5-HT(1A) receptor activation improves anti-cataleptic effects of levodopa in 6-hydroxydopamine-lesioned rats.

BACKGROUND AND THE PURPOSE OF THE STUDY: In Parkinson>s disease (PD) prolong use of L-DOPA causes some motor disorders such as wearing-off and L-DOPA induced dyskinesia (LID). In this investigation the effect of 8-OHDAPT, as a 5-HT(1A) agonist on anti-cataleptic effect of L-DOPA in 6-hydroxydopamine (6-OHDA) lesioned male Wistar rats was investigated. METHODS: Catalepsy was induced by unilateral injection of 6-OHDA (8 µg/2µl/rat) into the central region of the SNc. After 3 weeks as a recovery period, animals received intraperitoneally (i.p.) L-DOPA (15 mg/kg) twice daily for 20 days, and anti-cataleptic effect of L-DOPA was assessed by bar-test at days of 5, 10, 15 and 20. RESULTS AND MAJOR CONCLUSION: The results showed that L-DOPA had anti-cataleptic effect only until the day of 15, and its effect was decreased on the day of 20. On the day of 21, rats were co-injected with three different doses of 8-OHDAPT (0.1, 0.5 and 2.5 mg/kg, i.p.) and L-DOPA (15 mg/kg, ip). 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OHDAPT) improved anti-cataleptic effect of L-DOPA at the dose of 0.5 mg/kg. Moreover the effect of 8-OHDAPT on anti-cataleptic effect of L-DOPA (15 mg/kg, ip) was abolished by 1-(2-methyoxyphenyl)-4-[4-(2-phthalamido) butyl] piperazine hydrobromide (NAN-190; 0.5 mg/kg, i.p.) as a 5-HT(1A) receptor antagonist. According to the obtained results, it may be concluded that activation of 5-HT(1A) receptors by 8-OHDAPT may improve anti-cataleptic effect of L-DOPA in a 6-OHDA- induced rat model of PD. Further studies are required to clarify the exact mechanism of interaction between 5-HT(1A) and dopaminergic neurons.

alpha(1)- and alpha(2)-Adrenoceptor hyporesponsiveness in isolated bisected vas deferens of bile duct-ligated rats.

It has been suggested that cholestasis accompanied with changes in autonomic balance and hyporesponsiveness in muscarinic and adrenergic receptors of some organs, e.g. cardiovascular system. Increased plasma levels of epinephrine and norepinephrine has been shown during cholestasis suggesting augmented activity of sympathetic nervous system. In this study we evaluate both alpha(1) and alpha(2) responsiveness in isolated rat vas deferens, as a tissue with rich adrenergic innervations. Epididymal and prostatic halves of vas deferens responsiveness have been studied to phenylephrine and clonidine respectively in three groups of un-operated, sham-operated (sham), and bile duct-ligated (BDL) rats. Our results indicate that in vas deferens of BDL animals, the concentration-response curve of both phenylephrine and clonidine shifted to rightward compared to control group, while the position of concentration-response curve of sham group did not change significantly (P > 0.05). EC(50) of phenylephrine and IC(50) of clonidine were increased showing a decreased responsiveness of tissue to phenylephrine (P < 0.05) and clonidine (P < 0.001) in BDL rats. In this study, both subtype of alpha-adrenoceptors (alpha(1) and alpha(2)) has been studied in cholestatic rat vas deference. Our results showed that cholestasis induce hyporesponsiveness to phenylephrine and clonidine. These results are consistent with previous reports, suggesting the hyporesponsiveness of alpha(1)-adrenoceptors in pulmonary artery and papillary muscle and mesenteric beds. Our conclusion is that the cholestasis induces hyporesponsiveness to phenylephrine and clonidine in epididymal (alpha(1)-adrenoceptors) and prostatic (alpha(2)-adrenoceptors) halves of rat vas deferens respectively. Although the logical explanation to this hyporesponsiveness is the down regulation but it has been suggested that it is not because of down regulation.

Alpha 2-adrenoceptor and NO mediate the opioid subsensitivity in isolated tissues of cholestatic animals.

1. Our previous report showed that in acute cholestasis, the subsensitivity to morphine inhibitory effect on electrical-stimulated contractions develops significantly faster in guinea-pig ileum (GPI) and in mouse vas deferens (MVD) (45.2 and 29.9 times, respectively) compared with non-cholestatic subjects. 2. The possible contribution of alpha2-adrenoceptor and nitric oxide (NO) pathways on the development of tolerance was assessed in GPI and MVD of cholestatic subjects. 3. Daily administration of naltrexone (20 mg kg(-1)), yohimbine (5 mg kg(-1)), and Nomega-nitro-l-arginine methyl ester (l-NAME) (3 mg kg(-1)) to cholestatic animals significantly (P-value < 0.05) inhibited the process of subsensitivity in all groups. 4. Consistent with the literature, it was concluded that both the alpha2-adrenergic system and NO have close interaction with the opioid system and may underlie some of the mechanisms involved in the subsensitivity development to opioids in acute cholestatic states.

Clonidine attenuates naloxone-induced opioid-withdrawal syndrome in cholestatic mice.

Cholestasis is associated with elevated plasma level of endogenous opioid peptides. Naloxone-precipitated withdrawal syndrome has been described in a mouse model of acute cholestasis. Thus we aimed at determining whether central noradrenergic hyperactivity is involved in manifestation of naloxone-precipitated withdrawal syndrome in mice with obstructive cholestasis. Acute cholestasis was induced by bile duct resection in mice and physical dependence was observed by precipitating a withdrawal syndrome with naloxone (2 mg/kg, intraperitoneally) 5 days after induction of cholestasis. Administration of clonidine (0.1 mg/kg, intraperitoneally), an alpha2-adrenoceptor agonist, 15 min. before naloxone injection significantly alleviates withdrawal severity in cholestatic mice. However, pretreatment of animals with yohimbine (3 mg/kg, intraperitoneally), an alpha2-adrenoceptor antagonist, 15 min. before clonidine blocked this ameliorative effect of clonidine. The results of this study support the evidence for involvement of the alpha2-adrenoceptors in the withdrawal syndrome of cholestasis in a mouse model.

Mesenteric vascular bed responsiveness in bile duct-ligated rats: roles of opioid and nitric oxide systems.

Changes in vascular responsiveness are proposed as the basis for some of the cardiovascular complications in cholestasis. Cholestasis is also associated with accumulation of endogenous opioid peptides and evidence of overproduction of nitric oxide (NO). The possible role of NO or opioid system in cholestasis-induced mesenteric vascular bed responsiveness was investigated. Bile duct-ligated and sham-operated rats were treated for 6 days with either normal saline, naltrexone, an opioid antagonist (20 mg/kg/day) or L-NAME (N(omega)-nitro-L-arginine methyl ester), a nitric oxide synthase inhibitor (3 mg/kg/day). After 7 days, the superior mesenteric artery was cannulated and the mesenteric vascular bed was perfused according to the McGregor method. Baseline perfusion pressure of the mesenteric vascular bed was decreased in bile duct-ligated compared to sham-operated animals. ED(50) of phenylephrine-induced vasoconstriction was increased, but vasoconstriction R(max) was not different in the vascular bed of bile duct-ligated rats and of sham-operated ones. Acetylcholine-induced vasorelaxation was impaired in bile duct-ligated rats (increased ED(50) and decreased vasorelaxation R(max)). Sodium nitroprusside-induced vasorelaxation was not different between bile duct-ligated and sham-operated rats, implying that the smooth muscle components of vasorelaxation were intact. Chronic treatment with L-NAME partially restored both the acetylcholine-induced vasorelaxation and phenylephrine-induced vasoconstriction response in bile duct-ligated rats. Naltrexone treatment also partially restored the acetylcholine-induced vasorelaxation and phenylephrine-induced vasoconstriction in bile duct-ligated rats. There is impaired acetylcholine-induced vasorelaxation in cholestatic rats, probably due to a defect in endothelial function. This study also provided evidence for the involvement of increased opioidergic tone and NO overproduction in cholestasis-induced vascular hyporesponsiveness.

The effect of acute lithium and rubidium pretreatment on apomorphine-induced pecking in pigeons.

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 (D1 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 D1 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.

Alterations of physostigmine-induced yawning by chronic lithium administration in rats.

The effect of chronic lithium pretreatment on physostigmine-induced yawning was investigated in male rats. Intraperitoneal administration of physostigmine to rats induced yawning in a biphasic manner. However the maximum response was obtained by 0.2 mg/kg of the drug. Intracerebroventricular administrations of a putative M1 and M2 muscarinic receptor antagonists, pirenzepine and methoctramine decreased physostigmine-induced yawning. Intraperitoneal administration of a non-selective muscarinic receptor antagonist, atropine, also decreased the physostigmine-induced yawning significantly. Chronic lithium pretreatment (30 days) reduced yawning induced by physostigmine. The inhibitory effect of pirenzepine, methoctramine and atropine on physostigmine-induced yawning increased in rats pretreated with chronic lithium. These findings indicate that yawning is induced by a central cholinergic mechanism and that chronic pretreatment of lithium may interact with the cholinergic-induced behaviour.

The effects of dopaminergic and adrenergic drugs on twitch response of guinea-pig common bile duct.

1. Effects of various doses of bromocriptine and apomorphine, dopamine receptor agonists, on electrically evoked contractile responses of guinea pig common bile duct (CBD) were investigated in this study. 2. Bromocriptine and apomorphine produced a concentration-dependent reduction of the twitch heights. IC50 values for bromocriptine and apomorphine were 2.75 +/- 0.715 x 10(-6) M, and 1.69 +/- 0.11 x 10(-5) M, respectively. 3. Pretreatment with sulpiride, 0.1 and 1.0 microM, prevented bromocriptine- and apomorphine-induced inhibition. pA2 values of sulpiride against bromocriptine and apomorphine were 8.26 and 6.29, respectively. 4. Clonidine, 0.1-100 microM, produced 49.3 +/- 2.5% inhibition of twitch responses. Its effect was partially antagonized by 1 microM of yohimbine. 5. It would appear that both dopamine D2- and alpha 2-adrenergic presynaptic receptors are present on the guinea-pig CBD cholinergic nerve.

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.

Effects of adenosine analogues on apomorphine-induced penile erection in rats.

1. In the present work, the effect of adenosine agonists and antagonists on apomorphine-induced penile erection (PE) has been studied. 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. 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. 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 chronic lithium pretreatment on apomorphine-induced penile erection.

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. Subcutaneous (s.c.) administration of mixed 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 while the response decreased with increasing doses of apomorphine from 0.1 to 0.5 mg/kg. 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. The response induced by apomorphine (0.05-0.05 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. It is concluded that chronic lithium inhibits PE induced by dopaminergic mechanism(s).

Inhibition by lithium of neomycin-induced release of N-acetyl-beta-glucosaminidase in the rat heart.

The effects of neomycin, lithium and concurrent therapy of these drugs on subcellular distribution of lysosomal enzyme, N-acetyl-beta-glucosaminidase (NAG) in the heart was studied. Released activity of NAG was used as a marker for assessing myocardial lysosomal integrity. The activity of NAG was determined in non-sedimentable and sedimentable fractions after centrifugation of the tissue extracted for assessment of the subcellular distribution of the lysosomal enzyme. Daily intraperitoneal injection of 100 mg/kg/day of neomycin increased the ratio of the non-sedimentable activity (free) to the non-sedimentable plus sedimentable activities (total) of NAG. Daily intraperitoneal injection of lithium decreased the total activity of NAG but did not affect the ratio of free: total activities of the enzyme. Lithium in doses of 2 and 4 mM/kg/day one hour prior to neomycin reduced the neomycin-induced enhancement of the ratio of free: total activity of NAG. Neomycin like other aminoglycosides altered the acidic phospholipid metabolism in lysosomal membranes and/or impairment of some important lysosomal functions. In this regard, the protective effects of lithium may be due to interference of this ion with phosphoinositide cycle.

The effect of cyclosporine A and trifluoperazine on amylase secretion from rat parotid glands in vitro.

In the present study the effects of trifluoperazine (TFP) and/or cyclosporine A (CsA) on the amylase secretion of rat parotid gland lobules were investigated. Cyclosporine A, in doses of 10(-6), 3 x 10(-6) and 10(-5) M, caused a dose-dependent reduction in amylase secretion. Trifluoperazine, a well-established calmodulin antagonist, also significantly reduced amylase secretion by the gland, confirming that the secretion is calmodulin dependent. Concurrent administration of CsA and TFP showed a marked positive interaction in reducing the secretion of amylase. Thus, the hypothesis that CsA may have Ca2+/calmodulin antagonistic properties is supported by the present study.

Nicotine-induced purposeless chewing in rats: possible dopamine receptor mediation.

Intraperitoneal (i.p.) administration of nicotine to rats induced purposeless chewing. The response induced by different doses of the drug (0.0001, 0.001, 0.01 and 0.1 mg/kg) seems to be dose dependent, with a maximum effect at 0.01 mg/kg and then decreasing at a higher dose (0.1 mg/kg). Pre-treatment of animals with the nicotine antagonist mecamylamine (0.01 and 0.1 mg/kg, 30 min) and the D-2 receptor antagonist sulpiride (12.5-100 mg/kg, 90 min), but not the D-1 antagonist SCH 23390 (0.01 and 0.05 mg/kg, 30 min), decreased the chewing induced by nicotine (0.01 mg/kg). When animals were pre-treated with propranolol (5 and 10 mg/kg) 60 min, reserpine (2.5 mg/kg) 18 h or α-methyl-p-tyrosine (α-MPT; 250 mg/kg) 60 min before nicotine, the effect of the drug was reduced. However, reserpine (2.5 mg/kg) at 18 h plus α-MPT (250 mg/kg) 60 min prior to nicotine completely inhibited the drug response. Pre-treatment of animals with phenoxybenzamine (2.5 and 5 mg/kg i.p., 60 min) or atropine (5 and 10 mg/kg) did not change the nicotine response significantly. It is concluded that nicotine- induced purposeless chewing is mediated through dopaminergic and nicotinic mechanisms.

Comparison of various calcium channel blockers on guinea-pig isolated common bile duct.

1. The inhibitory effects of various calcium channel blockers; nifedipine, verapamil, diltiazem and a heterogenous compound, dantrolene, have been investigated on isolated common bile duct from guinea-pig. 2. All the compounds tested induced a concentration-dependent reduction of the amplitude of contractile response to electrical stimulation or increasing the calcium concentration of the bathing media. 3. Nifedipine was the most potent compound whereas the least potent was dantrolene; verapamil and diltiazem had intermediate potency. 4. The IC50 values for these compounds were calculated as: nifedipine 3.68 x 10(-9) M; verapamil, 4.93 x 10(-8) M; diltiazem, 4.2 x 10(-7) M; and dantrolene 5.51 x 10(-5) M. 5. All the compounds displaced the concentration-response curve of calcium chloride to the right in a concentration-dependent manner. Among the compounds studied, nifedipine had the highest and dantrolene had the lowest potency. 6. These results indicate the striking pharmacological effects of the calcium channel blockers on the common bile duct and may indicate a possible role for these compounds in the treatment of biliary colic.

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 effects of bromocriptine on pre-synaptic and post-synaptic alpha-adrenoceptors in the mouse vas deferens.

Noradrenaline (NA) and dopamine (DA) contracted the mouse vas deferens and reduced the responses to low frequency nerve stimulation (0.1 Hz). The relative potencies of antagonists suggested that these effects were due to stimulation of post-synaptic and pre-synaptic alpha-adrenoceptors respectively. Bromocriptine produced a non-competitive antagonism of contractile responses to NA (pD2' = 7.6) and DA (pD2' = 8.0) but had no effect on responses to carbachol. Bromocriptine also reduced single twitch responses of the vas to low frequency field stimulation (0.1 Hz), but did not affect stimulation at higher frequencies (1--20 Hz). Yohimbine selectively and rapidly reversed the inhibiting effects of bromocriptine on single twitches, although they could not easily be reversed by washing. Bromocriptine produced a yohimbine-reversible reduction in the stimulated overflow of tritium from vasa previously loaded with 3H--NA. Thus the mouse vas deferens does not appear to contain specific DA receptors and the results suggest that bromocriptine acts as a pre-synaptic alpha-adrenoceptor agonist and post-synaptic alpha-adrenoceptor antagonist in this tissue.