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 adenosine analogues on apomorphine-induced penile erection in rats

• 1.1. In the present work, the effect of adenosine agonists and antagonists on apomorphine-induced penile erection (PE) has been studied.
• 2.2. Subcutaneous (s.c.) injection of the nonselective D1/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. The response decreased with increasing doses of apomorphine, from 0.1 to 0.5 mg/kg.
• 3.3. Intraperitoneal (i.p.) injections of adenosine agonists 5′-N-ethylcarboxamidoadenosine (NECA) and N⁶-cyclohexyladenosine (CHA) decreased the response of apomorphine. Apomorphine-induced PE was increased by low doses (25, 50 mg/kg, i.p.) and decreased by high doses (75, 100 mg/kg, i.p.) of the adenosine antagonist theophylline, respectively. Inhibition of PE induced by NECA and CHA was antagonized by 8-PT pretreatment.
• 4.4. Intracerebroventricular (i.c.v.) administration of CHA, NECA, and theophylline produced the same effects as i.p. injections of these agents on PE responses. It is concluded that A-1 and A-2 adenosine receptor activation may inhibit PE induced by dopaminergic mechanism(s), which can be prevented by 8-PT pretreatment.

     

Effects of selective dopamine receptor compounds on single,spontaneously-active neostriatal neurons

• 1.1. The effects of selective dopamine receptor compounds on the spontaneous activity of single neostriatal neurons were examined extracellularly.
• 2.2. Intravenous administration of quinpirole, the D₂ agonist, elicited a dose-dependent depression in discharge rate.
• 3.3. Quinpirole-evoked depression was reversed by the D₂ antagonist eticlopride, but not the D₁ antagonist SCH 23390.
• 4.4. The partial D₁ agonist, SKF 38393 induced depression and excitation in equal proportion.
• 5.5. A dose of 0.25 mg/kg SCH 23390 blocked SKF 38393-induced depression but not excitation.
• 6.6. SKF 38393-induced excitation was antagonized by eticlopride and in some cases by a higher dose of SCH 23390.

     

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.     

The Effect of Fenoldopam on the Blood Pressure of the Rat

• 1.Fenoldopam mesylate, a benzazepine derivative, is a D₁ receptor agonist that lowers blood pressure through vasodilation of renal, mesenteric, coronary and cerebral vascular beds.
• 2.Experiments were performed in rats, and mean carotid blood pressure and heart rate were registered. Two series of experiments were performed: (1) fenoldopam as control group and (2) fenoldopam after pretreatment with one of the following drugs: the D₁ antagonist SCH 23390, the D₂ antagonist sulpiride, the selective β₁-adrenergic antagonist atenolol, the selective β₂-adrenergic antagonist ICI 118.551, the nonselective β-adrenergic antagonist propranolol and the neurotoxin that destroys catecholaminergic nerve terminals 6-hydroxydopamine (6-OH-DA).
• 3.Fenoldopam produced a dose-dependent hypotensive effect that was not modified by pretreatment of the rat with atenolol or propranolol; however, ICI 118.551 produced a significant reduction of the hypotensive response induced by fenoldopam.
• 4.Pretreatment of the animals with SCH 23390 produced a significant dose-related reversal of the rat blood pressure reduction induced by low doses of fenoldopam. Sulpiride produced a result similar to that induced by pretreatment with SCH 23390.
• 5.The pretreatment of the animals with 6-OH-DA surprisingly attenuated the response induced by fenoldopam and produced only a significant reversal of the reduction of mean blood pressure induced with the lower dose of fenoldopam.
• 6.The findings obtained in the present work do not provide further evidence of direct participation of β₂-adrenergic receptors on the mechanism of action of fenoldopam. Its action seems to be mainly due to activation of D₁ cardiovascular receptors.

     

Opposite influences of dopaminergic receptor subtypes on penile erection.

1. Mixed D-1/D-2 dopamine agonist apomorphine induced a penile erection (PE) in rats in a biphasic manner. 2. The response was decreased with increasing doses of the drug. 3. The maximum effect was obtained by 0.1 mg/kg of apomorphine. 4. In animals pretreated with D-1 antagonist SCH 23390, high doses of apomorphine showed higher PE response, while D-2 antagonist sulpiride pretreatment decreased the response of the low doses of the drug. 5. The inhibitory effect of sulpiride was dose-dependent. 6. The D-2 agonists bromocriptine or quinpirole induced a dose-dependent PE. 7. The effects of both drugs were decreased by sulpiride or SKF 38393 pretreatment. 8. Cholinergic drugs physostigmine and neostigmine did not induce PE, but antimuscarinic agent atropine decreased the effects of apomorphine, bromocriptine or quinpirole. 9. It is concluded that D-2 dopamine receptor stimulation may induce PE, while D-1 activation elicit an opposite effect. 10. However, cholinergic stimulation is not able to induce PE, cholinergic inhibition may decrease the PE induced by dopaminergic agents.     

The Role of Dopamine in the Expression of Morphine Withdrawal

• 1.Both L-dopa and low doses of apomorphine potentiated withdrawal symptoms such as jumping,“wet dog” shakes and burrows. L-dopa reduced hypothermia and potentiated body weight loss, whereas apomorphine produced opposite effects.
• 2.Higher doses of apomorphine attenuated jumping and burrows but had no effect on “wet dog” shakes. On the other hand, and with the exception of sulpiride, all other dopamine (DA) antagonists produced effects opposite those of the agonists with regard to jumping, “wet dog” shakes and burrows.
• 3.In addition, DA antagonists reduced hypothermia and body weight loss. The effects of DA agonists and antagonists were investigated in mice injected with 6-hydroxydopamine (6-OHDA) intracerebrally to examine whether DA-mediated effects are somehow linked to noradrenergic pathways.
• 4.Mice pretreated with 6-OHDA developed a higher degree of naloxone-induced withdrawal jumping than did untreated mice. 6-OHDA reversed the effects of apomorphine on “wet dog” shakes and burrows while abolishing those of L-dopa on all withdrawal symptoms, the only exception being jumping, which remained unchanged.
• 5.6-OHDA also reversed the effects of sulpiride on all withdrawal symptoms while reversing the effects of pimozide on jumping, and it abolished its effect on hypothermia.
• 6.These findings provide evidence suggesting that the effects of DA agonists and antagonists are dependent at least partly on intact noradrenergic pathways.

     

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 YM 435 and A 77636 on dopamine D-1 receptors in bovine retina in vitro

• 1.1. Homogenates of bovine retinas were used to study the capacities of two new dopamine (DA) receptor agonists, e.g. YM 435 and A 77636, to interact with D1 receptors.
• 2.2. Adenylate cyclase experiments. YM 435 and A 77636 enhanced cAMP accumulation, with EC₅₀ values of 1.97 μM and 22.9 nM, respectively. The receptor-mediated nature of the effects of these two novel D1 agonists was shown by the abilities of both SCH 23390 or (+)-butaclamol to inhibit the agonist-induced increase of cAMP formation.
• 3.3. Binding experiments. The same agonists were also tested for competition with ³H-SCH 23390 for binding to D1 receptors. IC₅₀ values for YM 435 and A 77636 were 8.15 μM and 6.15 nM, respectively.
• 4.4. The results of the present report demonstrate the suitability of bovine retina in vitro to evaluate the specificity of new DA D1 agonists at the receptor level.

     

Chronic manipulation of dietary salt modulates renal physiology and kidney dopamine receptor subtypes: Functional and autoradiographic studies

• 1.1. Compared to rats maintained on the normal NaCI (0.33%) diet, animals maintained on the low NaCl (0%) diet for 4 weeks exhibited increased plasma aldosterone and chloride and decreased urinary sodium excretion.
• 2.2. Rats maintained on the high NaCl (8%) diet for 4 weeks showed increased systolic blood pressure, water intake, urine volume, sodium and dopamine excretion and decreased plasma aldosterone and glomerular filtration rate.
• 3.3. Administration of SCH 23390 (10mg/kg, po), but not domperidone to the high salt diet rats attenuated the diuretic effect, indicating the involvement of DA₁ rather than DA₂ receptors. The dopamine decarboxylase inhibitor, carbidopa (30 mg/kg, i.p.), also reduced the high salt-induced diuresis.
• 4.4. Kidney sections from rats fed the low NaCl diet showed a 63–100% decrease (P < 0.001−0.02) in cortical and medullary DA₁ and DA₂ binding sites, while rats fed the high NaCl diet demonstrated only a 70% decrease (P < 0.01−0.02) in cortical DA₁ binding, without affecting DA₂ binding.
• 5.5. These data indicate that chronic modification of dietary salt profoundly affects the sodium, water and dopamine excretion and leads to selective modulation of renal dopamine receptor subtypes.

     

Dissimilar Effects of Lithium and Valproic Acid on GABA and Glutamine Concentrations in Rat Cerebrospinal Fluid

• 1.This study compared the effects of the antimanic drugs, lithium and valproic acid, on GABA and glutamine CSF concentration and on head-shakes during hyponatremia.
• 2.Hyponatremic and normonatremic rats were treated with 2 mEq/kg lithium and 360 mg/kg valproic acid. Behavioral observation was conducted for 120 min after which blood and CSF collection were performed under anesthesia.
• 3.Peritoneal dialysis with glucose induced moderate hyponatremia and doubled glutamine CSF concentrations. Both lithium and valproic acid significantly increased GABA CSF levels in normonatremic and hyponatremic animals. Valproic acid induced head-shakes and increased CSF glutamine concentration.
• 4.The results suggest that both antimanic drugs have similar effects on GABA, but lithium is preferred if the increase in glutamine concentration poses a problem, either in the presence or absence of hyponatremia.

     

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.     

Inhibition by ginseng total saponin of the development of morphine reverse tolerance and dopamine receptor supersensitivity in mice

• 1.1. Ginseng total saponin (GTS), 200 mg/kg i.p. 3 hr prior to morphine, inhibited the development of reverse tolerance to the ambulatory-accelerating effect of morphine.
• 2.2. GTS, 200 mg/kg, also prevented the development of dopamine receptor supersensitivity induced by the chronic administration of morphine, 10 mg/kg a day for 7 days.
• 3.3. These results suggest that GTS may be useful for the prevention and therapy of the adverse action of morphine.

     

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.     

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 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.     

Serotonin-induced paw edema in the rat: Pharmacological profile

• 1.1. Serotonin (5-HT) induced a linear increase in paw weight in rats within 1hr of an intraplantar injection (50μ1 vol) over a concentration range of 0.005–0.2mg/ml. At the 0.2 mg/ml concentration, a 16-fold increase in paw weight was observed as compared to saline-injected controls.
• 2.2. Serotonin antagonists, such as LY53857, were the most effective antagonists of 5-HT induced paw swelling, producing near complete antagonism and an approximate ED₅₀ of 0.1 mg/kg. A mixed 5-HT/histamine antagonist, cyproheptadine, also produced a nearly complete inhibition of the 5-HT response with an approximate ED₅₀ of 1.3 mg/kg.
• 3.3. Dopamine agonists (pergolide, quinpirole), yohimbine, dexamethasone and nifedipine also produced a significant degree of antagonism of the 5-HT response.
• 4.4. Clonidine, prazocin, chlorpheniramine, cimetidine, various dopamine antagonists, imipramine, cyclosporine A, piroxicam and superoxide dismutase were all ineffective at altering the paw swelling response to 5-HT.

     

3-(3-Hydroxyphenyl)-N-(1-Propyl)piperidine elicits convulsant effects in mice

• 1.1. The behaviour and EEG effects of the dopamine and sigma (σ) ligands (+) 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)3-PPP) were studied in mice.
• 2.2. (+) 3-PPP dose-dependently (60–100 mg/kg i.p.) produced behavioural and electrical tonic-clonic seizures.
• 3.3. The incidence of the tonic seizures elicited by 100 mg/kg of the drug was significantly (P < 0.05) prevented by spiperone (0.5 mg/kg i.p.) and haloperidol (0.5 mg/kg i.p.).
• 4.4. The results show an influence on the behavioural and electrical threshold of convulsions by (+) 3-PPP depending on a prevalent interference on dopamine receptors.

     

Comparison of the protective effect of (R)-α-methylhistamine and its prodrugs on gastric mucosal damage induced by ethanol in the rat

• 1.1. The gastroprotective activity of two azomethine prodrugs of (R)-α-methylhistamine was examined in lesions induced by absolute ethanol (1 ml/rat intragastrically for 1 h).
• 2.2. Pretreatment with (R)-α-methylhistamine as well as with the prodrugs (30 and 100 mg/kg intragastrically [IG]) significantly reduced macroscopically visible lesions caused by ethanol, with protection being almost complete at 100 mg/kg.
• 3.3. Histologically, in rats pretreated with the three compounds at a dose of 100 mg/kg, the evidence of damage was rare, with the appearance of gastric mucosa being similar in the different treatment groups.
• 4.4. Present results are suggestive of a local component in the protective activity of (R)-α-methylhistamine.

     

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.