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.     

Cooperation between D1- and D2-dopamine receptors in the nucleus accumbens.

Apomorphine, used in small doses (20-50 micrograms/kg), induced an increase in the activity of an endogenous inhibitor of cAMP dependent protein kinases (Walsh inhibitor, type I inhibitor) in nucleus accumbens of the rat. The action of apomorphine was blocked by sulpiride and aminophylline and enhanced by SCH-23390. Pretreatment with 6-OH-dopamine resulted in a shift of the dose-response curve for apomorphine to the left, suggesting supersensitivity of D2 receptors. Moreover, stimulation of D2 receptors induced a decrease in phosphorylation of DARPP-32, a specific protein, located in neurones containing D1 receptors. Large doses of apomorphine (over 0.5 mg/kg) provoked a decrease in type I inhibitor activity, blocked by SCH-23390 and enhanced by sulpiride and aminophylline. Moreover, SCH-23390 blocked a decrease in type I inhibitor activity induced by large doses of sulpiride and sulpiride blocked an increase in type I inhibitor activity produced by large doses of SCH-23390. The results suggest that D1 and D2 receptors in the nucleus accumbens could cooperate with the same adenylate cyclase and could be located on the same neurones.     

Effect of apomorphine on oxytocin concentrations in different brain areas and plasma of male rats

The effect of the dopamine (DA) agonist, apomorphine, on oxytocin concentrations in the hypothalamus, hippocampus, septum and plasma was studied in male rats. Apomorphine dose dependently increased the concentration of oxytocin in the plasma and hippocampus, the minimal effective dose being 80 micrograms/kg s.c., which induced a 65% increase in plasma and a 45% increase in the hippocampus. The maximal effect (210 and 125% above controls) was induced with 240 micrograms/kg s.c. In contrast, there was a significant decrease (32%) in the oxytocin concentration in the hypothalamus, but only after the highest doses of apomorphine, while no change was found in the septum. The apomorphine effect in the hippocampus and hypothalamus was prevented by the mixed DA D-1/D-2 receptor blocker, haloperidol (0.3 mg/kg i.p.), and by the DA D-2 receptor blocker, (-)-sulpiride (20 mg/kg i.p.), but not by the DA D-1 receptor blocker, SCH 23390 (0.2 mg/kg s.c.). Similar effects were found in plasma, although SCH 23390 inhibited the apomorphine effect by 45%. Our results suggest that apomorphine stimulates oxytocinergic transmission in male rats and provide biochemical support for the hypothesis that a DA-oxytocin link exists in the central nervous system.     

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.     

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.     

Dopamine receptor regulation of ethanol intake and extracellular dopamine levels in the ventral pallidum of alcohol preferring (P) rats

Sufficient evidence exists for the inclusion of the ventral pallidum (VP) into the category of a dopaminoceptive brain region. The effects of inhibiting dopamine D(1)- or D(2)-like receptors in the VP on (a) ethanol intake and (b) extracellular levels of dopamine, were investigated in the alcohol-preferring (P) rat. The D(1)-like antagonist, SCH-23390, and the D(2)-like antagonist, sulpiride (0.25-2 microg/0.5 microl) were bilaterally injected into the VP and ethanol (15%, v/v) intake was assessed in a 1 h limited access paradigm. The results indicate that microinjections of sulpiride significantly increased ethanol consumption (65% increase at the 2.0 microg dose). Whereas the D(1) antagonists SCH-23390 tended to decrease ethanol intake, the effect was not statistically significant. In a separate group of rats, reverse microdialysis of sulpiride and SCH-23390 (10-200 microM) were conducted in the VP of P rats. Local perfusion of only the 200 microM sulpiride dose significantly increased the extracellular levels of dopamine (maximal increase: 250% of baseline). On the other hand, local perfusion of SCH-23390 (10-200 microM) dose dependently increased the extracellular levels of dopamine 180-640% of baseline. Overall, the results of this study suggest that (a) tonic activation of D(2) postsynaptic receptors in VP imposes a limit on ethanol intake in the P rat; (b) there are few D(2) autoreceptors functioning in the VP; (c) there is tonic D(1)-like receptor mediated inhibitory feedback regulation of VP-dopamine release.     

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.     

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.     

Effects of intrastriatal injections of selective dopamine D-1 and D-2 agonists and antagonists on jaw movements of rats

The effects of bilateral intrastriatal injections of the selective D-1 and D-2 antagonists, SCH23390 and sulpiride on apomorphine-induced jaw movements were studied in ketamine-anaesthetized rats after C1 spinal transection. A photo-transducer attached to the lower mandible automatically detected jaw movements. Apomorphine (0.2, 0.5 and 1.0 mg/kg i.v.) dose dependently increased jaw movements, an effect prevented by prior administration into the ventral striatum of either SCH23390 (0.1, 0.5 and 1 microgram) or sulpiride (125 ng). To be effective, SCH23390 had to be given less than 30 min before apomorphine whereas sulpiride had to be given earlier. Sulpiride injected into the dorsal striatum potentiated the effects of apomorphine, an action prevented by administering the sulpiride with SCH23390. Local application of the selective D-1 and D-2 agonists, SKF38393 (5 micrograms) and quinpirole (10 micrograms) into sites within the ventral striatum from which repeated jaw movements could be obtained by electrical stimulation, also evoked jaw movements; the effects of combining the two drugs were much greater than the effects of either drug alone.     

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.     

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.     

Role of Dopamine Receptors on Electroencephalographic Changes Produced by Repetitive Apomorphine Treatments in Rats

Repeated psychostimulants induce electroencephalographic (EEG) changes, which reflect adaptation of the neural substrate related to dopaminergic pathways. To study the role of dopamine receptors in EEG changes, we examined the effect of apomorphine, the dopamine D1 receptor antagonist, SCH-23390, and the D2 receptor antagonist, haloperidol, on EEG in rats. For single and repeated apomorphine treatment groups, the rats received saline or apomorphine for 4 days followed by a 3-day withdrawal period and then apomorphine (2.5 mg/kg, i.p.) challenge after pretreatment with saline, SCH-23390, or haloperidol on the day of the experiment. EEGs from the frontal and parietal cortices were recorded. On the frontal cortex, apomorphine decreased the power of all the frequency bands in the single treatment group, and increased the theta (4.5~8 Hz) and alpha (8~13 Hz) powers in the repeated treatment group. Changes in both groups were reversed to the control values by SCH-23390. On the parietal cortex, single apomorphine treatment decreased the power of some frequency bands, which were reversed by haloperidol but not by SCH-23390. Repeated apomorphine treatment did not produce significant changes in the power profile. These results show that adaptation of dopamine pathways by repeated apomorphine treatment could be identified with EEG changes such as increases in theta and alpha power of the frontal cortex, and this adaptation may occur through changes in the D1 receptor and/or the D2 receptor.     

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.     

SCH 23390 antagonizes apomorphine- and ergot-induced hypothermia

The reportedly specific D-1 dopamine (DA) receptor antagonist SCH 23390 significantly reduced the hypothermia elicited by various DA receptor agonists like apomorphine, pergolide and lisuride. When tested against equihypothermic doses of each agonist, SCH 23390 significantly reduced the hypothermia elicited by apomorphine (0.2 mg/kg s.c.) and by pergolide (0.1 mg/kg i.p.) at doses of 0.025 mg/kg s.c. Doses of 0.050 mg/kg s.c. of SCH 23390 were necessary to reduce the hypothermia elicited by 0.012 mg/kg s.c. of lisuride. Pretreatment with the specific D-2 antagonist (-)sulpiride (50 mg/kg i.p.) completely prevented the hypothermia elicited by lisuride (0.012 mg/kg i.p.), pergolide (0.1 mg/kg i.p.) and apomorphine (0.2 mg/kg s.c.) and shifted to the right the dose-response curve for agonist-induced hypothermia. A study of the interaction between 0.05 mg/kg s.c. of SCH 23390 with various doses of the agonists showed that the effectiveness of SCH 23390 in antagonizing the hypothermia was maximal towards apomorphine and least towards lisuride for which significant antagonism was observed only against the lowest dose tested (0.012 mg/kg s.c.). The reportedly specific D-1 receptor agonist SKF 38393 given in doses up to 20 mg/kg i.p. or intracerebroventricularly up to 100 micrograms failed to influence body temperature while it evoked intense grooming and stimulated motility.     

On the mechanism of tolerance to morphine-induced Straub tail reaction in mice

The effect of 5-HT and opioid receptor antagonists on morphine-induced Straub tail was studied in mice. Straub tail behavior was induced by subcutaneous administration of different doses (20, 30, and 40 mg/kg) of morphine hydrochloride to mice. The effect of morphine was dose-dependent. Maximum response was obtained with 40 mg/kg of the drug. The response induced by morphine (20 and 40 mg/kg) was decreased by different doses of intraperitoneal injection of naloxone (1 and 2 mg/kg) or methysergide, mianserin, and ritanserin (1 and 2 mg/kg). The effect of morphine (40 mg/kg) was also reduced by intracerebroventricular injection of naloxone (0.4-0.8 microg/animal) or mianserin (2 and 4 microg/animal). Different groups of mice received one daily dose (50 mg/kg sc) of morphine sulfate for 3 days to develop tolerance to morphine. The Straub tail reaction induced by morphine hydrochloride (40 mg/kg) was tested on the fourth day. Naloxone injection (1 and 2 mg/kg ip) on Day 3 (1 h after morphine sulfate injection) or on Day 4 (1 h before test dose of morphine hydrochloride), decreased tolerance induced to morphine. Methysergide, mianserin, or ritanserin (intraperitoneal) on Days 2 and 3 (1 h after morphine sulfate injection) or on Day 4 (1 h before test dose of morphine hydrochloride), also decreased tolerance induced to morphine. Intracerebroventricular injection of either naloxone or mianserin also reduced tolerance to morphine. It is concluded that 5-HT(2) and opioid receptor mechanisms are involved in morphine-induced Straub tail reaction and tolerance induced to morphine also may be mediated through these receptors.     

Interactive effects of morphine and dopamine receptor agonists on spatial recognition memory in mice

Both opiates and dopamine play important roles in learning and memory. Although synergistic action between these two neurotransmitters has been found, their functional roles remain unclear. Here, low dose morphine (2.5 mg/kg) and low dose dopamine receptor agonists (apomorphine 0.05 mg/kg; SKF38393 0.01 mg/kg; bromocriptine 0.05 mg/kg), which have no effects on spatial recognition memory, were injected intraperitoneally into mice 30 minutes before a memory test in a two‐trial recognition Y‐maze. The Y‐maze is based on the innate tendency of rodents to explore novel environments and is therefore suitable for exploring the effects of morphine on learning and memory. Our results showed that both D1‐like and D2‐like dopamine receptor agonists dose‐dependently impaired the retrieval of spatial recognition memory in the Y‐maze, and co‐administration of memory ineffective doses of apomorphine (0.05 mg/kg), SKF38393 (0.01 mg/kg), or bromocriptine (0.05 mg/kg) and of morphine (2.5 mg/kg) resulted in impaired spatial recognition memory retrieval in mice. These findings suggest the existence of interactions between morphine and dopamine receptor agonists in memory processing and that activation of the dopamine system might contribute to morphine‐induced impairment of memory, which could provide insight into human addiction.     

The anti-influenza drug oseltamivir evokes hypothermia in mice through dopamine D2 receptor activation via central actions

Oseltamivir has a hypothermic effect in mice when injected intraperitoneally (i.p.) and intracerebroventricularly (i.c.v.). Here we show that the hypothermia evoked by i.c.v.-oseltamivir is inhibited by non-selective dopamine receptor antagonists (sulpiride and haloperidol) and the D₂-selective antagonist L-741,626, but not by D₁/D₅-selective and D₃-selective antagonists (SCH-23390 and SB-277011-A, respectively). The hypothermic effect of i.p.-administered oseltamivir was not inhibited by sulpiride, haloperidol, L-741,626 and SCH-23390. In addition, neither sulpiride, haloperidol nor SCH-23390 blocked hypothermia evoked by i.c.v.-administered oseltamivir carboxylate (a hydrolyzed metabolite of oseltamivir). These results suggest that oseltamivir in the brain induces hypothermia through activation of dopamine D₂ receptors.     

The effect of local and systemic application of dopaminergic agents on tail flick latency in the rat

Dopamine (DA) is thought to have a neurotransmitter role in the spinal cord of the rat. Intrathecal administration of the DA receptor agonist apomorphine has previously been shown to reduce nocifensive responses. The present experiments investigated the site of action of apomorphine, and the mechanisms by which DA agonists apparently produce antinociception. Small doses of apomorphine (40-80 micrograms/kg) increased the tail flick latency (TFL) in lightly anaesthetised rats when given intrathecally and intravenously but not intracerebroventricularly. This effect is probably mediated via D2 receptors since the D2 agonist LY171555 had a similar effect whereas the D1 agonist SK&F 38393 was inactive. Furthermore the D2 antagonist sulpiride blocked the effects of apomorphine and LY171555. The spinal monosynaptic reflex was not modified by 150 micrograms/kg apomorphine suggesting that sensory rather than motor processes are being influenced. Pretreatment with the serotonin receptor antagonist methysergide prevented the apomorphine induced increase in TFL. It is concluded that exogenously applied DA agonist can result in antinociception in the spinal cord and that this effect may be dependent upon activity in the spinal 5-hydroxytryptaminergic and noradrenergic systems.     

Hypothermia in mice: D2 dopamine receptor mediation and absence of spare receptors

The nonselective dopamine (DA) receptor agonists R(-)apomorphine (APO) and R(-)-N-n-propylnorapomorphine (NPA) elicited dose- and time-dependent hypothermia in mice with ED50 values of 300 and 18 micrograms/kg, respectively. The selective D2 agonist quinpirole (LY 171555) also elicited dose-dependent hypothermia, whereas the selective D1 agonist SKF 38393 had no effect. The selective D1 and D2 antagonists SCH 23390 (1 mg/kg) and sulpiride (200 mg/kg), respectively, did not significantly alter body temperature. The hypothermic effect of a maximal dose of NPA (0.2 mg/kg) was not blocked by SCH 23390 (1 mg/kg) but was significantly attenuated (p less than 0.001) by pretreatment with sulpiride (200 mg/kg). Pretreatment with sulpiride (200 mg/kg) produced a parallel, 40-fold shift to the right of the dose-response curve for NPA. Partial, irreversible DA receptor inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (2 mg/kg) reduced the maximal hypothermic effect of NPA (to 49% of control) without altering its ED50. Analysis of the data indicated a linear relationship between DA receptor occupancy and hypothermic response. The results demonstrate that DA agonist-induced hypothermia in mice is mediated by D2 receptors and that there is no receptor reserved for this response.