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).

     

Effects of lithium carbonate on apomorphine-induced sniffing behaviour in rats

Effects of lithium carbonate (Li2CO3) on sniffing induced by apomorphine have been tested in rats. Intraperitoneal administration of different doses of apomorphine (0.25, 0.5 and 1 mg/kg) induced a dose-dependent sniffing response. Chronic Li2CO3 exposure (0.1% in drinking water for 30-35 days) but not acute administration of the drug (320 mg/kg, intraperitoneally) decreased the response of apomorphine. The response to chronic Li2CO3 exposure was observed when apomorphine was injected 60 min., 24 hr or 72 hr after Li2CO3withdrawal, with maximum effect observed when the drug was administered 72 hr after withdrawal of Li2CO3. Blockade of sniffing induced by apomorphine by the D1 dopamine receptor antagonist, SCH23390 (0.005 mg/kg, intraperitoneally) or the D2 dopamine receptor antagonist, sulpiride (25 mg/kg, intraperitoneally) was not increased in acute Li2CO3-treated animals. In animals which were treated chronically with Li2CO3, the blockade of apomorphine response by sulpiride but not by SCH23390 was potentiated. It is concluded that chronic treatment of animals with Li2CO3 is able to alter D2 dopamine receptors response.     

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.     

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.     

Repeated administrations of dopamine receptor agents affect lithium-induced state-dependent learning in mice

The influence of repeated administration of dopamine receptor agents on the effect of lithium on lithium-induced state-dependent learning was examined in mice. Immediate post-training intraperitoneal (i.p.) administrations of lithium (10 and 20 m/kg) decreased the step-down latency of a single-trial inhibitory avoidance task. This was fully or partly reversed by pre-test administration of the same doses of the drug, with maximum response at the dose of 10 mg/kg, suggesting state-dependent learning was induced by lithium. Here, it has also been shown that repeated intracerebroventricular administrations of a mixed D1/D2 dopamine receptors agonist apomorphine (once daily injections of 0.5 microg/mouse for three consecutive days followed by five days of no drug treatment) increased the effect of lower doses of pre-test lithium (1.25, 2.5 and 5 mg/kg, i.p.) on the reinstatement of the step-down latency decreased by post-training lithium (10 mg/kg). On the contrary, not only repeated administrations of the dopamine D1 receptor antagonist SCH 23390 (0.5 and 1 microg/mouse) but also the dopamine D2 receptor antagonist sulpiride (0.3 and 1 microg/mouse) disrupted the state-dependent learning induced by lithium. These results suggest that state-dependent learning induced by lithium may be altered by repeated pretreatment of dopamine receptor agents.     

Effects of selective D1 and D2 dopamine antagonists on the development of behavioral sensitization to apomorphine

The objective of the present study was to determine whether the development of behavioral sensitization to apomorphine could be blocked by either D₁ or D₂ selective dopamine antagonists. In three experiments, male rats received 10–21 daily injections of a selective D₁ (SCH 23390; 0 or 0.5 mg/kg IP) or D₂ (sulpiride; 0, 30, or 100 mg/kg IP) antagonist followed by an apomorphine (0 or 1.0 mg/kg SC) injection. In two experiments, the rats were tested for locomotor activity in photocell arenas after the daily injections. In all experiments, the rats were tested for sensitization to apomorphine following the training phase. The results indicated that apomorphine produced a progressively greater increase in locomotor activity with each injection, and this apomorphine-induced increase in activity was completely blocked by both sulpiride and SCH 23390 treatments. However, although both sulpiride and SCH 23390 blocked apomorphine-induced activity, only SCH 23390 injections prevented the development of sensitization to apomorphine. That is, rats pretreated with sulpiride and apomorphine displayed significant sensitization when subsequently tested with a challenge dose of apomorphine alone. These findings suggest that the development of behavioral sensitization to apomorphine is related specifically to the stimulation of dopamine D₁ receptors.Portions of this paper were presented at the 1990 Society for Neuroscience meetings, St. Louis, MO, USA     

Effect of the D1 receptor agonist SKF 38393 on some behavioural effects of apomorphine in rats

Summary The dopamine receptor agonist apomorphine in experiments on rats in low doses (0.025–0.2 mg/kg, s.c.) induced yawning which reflected a selective activation of presynaptic dopamine receptors. In high doses (0.25–1.0 mg/kg) apomorphine induced stereotyped sniffing and yawning in consequence of postsynaptic D 2 receptor activation. Dopamine D 1 receptor agonist SKF 38393 inhibited yawning induced by low doses of apomorphine. The inhibitory effect of SKF 38393 on apomorphine-induced yawning was attenuated by pretreatment with specific D I receptor antagonist SCH 23390 [2-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1 H-3-benzazepine-7-ol]. On the other hand however, SKF 38393 potentiated sniffing induced by the high doses of apomorphine without affecting gnawing. These data indicate that D 1 receptor activation modulates both pre- and postsynaptic effects of apomorphine in opposite directions.     

Stimulation of dopamine D2 receptors induces an analgesia involving an opioidergic but non enkephalinergic link

In the hot plate test, the dopamine D2 receptor agonist RU 24926 as well as the mixed dopamine D1/D2 receptor agonist apomorphine dose dependently increased the nociceptive threshold of mice, as expressed by the jump latency. The dopamine D1 receptor agonist SKF 38393 was ineffective on this parameter. The effect of RU 24926 was antagonized by the dopamine D2 specific receptor antagonist sulpiride but not by the dopamine D1 specific receptor antagonist SCH 23390. It was not increased by SKF 38393. However, the effect of apomorphine was partially but significantly reduced by SCH 23390. Inhibitors of enkephalin-degrading peptidases (thiorphan and bestatin injected i.c.v. or acetorphan injected i.v.) did not potentiate the effect of apomorphine whereas the delta opioid antagonist IC 154, 129 did not reverse the apomorphine-induced analgesia. Finally, the effect of apomorphine was significantly decreased in mice rendered tolerant to morphine. It is concluded that, in mice, the antinociceptive effect induced by apomorphine results mainly from stimulation of D2 receptors. This stimulation probably involves an endogenous opioid, different from enkephalins, which acts at mu opioid receptors.     

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.     

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.     

Dopamine D2 receptors and spinal cord excitation in mice

Spinal cord excitation was induced in mice by morphine and the effects of dopamine D1 and D2 receptor antagonists on the Straub tail reaction were investigated. The dopamine D2 receptor antagonist, sulpiride (25-100 mg/kg i.p.), or haloperidol (0.25-1.0 mg/kg dose dependently inhibited the Straub tail reaction induced by subcutaneously injected morphine. A low dose of apomorphine (50 micrograms/kg s.c.) also reduced the Straub tail reaction. The dopamine D1 receptor antagonist, SCH-23390 (25-100 micrograms/kg i.p.), had no significant effect. Sulpiride (50 mg/kg i.p.) significantly inhibited the Straub tail reaction induced by intrathecally injected morphine (6 microgram/mouse). Intrathecal injection of apomorphine (12.5-25 micrograms/mouse) induced the Straub tail reaction dose dependently. The Straub tail reaction induced by intrathecally injected apomorphine was significantly inhibited by sulpiride. SCH-23390 had no significant effect on the Straub tail reaction induced by intrathecally injected morphine or apomorphine. These results support the proposal that the dopamine response involved in the Straub tail reaction is mediated by postsynaptic dopamine D2 receptors in the spinal cord of mice.     

Nicotine-induced grooming: a possible dopaminergic and/or cholinergic mechanism

The ability of nicotine, to induce grooming in rats was studied. Grooming was induced by i.p. injection of different doses (0.0675-0.5 mg/kg) of nicotine to rats. The effect was dose-dependent. However, the response was decreased with increasing doses of the drug from 0.25-0.5 mg/kg. Administration of the dopamine (DA) D1/D2 receptor agonist apomorphine (0.025-5 mg/kg, i.p.) also caused grooming in a dose-dependent manner. High doses of apomorphine (0.1-0.5 mg/kg, i.p.) also induced a lower degree of response. Combination of a low dose of nicotine (0.0675 mg/kg) with different doses of apomorphine did not show any interaction. However, there was an interaction between a high dose of nicotine and apomorphine. Thus, combination of a higher dose of nicotine (0.125 mg/kg) with apomorphine, reduced apomorphine-induced grooming. The muscarinic receptor antagonist atropine (5 and 10 mg/kg), peripheral nicotinic receptor antagonist hexamethonium (5 and 10 mg/kg), central nicotinic receptor antagonist mecamylamine (1 and 3 mg/kg) and D1 DA receptor antagonist SCH23390 (0.05 and 0.1 mg/kg) all decreased the response to nicotine. Atropine, mecamylamine and SCH23390 by themselves reduced spontaneous grooming. It is concluded that nicotine elicits grooming indirectly through a possible D1 dopaminergic mechanism. However, muscarinic and nicotinic cholinergic mechanism(s) may be involved.     

Involvement of dopamine receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats

In the present study, the effects of bilateral intrahippocampal CA1 injections of dopamine receptor agonists and antagonists on the acquisition and expression of morphine-induced place preference were examined in male Wistar rats. Subcutaneous administration of different doses of morphine sulphate (0.5-10 mg/kg) produced a conditioned place preference (CPP) dose-dependently. Using a 3-day schedule of conditioning, it was found that dopamine D1 receptor agonist, SKF 38393 (0.01-1 microg/rat), dopamine D1 receptor antagonist, SCH 23390 (0.25-1 microg/rat), dopamine D(2/3) receptor agonist, quinpirole (0.3-3 microg/rat) or dopamine D2 receptor antagonist, sulpiride (0.04-5 microg/rat) did not produce significant place preference. The administration of SKF 38393 (1 microg/rat) significantly potentiated the acquisition of morphine (0.5 and 2.5 mg/kg)-induced place preference. This potentiation was reversed by SCH 23390 (1 microg/rat) pretreatment. Quinpirole injection (0.3 microg/rat) induced CPP in combination with the lower doses of morphine but decreased the response of the higher doses of morphine. These responses of quinpirole were reversed by sulpiride (5 microg/rat) pretreatment. SCH 23390 or sulpiride reduced the acquisition of morphine (7.5 mg/kg)-induced place preference. The administration of sulpiride, but not other drugs, during acquisition showed an increase in the locomotor activity on the testing days. SKF 38393, SCH 23390 or sulpiride, but not quinpirole when used before testing, reduced the expression of morphine-induced place preference. Sulpiride, but not other drugs, increased locomotion when used before testing. It is concluded that dorsal hippocampal dopamine receptors may play an active role in morphine reward.     

Inhibitory effects of MK-801 on contextual sensitization to climbing behavior and on development of tolerance to hypothermia induced by a single high dose of apomorphine

A single high dose of apomorphine (10 mg x kg(-1)) produced not only contextual sensitization to and conditioning of climbing behavior, but also context-independent tolerance to hypothermia. MK-801 (0.15 and 0.3 mg x kg(-1)) inhibited contextual sensitization to and conditioning of climbing behavior. Development of tolerance to hypothermia was also inhibited by MK-801. Dopamine D1 antagonist, SCH23390 (0.5 mg x kg(-1)), but not D2 antagonist, sulpiride, inhibited sensitization to and conditioning of climbing behavior. D2 antagonist, sulpiride (50 mg x kg(-1)), but not D1 antagonist, SCH23390, inhibited development of tolerance to hypothermia. These results suggest that MK-801 inhibited contextual sensitization to climbing behavior and development of tolerance to hypothermia through glutamatergic modulation of dopaminergic functions at dopamine receptors.     

Apparent enhancement by SCH 23390 of apomorphine-induced locomotor activity in mice.

Effects of the dopamine (DA) D1 antagonist SCH 23390 and the DA D2 antagonist (-)-sulpiride on apomorphine-induced characteristic changes in spontaneous motor activity were investigated in mice using the system we have devised for automatically analyzing animal behaviors in mice. Apomorphine (3 mg/kg, SC) markedly increased parameters of spontaneous motor activity such as locomotor activity and rearing time. Apomorphine-induced increase in locomotor activity had peaks at 5-20 and 30-50 min after administration, and its trough was closely related to the marked increase in rearing time induced by this agonist. Apomorphine-induced locomotor activity accumulated over a 40-min period from 5 to 45 min after apomorphine injection, during which apomorphine-induced increase in rearing time peaked, was significantly increased by intraperitoneal administration of 0.03 and 0.1 but not 0.01 mg/kg SCH 23390. Apomorphine-induced increase in rearing time was dose-dependently depressed by this antagonist. In contrast, (-)-sulpiride (10-40 mg/kg, IP) decreased apomorphine-induced increases in rearing time and locomotor activity rather than enhancing the latter parameter. These data suggest that the apparent enhancement by SCH 23390 of apomorphine-induced locomotor activity is mediated through DA D1 receptors and does not always correlate with depression of apomorphine-induced rearing behavior in mice.     

Increased grooming behaviour is induced by apomorphine in mice treated with discriminant benzamide derivatives

Grooming behaviour in mice was dose dependently increased by SK&F 38393 (1.87-30 mg/kg), whereas it was dose dependently decreased by RU 24926 (2.5-10 mg/kg) or LY 171555 (0.4-1.6 mg/kg) alone or combined with SK&F 38393 or apomorphine (0.39-6 mg/kg). The inhibitory effect of 0.75 mg/kg apomorphine on grooming behaviour was not modified by SCH 23390, chlorpromazine, clozapine and thioridazine. In contrast, it was antagonized by eight other dopamine antagonists: a partial restoration to grooming scores lower or similar to those determined in control mice was obtained with flupentixol, haloperidol, metoclopramide, thioproperazine and tiapride, whereas a reversal to grooming scores higher than those determined in control mice was obtained with mice treated with (+/-)-sulpiride, amisulpride or RIV 2093. Furthermore, only SCH 23390, chlorpromazine and clozapine antagonized SK&F 38393 (1.87 mg/kg)-induced grooming behaviour, whereas the effects of flupentixol, thioridazine, metoclopramide, haloperidol and amisulpride in SK&F 38393-treated mice were parallel to those of control mice. Finally, SCH 23390 (20 micrograms/kg) antagonized the apomorphine-induced grooming in mice treated with amisulpride, (+/-)-sulpiride or tiapride. These data confirm the potential role of D-1 dopamine receptors in the expression of grooming behaviour and indicate that the dopamine receptors involved in the inhibition of grooming could be of the D-4 subtype. Our results also reveal that chlorpromazine and clozapine have D-1 antagonist properties and suggest that the modulation of apomorphine-induced grooming behaviour by dopamine antagonists in mice could be used as a test for their classification according to their activity at the different dopamine receptor subtypes.     

SCH 23390, a selective dopamine D1 antagonist, activates dopamine neurons but fails to prevent their inhibition by apomorphine

SCH 23390, a rather selective D1 receptor blocker, activates the firing rate of dopamine (DA) neurons in the substantia nigra (SN-DA neurons) in rats, similarly to haloperidol (a D1-D2 receptor antagonist) and sulpiride (a selective D2 receptor blocker). These neuroleptics produce no additional increase over the maximal activation produced by SCH 23390. Unlike haloperidol or sulpiride, SCH 23390 fails to prevent the inhibition by apomorphine of SN-DA neurons, a DA autoreceptor-mediated effect. It is suggested that the doses of SCH 23390 that stimulate DA neurons block D2 in addition to D1 receptors, or that D1 blockade results in the functional inactivation of a specific population of D2 receptors as well. The failure of SCH 23390 to block the apomorphine effect indicates that DA autoreceptors can be pharmacologically differentiated form postsynaptic DA receptors.     

Evidence of the involvement of D1 dopamine receptors in PCP-induced stereotypy and ataxia in rabbits

A behavioural study on the effects of D1 and D2 dopamine receptor antagonists (SCH 23390 and sulpiride respectively) and of an A1 adenosine receptor agonist (N6-L-phenylisopropyladenosine, L-PIA) against phencyclidine (PCP)-induced effects was assessed in adult male rabbits. SCH 23390 (0.003-0.01 mg/kg i.v.) and sulpiride (12.5 mg/kg i.v.) were able to significantly prevent PCP-induced stereotypy. Ataxia was reduced by SCH 23390 (0.003 mg/kg i.v.), while it was potentiated by sulpiride (12.5 mg/kg i.v.). Given alone at 12.5 mg/kg, sulpiride induced some EEG and behavioural effects in rabbits, while SCH 23390 (0.003 and 0.01 mg/kg) did not. L-PIA prevented both PCP-induced stereotypy and ataxia at the dose (0.1 mg/kg i.v.) devoid of behavioural or EEG effects by itself. Our results suggest that D1 dopamine receptors might play a more important role than D2 receptors in the expression of PCP-induced behaviour. They also propose that A1 adenosine receptors might be involved (e.g. via an influence on the dopamine release) in the behavioural effects of PCP.     

Effect of the dopamine D-1 antagonist SCH 23390 on rotational behaviour induced by apomorphine and pergolide in 6-hydroxy-dopamine denervated rats

The experiments concerned the effects of the D-1 dopamine antagonist SCH 23390 on the rotational behaviour induced by apomorphine and pergolide in 6-hydroxy-dopamine denervated rats. SCH 23390 dose dependently inhibited the rotational behaviour induced by apomorphine. A significant inhibitory effect was obtained after 0.05 mg/kg s.c. of SCH 23390, which involved a change of the typical two-peak pattern of rotation induced by apomorphine. While the first peak of rotation was not significantly modified, the last peak of rotation induced by apomorphine was inhibited in a dose-dependent manner. No significant inhibition of the total rotation induced by pergolide was observed after SCH 23390 pretreatment. SCH 23390 seemed to enhance the duration of the rotation induced by pergolide, resulting in an increase in the total number of turns. However, the intensity of the maximal peak of rotation induced by pergolide was significantly inhibited after 5.0 mg/kg s.c. of SCH 23390. Comparison of the potency with which SCH 23390 inhibited the apomorphine- and pergolide-induced maximal peaks of rotation reveals that SCH 23390 was approximately 100 times more potent in inhibiting the apomorphine than the pergolide response. The results, compared with those in our previous report, show that the D-2 dopamine antagonist sulpiride was 1000 times more potent in inhibiting the pergolide than the apomorphine rotation. The present results support the hypothesis that apomorphine and pergolide induce rotation in 6-hydroxy-dopamine denervated rats by differential actions on D-1 and D-2 receptor sites.     

The mode of action of bromocriptine following pretreatment with reserpine and α-methyl-p-tyrosine in rats

The ability of bromocriptine (BRC), a selective dopamine D-2 receptor agonist, to induce yawning responses was studied in rats pretreated with reserpine and -methyl-p-tyrosine (-MPT). BRC (1–20 mg/kg IP) evoked yawning responses, which were pronounced at 2.5 mg/kg and characterized by the head moving downward. Higher doses of BRC (5–20 mg/kg) dose-dependently delayed the onset and peak time of yawning. A low dose of the selective D-1 dopamine receptor agonist SK&F38393 did not induce yawning but enhanced the BRC-induced response. Pretreatment with reserpine (1 and 5 mg/kg SC), -MPT (100 and 300 mg/kg IP) and reserpine (1 mg/kg) plus -MPT (100 mg/kg) was able to significantly reduce BRC-induced yawning. The inhibitory effects were prevented by a low dose of SK&F38393 (0.5 mg/kg IP). In particular, combined treatment with reserpine (5 mg/kg) and BRC (10 and 20 mg/kg) elicited upright fighting and jumping behaviors which were inhibited by haloperidol (1 mg/kg IP), a non-selective D-1 and D-2 receptor antagonist, SCH23390 (0.05 mg/kg SC), a selective D-1 receptor antagonist, or sulpiride (20 mg/kg IP), a potent D-2 receptor antagonist, and were potentiated by SK&F38393 (0.5 mg/kg). SCH23390 (0.05 mg/kg) decreased BRC-induced yawning and the apomorphine (low doses)-induced potentiation of BRC yawning, and prevented the apomorphine (high doses)-induced reduction of BRC yawning. SCH23390 also inhibited apomorphine-induced stereotypy and BRC-induced potentiation of apomorphine stereotypy. Furthermore, haloperidol (0.02 and 1.0 mg/kg IP), sulpiride (20 mg/kg IP) or scopolamine (0.5 mg/kg IP) inhibited BRC-induced yawning, but prazosin (1.0 and 3.0 mg/kg IP), an -1 receptor antagonist, did not affect this behavior. These results suggest that BRC-induced yawning may be mediated via presynaptic dopaminergic neuron activity and that BRC, in addition to the stimulation of dopamine D-2 receptors, appears to require endogenous dopamine or receptor activation by another dopamine agonist (D-1 agonist) for the induction of yawning, stereotypy and upright fighting responses. The ability of dopamine agonists to induce these behaviors seems to depend apon the potency and ratio of D-2 versus D-1 receptor activity.