Repeated administration of dopaminergic agents in the dorsal hippocampus and morphine-induced place preference

The aim of the present experiments was to investigate whether repeated intra-hippocampal CA1 (intra-CA1) administration of dopaminergic agents can affect morphine-induced conditioned place preference (CPP). Effects of repeated intra-CA1 injections of dopamine (DA) receptor agonists and antagonists on morphine-induced CPP in rats were investigated using an unbiased 3-day schedule of place conditioning. Animals receiving once-daily subcutaneous (s.c.) injections of morphine (1-9 mg/kg) or saline (1.0 ml/kg, s.c.) showed a significant place preference in a dose-dependent manner: the maximum response was observed with 3 mg/kg morphine. Three days' intra-CA1 injections of apomorphine (0.25-1 microg/rat) followed by 5 days free of the drug, significantly decreased morphine CPP (1 and 3 mg/kg, s.c.). Moreover, pre-treatment with the highest dose of apomorphine (1 microg/rat) altered the effect of morphine to an aversive response. The morphine (1 and 3 mg/kg) CPP was also significantly decreased in animals that previously received three intra-CA1 injections of SKF 38393 (2-9 microg/rat), quinpirole (1-3 microg/rat) or sulpiride (1-3 microg/rat), and significantly increased in animals that had previously received three intra-CA1 injections of SCH 23390 (0.02 microg/rat). The 3-day pre-treatment with apomorphine, SKF 38393 or quinpirole reduced locomotor activity in the test session, while SCH 23390 and sulpiride did not have any influence on locomotor activity. It is concluded that repeated injections of DA receptor agents in the dorsal hippocampus, followed by 5 days free of the drugs, can affect morphine reward.     

Involvement of dopamine D2 receptors of the central amygdala on the acquisition and expression of morphine-induced place preference in rat

In the present study, the effects of intra-central amygdala (CeA) injections of dopamine (DA) D2-like receptor agonist and antagonist on the acquisition and expression of morphine-induced place preference in male Wistar rats have been investigated. Subcutaneous administration of different doses of morphine sulphate (0.5-10 mg/kg) produced a dose-dependent conditioned place preference (CPP). Using a 3-day schedule of conditioning, it was found that the DA D2/D3 receptor agonist, quinpirole (0.3-3 microg/rat), or the DA D2 receptor antagonist, sulpiride (0.04-5 microg/rat), did not produce a significant place preference or place aversion. Intra-CeA administration of quinpirole (0.3 and 1 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited a significant CPP. On the other hand, quinpirole (0.3 microg/rat) injection into the CeA induced CPP in combination with the lower doses of morphine (0.5 and 2.5 mg/kg), but decreased the response of higher dose (7.5 mg/kg) of morphine. This response of quinpirole was attenuated by sulpiride (0.2 microg/rat). Sulpiride by itself (0.04-5 microg/rat) reduced the acquisition of morphine (7.5 mg/kg)-induced place preference. The administration of the higher dose of sulpiride (1 and 5 microg/rat) or the higher dose of quinpirole (3 microg/rat) during acquisition decreased the locomotor activity of the animals on the testing days. The injection of the low dose of quinpirole (0.3 microg/rat) on the test day reduced the expression of morphine-induced CPP, but the high dose of quinpirole (3 microg/rat) potentiated this expression. The administration of sulpiride (5 microg/rat) attenuated the quinpirole response. The injection of sulpiride (1 and 5 microg/rat) abolished the expression of morphine-induced CPP. It is concluded that the CeA DA D2-like receptors may play an active role in morphine reward.     

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.     

D1 and D2 dopaminergic systems in the rat basolateral amygdala are involved in anxiogenic-like effects induced by histamine

Involvement of the dopamine receptors in the basolateral amygdala (BLA) in the effects of histamine on anxiety-like behaviors of the elevated plus maze in male Wistar rats was investigated. The results showed that bilateral intra-BLA injections of histamine (2.5, 5 and 7.5 μg/rat) induced an anxiogenic-like effect, revealed by decreases in percentage of open arm time (%OAT) and open arm entries (%OAE). Intra-BLA administration of dopamine D1 receptor agonist, SKF38393 (0.25 μg/rat), and dopamine D2 receptor agonist, quinpirole (0.03 and 0.05 μg/rat), decreased %OAT but not %OAE. Conversely, intra-BLA administration of dopamine D1 receptor antagonist, SCH23390 (0.5 and 1 μg/rat), and dopamine D2 receptor antagonist, sulpiride (0.3 and 0.5 μg/rat), increased %OAT and %OAE, suggesting an anxiolytic-like effect for both drugs. Interestingly, co-administration of a silent dose of SCH23390 or sulpiride prevented anxiogenic-like effects of SKF38393 and quinpirole, respectively. Conjoint administration of a sub-effective dose of SKF38393 (0.125 μg/rat) or quinpirole (0.01 μg/rat) along with lower doses of histamine (1 and 2.5 μg/rat) induced anxiolytic-like effects. On the other hand, intra-BLA pretreatment with a silent dose of SCH23390 (0.25 μg/rat) or sulpiride (0.1 μg/rat) prevented the anxiogenic-like effect of higher doses of histamine (5 and 7.5 μg/rat). No significant change was observed in total closed arm entries, as an index for motor activity of the animals. It can be concluded that the dopamine D1 and D2 receptors in the BLA may be involved in the anxiogenic-like effects induced by histamine.     

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.     

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.     

The effects of selective dopamine D1 or D2 receptor antagonists on the establishment of agonist-induced place conditioning in rats

The ability of the dopamine D1 antagonist, SCH 23390 (0.01, 0.1, 1.0, 2.0 mg/kg) or the D2 antagonist, metoclopramide (1.0, 10.0, 20.0 mg/kg), to block the establishment of place conditioning with either the nonselective dopamine agonist, amphetamine (2.0 mg/kg), the D1 agonist, SKF 38393 (10.0 mg/kg), or the D2 agonist, quinpirole (1.0 mg/kg), was evaluated in rats. The experimental protocol consisted of three phases. During the preexposure phase, rats explored two distinctive compartments joined by a small tunnel. During the 8-day conditioning phase, rats were pretreated with either saline, SCH 23390 or metoclopramide; 1 hr later the animals were treated with an agonist and confined to one compartment for 30 min. On alternate days, rats received saline and were placed in the opposite compartment. Test days occurred over the remaining 3 days during which drug-free animals were allowed access to both compartments. A significant increase or decrease in the amount of time spent in the drug-paired environment was indicative of a place preference or aversion, respectively. SCH 23390 and metoclopramide were effective in blocking amphetamine-induced place preference and SKF 38393-induced place aversion. At lower doses, the D1 and D2 antagonist blocked the place preference induced by quinpirole, however, higher doses were not effective. In general, these data suggest that both receptor subtypes participate in the establishment of place conditioning with amphetamine, SKF 38393 or quinpirole.     

Ontogeny of locomotor activity and grooming in the young rat: role of dopamine D1 and D2 receptors

Locomotor activity and grooming were assessed in 11- and 17-day-old rat pups after treatment with selective dopamine (DA) D-1 and D-2 agonists (SKF 38393 and quinpirole, respectively) and antagonists (SCH 23390 and sulpiride, respectively). Quinpirole enhanced the locomotor activity of both the 11- and 17-day-olds, effects antagonized by either SCH 23390 or sulpiride. Drug-induced increases in grooming were apparent only after high doses (30.0 mg/kg i.p.) of SKF 38393 (11- and 17-day-olds) or when SKF 38393 (15.0 mg/kg i.p.) was given in conjunction with sulpiride (11-day-olds). In general, these results suggest that challenge with selective DA agonists and antagonists induces patterns of responding which are similar to those typically observed in adult rats. Moreover, these results indicate that rat pups, like adults, require a functioning DA D-1 receptor system for the expression of DA D-2-mediated activity.     

The actions of (-)N-n-propylnorapomorphine and selective dopamine D1 and D2 receptor agonists to modify the release of [3H]dopamine from the rat nucleus accumbens

The ability of (-)N-n-propylnorapomorphine and selective D1 and D2 dopamine receptor agonists and antagonists to modify the release of [3H]dopamine, induced by potassium from the nucleus accumbens, was studied using an in vitro superfusion technique. (-)N-n-Propylnorapomorphine, in picomolar concentrations, inhibited the release of [3H]dopamine, the inhibition being antagonised by fluphenazine and the selective D2 receptor antagonist sulpiride; the selective D1 receptor antagonist SCH 23390 was ineffective. The selective D1 receptor agonist SKF 38393 and the selective D2 agonist quinpirole, both inhibited the potassium-induced release of [3H]dopamine; no synergistic effect was observed to a combined treatment with SKF 38393 and quinpirole. The effects of SKF 38393 and quinpirole were selectively antagonised by SCH 23390 and sulpiride, respectively, although both antagonists failed to modify the release of [3H]dopamine when administered alone. Receptor antagonists for other transmitter sites, e.g. noradrenaline, 5-hydroxytryptamine and acetylcholine, failed to modify potassium-induced release of [3H]dopamine, when administered alone or to prevent the inhibition of the release caused by (-)N-n-propylnorapomorphine. It is concluded that the action of dopamine agonists on both dopamine D1 and D2 receptors in the nucleus accumbens can reduce the release of [3H]dopamine in the in vitro system. Comparable actions in vivo may contribute to the ability of dopamine agonists to moderate locomotor responding.     

Acute effects of D-1 and D-2 dopamine receptor agonist and antagonist drugs on basal ganglia [Met5]- and [Leu5]-enkephalin and neurotensin content in the rat.

The effects of acute systemic injection of the D-1 agonist SKF 38393 (2.5-20 mg/kg) or the D-1 antagonist SCH 23390 (0.25-2.0 mg/kg), and of the D-2 agonist quinpirole (0.12-1.0 mg/kg) or the D-2 antagonist sulpiride (25-100 mg/kg) on the neuropeptide content of rat basal ganglia were investigated. In striatum, the [Met5]- and [Leu5]-enkephalin content was unaffected by administration of SKF 38393 or SCH 23390. Quinpirole had no effect on [Met5]- and [Leu5]-enkephalin levels but sulpiride produced an increase in both [Met5]- and [Leu5]-enkephalin content. In the nucleus accumbens, SKF 38393 decreased and SCH 23390 increased [Met5]- and [Leu5]enkephalin levels. Quinpirole decreased [Met5]- and [Leu5]-enkephalin levels, while sulpiride decreased [Leu5]-enkephalin levels alone. The content of [Leu5]- but not [Met5]-enkephalin levels in the substantia nigra was increased by administration of SKF 38393, and decreased by SCH 23390. Quinpirole and sulpiride were without effect on the [Met5]- or [Leu5]-enkephalin content of substantia nigra. Neurotensin levels in striatum were increased by administration of SKF 38393 and decreased by SCH 23390. Similarly, quinpirole decreased the neurotensin content while sulpiride caused an increase. In the nucleus accumbens, the neurotensin content was not affected by administration of SKF 38393 but increased by SCH 23390. Neither quinpirole nor sulpiride altered neurotensin levels in the nucleus accumbens. Neurotensin levels in substantia nigra were unaffected by the administration of SKF 38393 and SCH 23390, or by quinpirole and sulpiride. These results indicate that acute administration of D-1 and D-2 agonist and antagonist drugs can alter the levels of [Met5]- and [Leu5]-enkephalin and neurotensin in basal ganglia. However, there are marked differences between brain regions in the regulation of peptide levels by acute D-1 and D-2 receptor occupation.     

多巴胺D_1受体参与吗啡介导的小鸡条件性位置偏爱的表达

目的 :利用条件性位置偏爱模型探求吗啡对小鸡的奖赏作用及其相关的多巴胺机制。方法 :ip 2mg·kg-1吗啡对小鸡进行 4次条件化训练后进行条件性位置偏爱测试 ,测试前 15min分别ip生理盐水、0 .2 5mg·kg-1多巴胺D1受体拮抗剂SCH2 3390或者等剂量的多巴胺D2 受体拮抗剂雷氯必利 (raclopride) ,观察其干预效果。结果 :吗啡诱导出小鸡的条件性位置偏爱 (P <0 .0 1) ,条件性位置偏爱的表达被SCH2 3390阻断 (P <0 .0 5 ) ,而不受雷氯必利的影响 (P >0 0 5 )。结论 :吗啡的奖赏作用在鸟类中也有体现 ,小鸡可以成为研究药物成瘾的合适的模型。多巴胺D1受体可能参与对吗啡药物渴求的形成。     

Differential roles of dopamine D1 and D2 receptors in the nucleus accumbens in attentional performance on the five-choice serial reaction time task.

Nucleus accumbens (NAC) dopamine may play a role in attentional and executive processes, as it modulates cortico-limbic inputs, including afferents from the prefrontal cortex. The present study examined the role of NAC dopamine D1 and D2 receptors in visual attentional processes and response control in rats as assessed in the five-choice serial reaction time task (5CSRT). Rats were trained to detect the location of brief (0.5 s) visual targets presented randomly in an array of five apertures to receive food reward. They were tested after bilateral infusions of a D1 receptor antagonist (SCH 23390) and agonist (SKF 38393) and a D2 receptor antagonist (sulpiride) and agonist (quinpirole) into the NAC. While intra-NAC SCH 23390 decreased accurate responding and increased response omissions, SKF 38393 improved accuracy and decreased omissions at the lowest dose (0.1 microg/side). At higher doses, SKF 38393 increased premature 'impulsive' responding. Sulpiride impaired the attentional accuracy of responding and slowed the latency to collect the earned food reward. By contrast, intra-NAC infusions of quinpirole did not significantly affect attentional accuracy, but increased perseverative responding. Optimal performance on the 5CSRT depends on both D1 and D2 receptors in the NAC, but they modulate different aspects of performance. D1 receptor agents had more selective effects on attentional accuracy while D2 receptor stimulation did not affect accuracy or premature responses, but enhanced perseverative responding. The data are discussed in terms of the different functions of NAC dopamine receptors in the processing of information from its different cortico-limbic inputs.     

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).     

Suppression of morphine-induced conditioned place preference by l-12-chloroscoulerine,a novel dopamine receptor ligand

The effect of l-12-chloroscoulerine (l-CSL), a novel ligand with dual dopamine D1 receptor agonistic and D2 receptor antagonistic actions, on the development of morphine-induced conditioned place preference (CPP) was investigated in mice. Morphine (10 mg/kg)-induced place preference was dose dependently suppressed by coadministration of l-CSL (5, 10 and 20 mg/kg), which induced neither place preference nor place aversion when administered alone at a dose of 20 mg/kg. The D1 receptor antagonist SCH23390 (0.1 mg/kg) suppressed, whereas the D2 receptor agonist (+/-)-2-(N-phenylethyl-N-propyl)-amino-5-hydroxytetralin (PPHT) (0.5 mg/kg) had no influence on the development of morphine-induced place preference. However, SCH23390 (0.1 mg/kg) did not affect, whereas PPHT (0.5 mg/kg) reversed the suppressive effect of l-CSL on the development of morphine-induced place preference. These results indicate that l-CSL suppresses the development of place preference of morphine by blocking D2 receptors.     

Effect of dopamine receptor agonists on sensory nerve activity: possible therapeutic targets for the treatment of asthma and COPD

Sensory nerves regulate central and local reflexes such as airway plasma leakage, and cough and their function may be enhanced during inflammation. Evidence suggests that dopamine receptor agonists may inhibit sensory nerve-mediated responses. In this study dopamine inhibited vagal sensory nerve induced microvascular leakage in the rat. In order to characterize the receptor involved rat vagus preparations were utilized. Quinagolide (D(2/3) agonist), ropinirole (D(2/3/4) agonist), SKF 38393 (D(1/5) agonist), AR-C68397AA (Viozan) (dual D(2)/B(2) agonist) and dopamine inhibited hypertonic saline induced depolarization by approximately 50%. Data suggests that AR-C68397AA and quinagolide also inhibited depolarization of the human vagus. The quinagolide response was blocked by sulpiride (D(2/3) antagonist) but not SCH 23390 (D(1/5) antagonist); ropinirole was partially blocked by sulpiride, totally blocked by spiperone (at a concentration that blocks all dopamine receptors) but not by SCH 23390. The response to SKF 38393 was not blocked by sulpiride but was by SCH 23390. The inhibition evoked by AR-C68397AA was only partially blocked by SCH 23390 but not by sulpiride or spiperone whereas dopamine was blocked by spiperone. The effect of dopamine was not stimulus-specific as it inhibited capsaicin-induced depolarization of the rat vagus in a spiperone sensitive manner. In conclusion, dopamine receptor ligands inhibit depolarization of the rat and human vagus. These data suggest that dopamine receptor agonists may be of therapeutic benefit in the treatment of symptoms such as cough and mucus secretion which are evident in respiratory diseases such as asthma and chronic obstructive pulmonary disease.     

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.     

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 role of D1 and D2 dopamine receptors in the acquisition and expression of cocaine-induced conditioned increases in locomotor behavior

Certain motoric effects of cocaine increase in intensity with repetitive administration. Conditioned drug effects are among primary determinants of such sensitization. The purpose of these experiments was to evaluate the role of D1 and D2 dopamine (DA) receptor mechanisms in the acquisition and expression of cocaine conditioning. On Day 1, rats were injected with cocaine (40mg/kg) either before (PAIRED) or after (UNPAIRED) exposure to a locomotor activity chamber. On Day 2, all animals were injected with a low dose of cocaine (10mg/kg) prior to placement in the locomotor chambers. Conditioning on Day 2 was evidenced by significantly higher activity levels in the PAIRED group relative to the UNPAIRED or saline-treated groups. Pretreatment with D1 (SCH 23390) or D2 (raclopride, sulpiride, haloperidol) DA antagonists on Day 1 prevented the development of conditioning as assessed on Day 2, indicating that both receptor subtypes are involved in acquisition. However, pretreatment with raclopride or SCH 23390 on Day 2, prior to cocaine injections, did not eliminate the differences in behavior between the conditioned and non-conditioned groups. Neither D1 (SKF 82958, SKF 38393) nor D2 (quinpirole) agonists administered alone were effective in establishing conditioning, while a combination of SKF 82958 and quinpirole was effective, suggesting that conditioning in this experimental paradigm requires the concurrent activation of both receptor subtypes. In the final study it was found that conditioned cocaine effects could be revealed only in the presence of quinpirole or apomorphine on Day 2. The D1 agonists (SKF 38393 and SKF 82958) were ineffective. This would suggest either that only quinpirole and apomorphine are effective in amplifying the conditioned effects of cocaine on Day 2 or that the cues produced by these drugs are more similar to those produced by cocaine than those produced by D1 agonists.     

Behavioural effects of selective dopamine D-1 and D-2 agonists and antagonists in guinea-pigs

This study describes specific behaviours in guinea-pigs after dopamine D-1 and D-2 receptor activation which differed to those described in other rodent species. Intraperitoneal (IP) administration of the dopamine D-2 receptor agonist quinpirole (1.5, 3 and 6 mg/kg) to guinea-pigs dose-dependently initiated locomotor activity and other behaviours including rearing, head-down sniffing, chewing, circling, licking and head/body shaking. Locomotor activity induced by quinpirole (3 mg/kg) was reduced by the D-2 receptor antagonists sulpiride, (100 mg/kg IP) and raclopride (10 mg/kg IP). The dopamine D-1 receptor agonist SKF 38393 (8, 16 and 32 mg/kg IP) produced little or no behavioural effect, nor did the D-1 receptor antagonist SCH 23390 (0.2 and 0.4 mg/kg IP). A 16 mg/kg dose of SKF 38393, given in combination with 3 mg/kg quinpirole, produced responses similar to quinpirole alone, whereas 32 mg/kg SKF 38393 combined with quinpirole induced vacuous oral chewing, with attenuation of locomotor activity and circling, but not other behaviours produced by this dose of quinpirole. In contrast to previous studies in rats, the responses to quinpirole (3 mg/kg) were not significantly affected by SCH 23390 (0.2 and 0.4 mg/kg). It is concluded that the guinea-pig may be a useful and interesting species for study of the behavioural effects of D-1 and D-2 agonists and antagonists, as its responses appear to differ from those of other rodent species, but are similar to some responses to D-1 agonists observed in primates.     

Selective protection from the inhibition by EEDQ of D1 and D2 dopamine agonist-induced rotational behavior in mice

Mice with unilateral lesions of dopamine nigrostriatal neurons produced by injecting 6-hydroxydopamine into the striatum exhibited contralateral rotational behavior to the non-selective dopamine agonist apomorphine, the D1 dopamine agonist SKF 38393, and the D2 agonist quinpirole. The non-specific dopamine antagonist EEDQ blocked the circling responses to the three agonists. Pretreatment with specific, reversible dopamine antagonists before the EEDQ injection selectively prevented this blockade. Thus, if mice were pretreated with the D1 receptor antagonist SCH 23390 before EEDQ and the animals challenged with the D1 and D2 agonists 24 hours later, the rotational response to quinpirole was still inhibited, but the response to SKF 38393 was now evident. Similarly, in mice pretreated with the D2 receptor antagonist sulpiride before EEDQ and again challenged with the D1 and D2 agonists 24 hours later, the rotational response to SKF 38393 was still inhibited but the response to quinpirole was no longer inhibited. These results indicate that in vivo blockade of either D1 or D2 subpopulations of dopamine receptors may be achieved by selective protection with a reversible dopamine antagonist given prior to the administration of an irreversibly acting dopamine antagonist such as EEDQ.