural effects of D-2 agonists can be promoted by concomitant D-1 receptor activation. The present experiment explored whether such effects could be elicited by the putative autoreceptor-selective D-2 agonist B-HT 920, when combined with the D-1 agonist SK&F 38393. Except for occasional jerks induced by B-HT 920, neither agonist caused significant dopaminergic stimulation when given separately, whereas combined treatment with SK&F 38393 and B-HT 920 induced clear-cut motor activation — particularly focused stereotyped licking and sniffing — in reserpine/AMT-pretreated rats. Both the D-1 antagonist SCH 23390 and the D-2 antagonist spiperone abolished these effects, while the SK&F/B-HT-induced stimulation was not significantly affected by the alpha₂-blocker idazoxan. It appears that classical postsynaptic DA receptor-stimulatory properties of B-HT 920 can indeed be demonstrated, provided that sufficient D-1 receptor tone prevails.     

Involvement of dopamine receptor subtypes in mouse thermoregulation

The effects of dopamine agonists on core body temperature (BT) were tested in mice. Apomorphine (APO) reduced BT of the mice dose dependently. The response was inhibited by the D-2 antagonist sulpiride, but not by the D-1 antagonist SCH 23390. The D-2 agonist quinpirole also decreased BT and this was prevented by sulpiride pretreatment. Administration of the D-1 agonist SKF 38393 increased BT. This hyperthermia was decreased by SCH 23390 pretreatment. In reserpinized animals, APO caused a dose-related increase in BT. The hyperthermic response of the drug was abolished in animals pretreated with a combination of sulpiride with SCH 23390, but not by single administration of sulpiride or SCH 23390. Quinpirole and SKF 38393 caused hyperthermia in reserpinized mice. The response was decreased in animals pretreated with sulpiride or SCH 23390, respectively. BT of the intact mice was decreased, while that of reserpinized animals was increased by SCH 23390 but not by sulpiride pretreatment. It is concluded that the presynaptic dopamine neurons are involved in hypothermia, while both post-synaptic D-1 and D-2 dopamine receptors may mediated the hyperthermia induced by dopaminergic agents.     

Differential effects of dopamine agonists on locomotion in intact and reserpine-treated mice.

1. Apomorphine and bromocriptine induced a dose-dependent locomotion in mice. The responses of both drugs were decreased by SCH 23390 or sulpiride pretreatment. 2. Locomotor activity induced by apomorphine was increased and that of bromocriptine was decreased by reserpine. 3. SKF 38393 or quinpirole also induced locomotion. The response of SKF 38393 was decreased by reserpine. 4. Combination of SKF 38393 with bromocriptine induced a significant locomotor activity different from that of SKF 38393 or bromocriptine in reserpinized animals. 5. Combination of quinpirole with bromocriptine even decreased the response of bromocriptine in intact animals. 6. In conclusion, bromocriptine needs intact dopaminergic neurons and activation of D-1 receptor for expression of locomotion. High doses of quinpirole may induce locomotor activity possibly through D-1/D-2 receptor activation and quinpirole may potentiate the effect of bromocriptine on autoreceptor for inducing sedation.     

D-1/D-2 behavioural interactions in the rat involving striatal dopamine D-1 receptors

Simultaneous systemic administration of SKF 38393 (1-15 mg/kg i.p.) and LY 171555 (0.625-20 mg/kg s.c.) showed clear evidence of dopamine D-1/D-2 behavioural interactions compared to either treatment given alone. Similar interactions were observed between an intermediate systemic dose of LY 171555 (5 mg/kg) and SKF 38393 (1-10 micrograms) microinjected bilaterally into the caudate-putamen, but not into the substantia nigra pars reticulata, suggesting that striatal dopamine D-1 receptors are the ones responsible for mediating the altered behavioural responses to D-2 agonists in the intact rat.     

Partial agonistic action of clozapine at dopamine D2 receptors in dopamine depleted animals

 In the present experiments, the locomotor and stereotypic stimulant effects of the atypical antipsychotic agent, clozapine were studied in mice depleted of their brain dopamine by reserpine and alpha-methyl-p-tyrosine pretreatment. Clozapine at a dose of 1mg/kg produced slight stimulation of locomotor activity, but failed to produce any stereotypy. However, clozapine at 0.5 or 2 mg/kg failed to show increase in locomotor activity or stereotypy. Clozapine potentiated the locomotor activity and stereotypy induced by selective dopamine D₁ receptor agonist, SKF 38393 but blocked locomotor activity and stereotypy induced by dopamine D₂ agonist, B-HT 920 (1 mg/kg) and stereotypy induced by higher dose of B-HT 920 (2 mg/kg). The synergistic action of clozapine and SKF 38393 was partially blocked by the dopamine D₁ selective antagonist SCH 23390 and the dopamine D₂ selective antagonist, sulpiride, respectively. Clozapine potentiated the stereotypy induced by apomorphine (0.5 and 1 mg/kg) but did not affect locomotor stimulating activity of apomorphine. These behavioral effects of clozapine suggested that it has partial agonistic action at dopamine D₂ receptors. Received: 22 July 1997/Final version: 17 August 1997