Inhibitory effects of carbamazepine on clonidine-induced aggressive behavior in mice

A behavioral study was made of the effect of carbamazepine (CBZ) on aggressive behavior evoked by high dose of clonidine in mice. This aggressive behavior has been reported to involve blockade of central adenosine receptors with which CBZ has been suggested to interact. After a single injection of clonidine (50 mg/kg i.p.), aggressive responses such as attacking and biting began within 5-10 min, were most marked at 20 min and usually ceased within 60 min. This behavior was attenuated by CBZ (45 mg/kg i.p.) but potentiated by caffeine (20 mg/kg i.p.). In addition, it was markedly inhibited by haloperidol (1.0 mg/kg i.p.), but unaffected by prazosin (1.5 mg/kg i.p.) and yohimbine (1.0 mg/kg i.p.). The inhibitory effect of CBZ on the aggressive behavior was dose-dependent at doses ranging from 15 to 60 mg/kg, while a high dose of CBZ alone induced sedation. The stimulatory effect of caffeine on the aggressive behavior was antagonized by pretreatment with CBZ (50 mg/kg i.p.). These results suggest that the receptor involved in clonidine-induced aggressive behavior was not mediated through the alpha-2 adrenoreceptor, but rather the adenosine receptor, and that the effect of carbamazepine on the adenosine receptor was agonistic in contrast with the effect of caffeine (an adenosine antagonist).     

The role of alpha2-adrenoceptors in the modulatory effects of morphine on seizure susceptibility in mice

PURPOSE: To evaluate the effect of the alpha2-adrenoceptor agonist clonidine and the antagonist yohimbine on the dual modulation of seizure susceptibility induced by morphine and the anticonvulsant effect of acute stress in mice. METHODS: The thresholds for the clonic seizures induced after intravenous administration of pentylenetetrazole (PTZ) or bicuculline were assessed in mice weighing 23-30 g. Acute stress was induced by restraining mice for 2 h in a restrainer. RESULTS: Morphine at lower doses (0.5, 1, and 3 mg/kg) increased and, at higher doses (15, 30, and 75 mg/kg), decreased the seizure threshold. Pretreatment with clonidine (0.001-0.1 mg/kg) inhibited the anticonvulsant effect of morphine, while potentiating its proconvulsant effect. Conversely, yohimbine (0.5-2 mg/kg) potentiated the anticonvulsant effect of morphine but inhibited its proconvulsant effects. Acute stress induced an anticonvulsant effect that was reversible by naloxone (1 mg/kg) or clonidine (0.05-0.1 mg/kg) or a combination of their lower doses (0.3 and 0.01 mg/kg, respectively), while being potentiated by yohimbine (1 mg/kg). CONCLUSIONS: alpha2-Adrenoceptors play a dual role in the anticonvulsant effects of morphine. The activation of these receptors also can decrease the anticonvulsant effect of acute restraint stress in mice.     

Evidence for involvement of central noradrenergic neurons in the cardiovascular depression induced by morphine in the rat

Summary Morphine caused in the anaesthetized rat reduction in brain noradrenaline (NA) turnover, hypotension and bradycardia, similarly to the antihypertensive,-adrenergic agonist, clonidine. All effects of morphine were antagonized by naloxone, as well as the-receptor antagonist, yohimbine. In contrast, naloxone did not affect the circulatory depression and reduction in brain NA utilization by clonidine, which both previously have been found to be antagonized by yohimbine. In contrast to clonidine, morphine even in high doses did not facilitate the flexor reflex activity of acutely spinalized rats. Pretreatment with protriptylin largely attenuated the circulatory depressive effects of morphine, as it has previously been found to block the corresponding effects of clonidine. Thus, the morphine-induced cardiovascular depressive effects are primarily elicited by activation of opiate receptors. However, the inhibition of brain NA neurotransmission by morphine appears critically involved in the mediation of the circulatory depression.     

Adrenergic modulation of gastric stress pathology in rats: a cholinergic link

The effects of some adrenergic drugs were evaluated on cold restraint-induced gastric ulcers in rats. The beta-adrenergic antagonist, (+/-)-propranolol (1 and 10 mg/kg), as well as the beta-agonist, isoproterenol (0.05 and 0.5 mg/kg) potentiated the gastric pathology. On the other hand, the alpha-agonist, clonidine (0.5 mg/kg) attenuated and the alpha-antagonist, yohimbine (1 mg/kg) aggravated stress ulcer development. The anticholinergic agent, atropine methylnitrate (1 mg/kg), reduced both the frequency and severity of stress ulcers and also antagonized the potentiating effects of (+/-)-propranolol, isoproterenol and yohimbine. The results suggest a cholinergic role in the adrenergic modulation of gastric stress pathology.     

Morphine action on cholecystokinin octapeptide release from rat periaqueductal grey slices: sensitisation by naloxone

Cholecystokinin (CCK) has potent antinociceptive properties when given either peripherally or centrally. An interaction between opiate and CCK-induced antinociception is indicated as CCK-induced analgesia is potentiated by naloxone. Since CCK cells in Periaqueductal grey (PAG) are known to be sensitive to both noxious stimuli and i.v. morphine, the possibility that the PAG was the site of such an interaction was investigated by an in vitro study of the effects of morphine and naloxone on CCK release in PAG. The K+-evoked release of CCK from tissue slices of PAG was unaffected by a wide range of concentrations of morphine. However, after pretreatment with naloxone (10(-9) M), morphine (10(-7)-10(-6) M) caused a significant, dose dependent attenuation of CCK release (70% inhibition at 10(-6) M). These results suggest that the release of CCK in PAG is modulated by opioid systems.     

Inhibition of sympathetic preganglionic discharges by epinephrine and and alpha-methylepinephrine

The present study was undertaken to determine the effect of iontophoretic applications of epinephrine (E) and its derivative alpha-methylepinephrine (mE) on the discharges of sympathetic preganglionic neurons (SPNs). Spontaneously active SPNs located in thoracic segment T2 were antidromically identified in White Carneaux pigeons anesthetized with urethane and immobilized with purified alpha-cobratoxin. All SPNs tested were inhibited by E, mE, several other catecholamines, clonidine, GABA, glycine and morphine. The inhibitory effects of E and mE but not those of GABA were antagonized by iontophoretic applications of the preferential alpha 2-antagonists piperoxane and yohimbine, but not by the alpha 1-antagonist prazosin or the beta-antagonist sotalol when similarly applied. The inhibitory effects of GABA, glycine and morphine were respectively antagonized by bicuculline methiodide, strychnine and naloxone, but these antagonists failed to alter the action of E. It is concluded that (1) epinephrine and its alpha-methyl derivative inhibit the discharges of SPNs via the activation of alpha 2-receptors and (2) the epinephrine-induced inhibition does not result from the secondary release of GABA, glycine or opioid peptides from afferent terminals or interneurons.     

Effects of adenosine and its analogues on porcine basilar arteries: are only A2 receptors involved?

The aim of this study was to test the effect of adenosine and four of its analogues, 5'-(N-ethyl)carboxamidoadenosine (NECA), 2-chloroadenosine (2-CADO), L-phenylisopropyladenosine (L-PIA), and N6-cyclohexyl-adenosine (CHA), on prostaglandin (PG) F2 alpha-constricted pig basilar arteries, and from their rank order of potency determine the receptor type involved. The order of potency for the relaxation of the PGF2 alpha constriction was NECA greater than adenosine, 2-CADO greater than L-PIA greater than CHA, which is in keeping with the A2 receptor subtype. The study also investigated the effects of a known adenosine antagonist, namely, the xanthine derivative 8-phenyltheophylline, which at concentrations having no intrinsic effect (10(-8) and 10(-7) M) produced a significant shift to the right only for the NECA dose-response curve.     

N6 (L-Phenylisopropyl)adenosine (L-PIA) increases slow-wave sleep (S2) and decreases wakefulness in rats

Rats implanted with electrodes for polygraphic recording were administered with L-PIA (0.115 mg/kg, i.p.), caffeine (15 mg/kg, i.p.) or L-PIA (0.115 mg/kg, i.p.) + caffeine (15 mg/kg, i.p.) and recorded for 6 h. The results show that administration of L-PIA increased S₂ by 54 min suggesting that stimulation of adenosine receptors promotes deep sleep. Administration of L-PIA failed to produce the same effect in the presence of caffeine, a finding consistent with the hypothesis that the CNS stimulant effect of caffeine and other methylxanthines is due to their ability to antagonize depressant effects of endogenous adenosine.     

N (L-Phenylisopropyl)adenosine (L-PIA) increases slow-wave sleep (S2) and decreases wakefulness in rats

Rats implanted with electrodes for polygraphic recording were administered with L-PIA (0.115 mg/kg, i.p.), caffeine (15 mg/kg, i.p.) or L-PIA (0.115 mg/kg, i.p.) + caffeine (15 mg/kg, i.p.) and recorded for 6 h. The results show that administration of L-PIA increased S₂ by 54 min suggesting that stimulation of adenosine receptors promotes deep sleep. Administration of L-PIA failed to produce the same effect in the presence of caffeine, a finding consistent with the hypothesis that the CNS stimulant effect of caffeine and other methylxanthines is due to their ability to antagonize depressant effects of endogenous adenosine.     

Preferential effects of caffeine on limbic and cortical dopamine systems

In this study, we investigated the effects of acute caffeine administration on the activity of midbrain dopamine neurons. Caffeine significantly depressed the firing rates of dopamine neurons in the ventral tegmental area (A10 group), but had no significant effect on the firing rates of dopamine neurons in the substantia nigra zona compacta (A9 group). The action of caffeine in A10 was completely blocked by pretreatment with the adenosine agonist L-phenyl-isopropyl-adenosine (L-PIA), confirming numerous lines of evidence that caffeine and other xanthines act as competitive antagonists at adenosine receptors. The dopamine antagonist haloperidol also antagonized the effects of caffeine. This finding is consistent with a mechanism of caffeine-induced depression of dopamine neuron activity involving dopamine release, similar to that observed during amphetamine administration. Finally, the benzodiazepine diazepam also antagonized the dopaminergic effects of caffeine. It appears that, in the rat, caffeine administration inhibits mesolimbic and mesocortical projecting dopamine neurons, but has no effect on dopamine neurons that project to the striatum.     

Inhibition of sympathetic preganglionic discharges by epinephrine and α-methylepinephrine

The present study was undertaken to determine the effect of iontophoretic applications of epinephrine (E) and its derivative α-methylepinephrine (mE) on the discharges of sympathetic preganglionic neurons (SPNs).Spontaneously active SPNs located in thoracic segment T2 were antidromically identified in White Carneaux pigeons anesthetized with urethane and immobilized with purified α-cobratoxin.All SPNs tested were inhibited by E, mE, several other catecholamines, clonidine, GABA, glycine and morphine.The inhibitory effects of E and mE but not those of GABA were antagonized by iontophoretic applications of the preferential α₂-antagonists piperoxane and yohimbine, but not by the α₁-antogonist praxosin or the β-antagonist sotalol when similarly applied.The inhibitory effects of GABA, glycine and morphine were respectively antagonized by bicuculline methiodide, strychnine and naloxone, but these antagonists failed to alter the action of E.It is concluded that (1) epinephrine and its α-methyl derivative inhibit the discharges of SPNs via the activation of α₂-receptors and(2) the epinephrine-induced inhibition does not result from the secondary release of GABA, glycine or opioid peptides from afferent terminals or interneurons.     

Effect of clonidine on colonic motility in rats

Clonidine, an alpha(2)-adrenoceptor agonist, has been reported to inhibit gastric and small intestinal motility in rats. Whether clonidine also inhibits colonic motility is still not clear. The aim of this study was to examine the effect of clonidine on colonic motility and its possible site of action in adult Wistar rats. Colonic motilities in anesthetized rats in vivo or motilities of the isolated colon of rats in vitro were recorded. Clonidine was administered intravenously (i.v.) and intracerebroventricularly (i.c.v.) in vivo while bath administration was used in in vitro study. Clonidine i.v. or i.c.v. significantly inhibited colonic motility. This inhibitory effect was antagonized by pre-administration of yohimbine, an alpha(2)-adrenoceptor antagonist, but not by pre-administration of prazosin, an alpha(1)-adrenoceptor antagonist. Also, we have unpublished data indicating that the sympathectomy antagonized the inhibitory effect of systemically administered clonidine. A significant depression of colonic motility on the isolated colon was induced by bath administration of noradrenaline, while no such inhibition was seen by clonidine. The results of the present study suggested that clonidine inhibits colonic motility in rats through activation of central alpha(2)-adrenergic receptor.     

Cardiovascular effects of microinjections of adenosine analogs into the fourth ventricle of rats

Rats were implanted with chronic indwelling cannulae into the posterior region of the fourth ventricle. After recovery from surgery, acute experiments on blood pressure were conducted under urethane anesthesia. The blood pressure and heart rate responses following administration of two adenosine analogs, NECA and L-PIA were examined. Microinjections of both analogs produced dose-dependent reductions in blood pressure and heart rate. NECA was approximately 20-fold more potent than L-PIA in reducing blood pressure and depressing heart rate. The cardiovascular effects of both analogs were antagonized by parenteral injections of caffeine. These findings show that microinjections of analogs of adenosine into the fourth ventricle can influence areas of the central nervous system involved in cardiovascular control.     

The involvement of endogenous opioids and nitricoxidergic pathway in the anticonvulsant effects of foot-shock stress in mice

The involvement of endogenous opioids and nitric oxide (NO) in the anticonvulsant effects of stress against pentylenetetrazole (PTZ)- or electroconvulsive shock-induced seizures was assessed in mice. The prolonged and intermittent foot-shock stress, which induced opioid-mediated analgesia, had significant protective effects against both seizure types which was reversible by naloxone (0.3, 1 or 2 mg/kg), while brief and continuous foot-shock did not alter the seizure susceptibility. Pre-treatment with non-specific nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 1, 2, 5, 10 or 30 mg/kg), but not with specific inducible NOS (iNOS) inhibitor, aminoguanidine (50 or 100 mg/kg), blocked the stress-induced anticonvulsant effects. The lower doses of naloxone (0.3 mg/kg) and L-NAME (2 mg/kg) showed additive effects in blocking the stress-induced anticonvulsant properties. L-arginine at a per se non-effective dose of 20 mg/kg potentiated the stress-induced anticonvulsant properties, an effect which was inhibited by L-NAME but not by aminoguanidine. Furthermore, a low dose of morphine (0.5 mg/kg) showed potentiation with stress in increasing PTZ seizure threshold. This potentiation was reversed by either naloxone or L-NAME at low doses but not by aminoguanidine. Taken together, these results show that NO synthesis, through constitutive but not iNOS, is involved in opioid-dependent stress-induced anticonvulsant effects against electrical and PTZ-induced convulsions.     

Intraperitoneal and intraamygdala N(6)-cyclohexyladenosine suppress hippocampal kindled seizures in rats

Effects of intraperitoneal and intraamygdala N(6)-cyclohexyladenosine (CHA), a selective adenosine A(1) receptor agonist, and 1,3-dimethyl-8-cyclopentylxanthine (CPT), a selective adenosine A(1) receptor antagonist, were examined in fully hippocampal kindled rats. Intraperitoneal administration of CHA (0. 25, 0.5 and 1 mg/kg) decreased hippocampal secondary afterdischarge duration (SAD) and amygdala afterdischarge duration (ADD). Only the 1 mg/kg dose induced a significant increase in latency to stage 4. Intraperitoneal administration of CPT (0.25, 0.5 and 1 mg/kg) induced a significant increase in stage 5 duration, hippocampal SAD and ADD. Pretreatment of animals with CPT (1 mg/kg), antagonized effects of CHA on seizure parameters. Intraamygdala microinfusion (1 microl over 2 min) of CHA (5 nM-1 mM) significantly reduced hippocampal SAD and amygdala ADD. These effects were antagonized by intraamygdala CPT (1 microM). Results obtained suggest that in hippocampal kindled rats, amygdala may be regarded as a relay point for AD propagation specially in recruit activity of the hippocampus.     

Pharmacological identification of the alpha-adrenergic receptor type which inhibits the beta-adrenergic activated adenylate cyclase system in cultured astrocytes

The adrenergic agonist norepinephrine can exert its influence on cell function by activating both alpha- and beta-adrenergic receptors. In astrocytes, the alpha-adrenergic receptor activity of norepinephrine is known to inhibit the cyclic AMP response elicited by its action at beta-adrenergic receptors. Pharmacological studies were conducted to identify the subtype of alpha-adrenergic receptor which mediates this inhibitory action. The alpha 2-adrenergic antagonist yohimbine potentiated the cyclic AMP response elicited by norepinephrine, whereas the alpha 1-adrenergic antagonist prazosin did not affect the response. The alpha 2-adrenergic agonist clonidine inhibited the cyclic AMP response elicited by the beta-adrenergic agonist isoproterenol and this inhibition could be blocked by yohimbine but not by prazosin. In contrast, the alpha 1-adrenergic agonist phenylephrine did not inhibit the cyclic AMP response to isoproterenol. These studies indicate that the inhibitory action of norepinephrine is mediated by its action at alpha 2-adrenergic receptors.     

The site and the mode of analgesic actions exerted by clonidine in monkeys

We used intracerebral administration of clonidine in monkeys to map effective sites for analgesia. The jaw opening reflex elicited by tooth pulp stimulation was used for analgesia testing. We found that the most consistently effective sites for analgesia in monkeys are in at least three brain regions: the diencephalic periventricular gray, the dorsal raphe nuclei, and the periaqueductal gray. In addition, the analgesia induced by intracerebral administration of clonidine was effectively antagonized by pretreatment of animals with either naloxone (a narcotic antagonist) or yohimbine (an alpha-adrenergic antagonist). These results suggest the existence of an opiate and an adrenergic antinociceptive mechanism in the diencephalic periventricular gray, the dorsal raphe nuclei, and the periaqueductal gray activated by clonidine in primates.     

Effects of clonidine and alpha-adrenoceptor antagonists on motor activity in DSP4-treated mice II: interactions with apomorphine

Adult mice were administered either the noradrenaline (NA) neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or distilled water (control), 10-12 days before motor activity testing, and 6 h before testing all the mice were administered reserpine (10 mg/kg), the monoamine-depleting agent. The interactive effects of (I) clonidine, the alpha(2)-adrenoceptor agonist, with the dopamine (DA) agonist, apomorphine, and the alpha(2)-antagonist, yohimbine, and (II) with either yohimbine or the alpha(1)-antagonist, prazosin, upon motor behaviour in activity test chambers were studied in reserpinized DSP4-treated and control mice. It was shown that apomorphine (3 mg/kg) increased locomotor and total activity in both reserpinized DSP4-treated and control mice but the effect was attenuated in the DSP4 mice. Co-administration of clonidine (3 mg/kg) with apomorphine potentiated the effects of apomorphine on motor activity and this effect was enhanced markedly by DSP4 pretreatment. Yohimbine (10 mg/kg) antagonized the motor activity-stimulating effects of apomorphine in both DSP4-treated and control mice. Co-administration of clonidine with apomorphine, following yohimbine, restored motor activity levels to those obtained in the absence of yohimbine and this effect upon locomotor activity was enhanced by DSP4 pretreatment. The effects of clonidine on motor activity were enhanced by NA-denervation. Prazzosin (3 mg/kg) enhanced the locomotor activity of both reserpinized DSP4-treated and control mice after the initial 30-min period but was not affected by DSP4 treatment. Analysis of post-decapitation convulsions (PDCs) indicated loss of the reflex by DSP4 pretreatment. Reserpine pretreatment abolished the initial, exploratory phase (30 min) of motor activity. These results demonstrate interactions between NA and DA systems that may bear eventual relevance to neurologic disorders such as parkinsonism.     

Endotoxin pretreatment modifies peristalsis and attenuates the antipropulsive action of adrenoceptor agonists in the guinea-pig small intestine

The action of endotoxin to alter gastrointestinal motility in vivo may reflect a direct effect on the gut or result from vascular and other systemic manifestations of this sepsis model. Here we examined whether in vivo pretreatment of guinea-pigs with endotoxin modifies peristalsis in the isolated gut and influences the antipropulsive action of adrenoceptor agonists. Distension-induced peristalsis was recorded in fluid-perfused segments of the small intestine taken from animals pretreated intraperitoneally with endotoxin (1 mg kg(-1)Escherichia coli lipopolysaccharide) or vehicle 4 or 20 h before. Clonidine, adrenaline, noradrenaline, dopamine and dobutamine inhibited peristalsis with differential potency. Endotoxin pretreatment lowered the peristaltic pressure threshold and altered other parameters of baseline peristalsis in a time-related manner. The potency and efficacy of clonidine to inhibit peristalsis were markedly decreased after endotoxin administration, while the potency of the other test drugs was less attenuated. The antipropulsive action of clonidine in control segments was reduced by yohimbine and prazosin, whereas in segments from endotoxin-pretreated animals it was antagonized by yohimbine but not prazosin. We conclude that systemic endotoxin pretreatment of guinea-pigs modifies baseline peristalsis by an action on the gut and inhibits the antipropulsive action of adrenoceptor agonists through changes in adrenoceptor activity.     

Alpha 2-adrenoreceptor subtypes regulate ACTH and beta-endorphin secretions during stress in the rat

The effect of different alpha 2-adrenoreceptor subtype agonists and antagonists on adrenocorticotrop hormone (ACTH) and beta-endorphin release induced by ether stress was examined. Ether inhalation-induced ACTH and beta-endorphin increase was inhibited by i.c.v. administration of 30 micrograms but not 1 and 10 micrograms clonidine (alpha 2-adrenoreceptor agonist). I.c.v. oxymetazoline (alpha 2A-adrenoreceptor agonist; 1-10-30 micrograms) or the alpha 1-agonist methoxamine (100 micrograms/rat) failed to inhibit the stress-induced rise. Pretreatment with the alpha 1/alpha 2B.C-antagonist prazosin (0.5 mg/kg, i.p.) prevented the effect of clonidine on the ether stress, while the alpha 1/alpha 2A-antagonist WB-4101 (0.5 mg/kg, i.p.) was unable to counteract the inhibitory effect of clonidine. Prazosin alone had no effect on the ether-induced plasma ACTH and beta-endorphin elevation. These results suggest that noradrenaline in the central nervous system may inhibit the stress-induced hypothalamo-pituitary-axis and pituitary beta-endorphin activation via alpha 2B.C-adrenoceptor subtypes and prazosin may antagonize its effect on these receptors.