Characterization of dopamine receptors involved in apomorphine-induced pecking in pigeons.

1. The possible involvement of subtypes of dopamine-receptors in apomorphine induced pecking was studied in pigeons. Different doses of apomorphine induced pecking in pigeons which was dose-dependent. 2. The response was decreased by SCH 23390 (D-1 antagonist) or high doses of sulpiride (D-2 antagonist) pretreatment, but increased by lower doses of sulpiride. 3. Combination of SCH 23390 with sulpiride completely antagonized the apomorphine effect. 4. Single dose administration of SKF 38393 (D-1 agonist) or bromocriptine (D-2 agonist) and combination of these drugs did not induce pecking, although either SK 23390 or bromocriptine increased the apomorphine-induced pecking which was decreased by SCH 23390 or sulpiride pretreatment. 5. It may be concluded that pecking, induced by apomorphine in pigeons, is elicited through activation of both D-1 and D-2 dopamine-receptors.     

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.     

Evaluation of dopamine receptor involvement in rat feeding behaviour.

1. The anorectic effect of dopamine agonists and antagonists were studied in rats. 2. Dopamine agonists bromocriptine, quinpirole or SKF 38393 treatment induced, a dose-dependent anorexia in rats. 3. Anorectic effect of bromocriptine was decreased in animals pretreated with pimozide (D-2 antagonist), but not by sulpiride (D-2 antagonist) or SCH 23390 (D-1 antagonist) pretreatment. 4. Anorexia induced by quinpirole was decreased by sulpiride or pimozide, but not by SCH 23390 administration. 5. While sulpiride and SCH 23390 failed to antagonize the anorectic response of SKF 38393, methergoline (5-HT antagonist) decreased anorexia induced by the drug. 6. A combination of quinpirole with SKF 38393 did not elicit potentiated anorectic response. 7. Decrease in food intake induced by bromocriptine, quinpirole or SKF 38393 was potentiated in reserpinized animals, although single administration of reserpine also induced a marked decrease in feeding. 8. Single administration of sulpiride, pimozide or methergoline did not change the feeding behaviour of rats, but SCH 23390 induced anorexia. 9. It is concluded that D-2 activation may induce inhibition of feeding and anorexia induced by SKF 38393 may be mediated through serotonergic mechanism(s).     

Influences of dopamine receptors on chewing behaviour in rats.

1. Intraperitoneal (i.p.) injection of different doses of pilocarpine induced purposeless chewing in rats. Physostigmine (i.p.), but not neostigmine (i.p.) also induced chewing behaviour. 2. Subcutaneous (s.c.) pretreatment of animals with the D-1 receptor blocker SCH 23390 decreased the number of chews induced by pilocarpine. 3. The D-2 dopamine antagonist sulpiride (i.p.) and anticholinergic atropine (i.p.) pretreatment also decreased the frequency of chews induced by the drug. 4. The response induced by pilocarpine (1 mg/kg i.p.) also was dose-dependently decreased in animals pretreated with apomorphine (0.25-1 mg/kg s.c.). 5. Administration of low doses of apomorphine (s.c.) also induced chewing, which was decreased with increasing the doses of the drug. 6. Chewing-induced by apomorphine was decreased by sulpiride or atropine and increased by SCH 23390 pretreatment. 7. Single administration of D-2 dopamine agonist bromocriptine also showed a slight but significant purposeless chewing, which was decreased by sulpiride pretreatment. 8. Single administration of D-2 agonist quinpirole, D-1 agonist SKF 38393 or D-1 antagonist SCH 23390, but not sulpiride caused a slight chewing. 9. It may be concluded that D-1 or D-2 activation exert opposite influences on chewing behaviour in rats, although to prove this effect more elucidation is needed.     

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.     

Alterations of bromocriptine-induced penile erection by chronic lithium in rats

In the present study, the effects of chronic lithium pre-treatment (30 days) on penile erection (PE) induced by bromocriptine were investigated in rats. Intraperitoneal administration of the dopamine receptor agonist, bromocriptine (4-32 mg/kg) induced PE in a biphasic manner. The maximum response was obtained with 8 mg/kg of bromocriptine and the effect was decreased with increasing doses of the drug from 8 to 32 mg/kg. When animals were pre-treated with different doses of the D-1 dopamine receptor antagonist, SCH 23390, or the D-2 dopamine receptor antagonist, sulpiride, the PE response was decreased. The response induced by bromocriptine (4-32mg/kg) was reduced in animals pre-treated with chronic lithium. SCH 23390 did not produce a larger inhibitory effect on the bromocriptine response in animals pre-treated with chronic lithium, but the inhibitory effect of sulpiride was increased in this condition. It is concluded that chronic lithium treatment may alter the D-1/D-2 receptor activity and inhibit bromocriptine-induced PE.     

Blockade of both D-1 and D-2 dopamine receptors may induce catalepsy in mice.

1. The catalepsy induced by dopamine antagonists has been tested and the possible dopamine subtypes involved in catalepsy was determined. 2. Dopamine antagonist fluphenazine, D-1 antagonist SCH 23390 or D-2 antagonist sulpiride induced catalepsy. The effect of fluphenazine and sulpiride was dose-dependent. Combination of SCH 23390 with sulpiride did not induce catalepsy potentiation. 3. D-1 agonist SKF 38393 or D-2 agonist quinpirole decreased the catalepsy induced by fluphenazine, SCH 23390 or sulpiride. 4. Combination of SKF 38393 with quinpirole did not cause potentiated inhibitory effect on catalepsy induced by dopamine antagonists. 5. The data may indicate that although D-2 receptor blockade is involved in catalepsy, the D-1 receptor may plan a role.     

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 D-1 or D-2 receptor stimulation on memory retrieval in mice

Mice were trained in one-way active avoidance procedure and retention was tested at 4, 8, 16 and 24 h after training of animals and compared with non-shocked or untrained animals. The effect of drugs was tested on retrieval 24 h after training in other groups of mice. High doses of apomorphine or bromocriptine impaired, while low doses of the drugs improved, retrieval of avoidance. High doses of sulpiride reversed the impairment induced by high doses of these dopamine agonists. Low doses of sulpiride antagonized the improvement of retrieval induced by low doses of apomorphine. SKF 38393 treatment of animals also improved the retrieval. The retrieval impairment induced by higher doses of apomorphine or the improvement induced by different doses of SKF 38393 was antagonized by SCH 23390 pre-treatment. Single administration of SCH 23390 or low doses of sulpiride also impaired retrieval. It is concluded that stimulating post-synaptic D-2 dopamine receptors impairs retrieval whilst activation of pre-synaptic D-2 or post-synaptic D-1 receptors improves memory retrieval.     

The Effect of Acute Lithium and Rubidium Pretreatment on Apomorphine-Induced Pecking in Pigeons

Abstract: The effects of different doses of lithium (5-320 mg/kg intramuscularly) and rubidium (0.25-32 mg/kg intramuscularly) on apomorphine-induced pecking were investigated in pigeons. These two cations did not induce pecking by itself. Intramuscular administration of apomorphine (a mixed D1/D2 dopamine receptors agonist, 0.1-1.6 mg/kg) induced pecking in a dose-dependent manner. SCH 23390 (Dl dopamine receptor antagonist, 0.02-0.08 mg/kg) and sulpiride (D2 dopamine receptor antagonist, 25-100 mg/kg) decreased apomorphine-induced pecking dose-dependently. Combination of SCH 23390 (0.04 mg/kg) with sulpiride (50 mg/kg) caused a stronger inhibitory effect on apomorphine response. This indicates that both Dl and D2 dopamine receptors are involved in apomorphine-induced pecking. The response induced by apomorphine (0.2-0.8 mg/kg) was decreased in animals pretreated with lithium and rubidium. In these conditions, SCH 23390 and sulpiride produced a larger inhibitory effect on the apomorphine response, suggesting that acute lithium and rubidium pretreatment inhibit pecking by interfering with dopaminergic mechanisms.     

Bromocriptine induces climbing behaviour: possible D-1 or D-2 dopamine receptor involvement

The ability of bromocriptine (BRC), a dopamine D-2 receptor agonist, to induce climbing behaviour was studied in mice. BRC (2–32 mg/kg IP) evoked climbing behaviour. The maximum effect was obtained with 8 mg/kg, while higher doses of BRC (16 and 32 mg/kg) were less effective. Climbing began about 2 h after injection and was most marked 5 h after bromocriptine administration. Pretreatment of animals with the dopamine antagonist pimozide (0.5 mg/kg IP) decreased BRC-induced climbing. Sulpiride (0.25–1.25 mg/kg IP), a potent D-2 antagonist and/or SCH 23390 (0.025 and 0.05 mg/kg SC), a D-1 receptor antagonist, also decreased the response. Furthermore, the climbing behaviour induced by BRC was abolished by pretreatment with reserpine plus alpha-methyl-p-tyrosine (AMPT). Concomitant administration of apomorphine (APO) and BRC potentiated the effect of APO on climbing. Concomitant injection of BRC and SKF 38393 (SKF, D-1 agonist) reduced the effect of SKF on climbing, while administration of BRC 4 h before SKF potentiated the effect of both drugs. It is suggested that BRC induces climbing through D-1 and/or D-2 dopamine receptors.     

Different effects of direct and indirect dopamine receptor agonists on immobility time in reserpine-treated mice.

1. The effects of dopamine agonists on the immobility time in mice were examined. 2. Apomorphine (APO), bupropion (BUP), bromocriptine (BRC) and quinpirole but not SKF 38393 elicited anti-immobility effect. The effect of the agonists was decreased by the D-2 antagonist sulpiride but not by the D-1 antagonist SCH 23390. 3. In animals pretreated with reserpine, the anti-immobility effects of APO and quinpirole were potentiated, while the response of BPU was decreased and that of BRC was not changed. 4. It is concluded that D-2 dopamine receptors are involved in the anti-immobility effects of dopaminergic agents, D-2 dopamine receptors may become hypersensitive by reserpine and BUP exerts its response through indirect dopaminergic if mechanism.     

Effects of chronic lithium pretreatment on apomorphine-induced penile erection

• 1.1. The effects of chronic lithium pretreatment (600 mg/l in drinking rats, 30 days) on penile erection (PE) induced by apomorphine were investigated in rats. This treatment resulted in a serum Li concentration after 30 days of 0.31 ± 0.01 mmol/l.
• 2.2. Subcutaneous (s.c.) administration of mixed Dl/D2 dopamine receptor agonist apomorphine (0.05–0.5 mg/kg) induced PE in a biphasic manner. The maximum effect was obtained with 0.1 mg/kg of the drug while the response decreased with increasing doses of apomorphine from 0.1 to 0.5 mg/kg.
• 3.3. Pretreatment of animals with 0.0125-0.1 mg/kg of D1 dopamine receptor antagonist SCH 23390 or D2 dopamine receptor antagonist sulpiride (12.5–100 mg/kg) decreased apomorphine-induced PE. Combination of SCH 23390 (0.025 mg/kg) with sulpiride (12.5 mg/kg) caused a stronger inhibitory effect on apomorphine response. This indicates that both D1 and D2 dopamine receptors may be involved in PE induced by apomorphine.
• 4.4. The response induced by apomorphine (0.05-0.5 mg/kg) was decreased in animals pretreated with chronic lithium. The inhibitory effect of sulpiride on apomorphine response, increased in animals pretreated with lithium, in contrast the inhibitory effect of SCH 23390 did not change in this condition. However, a combination of SCH 23390 with sulpiride increased inhibitory effect on apomorphine response in lithium pretreated rats.
• 5.5. It is concluded that chronic lithium inhibits PE induced by dopaminergic mechanism(s).

     

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.     

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

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

Motor activity following the administration of selective D-1 and D-2 dopaminergic drugs to normal common marmosets

In normal common marmosets administration of the D-1/D-2 agonist apomorphine or the selective D-2 agonist quinpirole caused a dose-dependent increase in motor activity and induced stereotyped behaviour. Both the selective D-2 antagonist raclopride and the selective D-1 antagonist SCH 23390 inhibited normal locomotor activity and induced catalepsy. Quinpirole- and apomorphine-induced motor activity were potently inhibited by pretreatment with raclopride. The effects of quinpirole, but not apomorphine, were weakly inhibited by SCH 23390. The selective D-1 partial agonist SKF 38393 decreased motor activity and did not induce grooming, oral movements or other behaviours. SKF 38393 inhibited motor activity induced by the administration of quinpirole but did not alter apomorphine-induced motor behaviour. Locomotor activity in normal common marmosets appears to be mediated mainly via D-2 systems. In contrast to rodents, administration of SKF 38393 does not induce behavioural activation and there does not appear to be a facilitating effect of D-1 systems on D-2 function in the normal common marmoset. However, the ability of both SKF 38393 and SCH 23390 to inhibit quinpirole locomotor activity suggests some interaction between D-1 and D-2 systems to occur in this species.     

Effects of dopaminergic agents on antinociception in formalin test.

Morphine caused a dose-related antinociception in early phase and late phase of formalin test in mice. The D2 dopamine agonist quinpirole, but not the D1 dopamine agonist SKF 38393, increased the antinociceptive effect of morphine in both phases of the test. The antinociceptive effect of quinpirole also was decreased by sulpiride or domperidone pretreatment in the early phase of test. The D1 antagonist SCH23390, the D2 antagonist sulpiride, or the peripheral D2 dopamine antagonist domperidone, increased the morphine effect. Single administration of SKF38393, quinpirole, SCH23390, sulpiride, and domperidone also induce antinociception. The response of SCH23390, but not that of other dopamine agents, was antagonized with naloxone. The effects of the drugs alone and in combination with morphine have been discussed.     

Differential ability of selective and non-selective dopamine agonists to induce climbing in the rat indicates the involvement of both D-1 and D-2 receptors in this behaviour

Approximately 50% of female Wistar rats examined exhibited a continuous climbing response to a screening dose of apomorphine. In animals identified as climbing, the mixed D-1/D-2 agonists apomorphine, pergolide andl-dopa, and the indirectly acting agonists nomifensine and (+)-amphetamine, induced a dose-related climbing response. The selective D-1 agonist SKF 38393 caused only minimal climbing, and the selective D-2 agonists bromocriptine, lisuride and LY 141865 induced a weak climbing response. All agonists examined, except SKF 38393, caused a dose-related stereotypy response. The selective D-1 antagonist SCH 23390, and the selective D-2 antagonist sulpiride, both produced maximum inhibition of apomorphine-induced climbing. SCH 23390 also inhibited stereotyped behaviour, but sulpiride was less effective. In animals identified as non-climbers using the screening dose of apomorphine, onlyl-dopa induced a marked climbing response. Nomifensine and bromocriptine produced weak or discontinuous climbing in this group, while the other agonists examined had little or no effect. In contrast all drugs examined, except SKF 38393, induced stereotyped behaviour of the same intensity observed in the climbers. It is concluded that stimulation of both D-1 and D-2 receptors is necessary to induce a continuous climbing behaviour in rats. D-2, but not D-1 stimulation, alone can induce a weak or discontinuous climbing response, but concomitant stimulation of D-1 receptors potentiates this effect. Failure of some rats to climb does not appear to be related to relative degrees of D-1 and D-2 stimulation.     

The effects of selective dopamine receptor agonists and antagonists on body temperature in rats

Body temperature was measured at repeated time intervals following the administration of various dopamine agonists and antagonists. The D-1 and D-2 receptor agonist, apomorphine, produced dose-dependent hypothermia. This effect was inhibited by the D-2 receptor antagonist, spiroperidol. Stimulation of D-2 receptor by LY171555 produced dose-dependent hypothermia, which was attenuated by pretreatment with spiroperidol and not altered by the D-1 receptor antagonist SCH23390. The D-1 receptor agonist, SK&F38393 had no effect on body temperature. SCH23390 administered alone produced initial hyperthermia and subsequent hypothermia. When administered with apomorphine, SCH23390 both attenuated and potentiated the hypothermic response, depending on the dose and time of administration of each drug. The results suggest that dopamine receptor agonists induce hypothermia by stimulation of the D-2 receptor subtype.     

Role of D-1 and D-2 receptors in apomorphine-induced pecking in chicks

The possible involvement of subtypes of dopamine (DA) receptors in pecking induced by apomorphine (APO) in chicks was studied. D-1/D-2 agonist APO dose-dependently induced pecking in chicks. The APO response was decreased in animals pretreated with either the D-2 receptor antagonist sulpiride or the D-1 receptor antagonist SCH 23390. The inhibitory effects of both antagonists were also dose dependent. The pecking induced by APO was completely inhibited in animals pretreated with a combination of SCH 23390 and sulpiride and was potentiated with reserpine. Single administration of D-2 agonist quinpirole or D-1 agonist SKF 38393 did not induced pecking, although quinpirole, but not SKF 38393 caused considerable response in reserpine or reserpine + -methyl-p-tyrosine (AMPT)-treated animals. When quinpirole was administered with SKF 38393, a slight pecking response was shown. This was also potentiated in reserpine or reserpine + AMPT-treated chicks. The results may indicate that both D-1 and D-2 DA receptors are involved in pecking induced by APO, and reserpine treatment caused the sensitization of the D-2 receptors for the induction of pecking in chicks.