Effect of imipramine on the expression and acquisition of morphine-induced conditioned place preference in mice

The effect of imipramine and alpha-adrenoceptor agonists and antagonists on the acquisition or expression of morphine-induced conditioned place preference (CPP) was studied in mice. An unbiased CPP paradigm was used to study the effect of the agents. In the first set of experiments, the drugs were used during the development of CPP by morphine or they were used alone in order to see if they induce CPP or conditioned place aversion (CPA). Our data showed that intraperitoneal injection of morphine sulphate (2.5-10 mg/kg) induced CPP in mice. Imipramine (0.5-2.5 mg/kg), phenylephrine (0.5-2 mg/kg), yohimbine (0.5-2 mg/kg) or prazosin (0.1-1 mg/kg) did not influence CPP, but clonidine (0.002-0.05 mg/kg) induced CPA. Yohimbine increased, while clonidine and prazosin reversed, morphine-induced CPP. Phenylephrine did not influence the CPP induced by morphine. In the second set of experiments, when the drugs were used before testing on Day 6, in order to test their effects on the expression of morphine-induced CPP, imipramine (0.5-5 mg/kg) reversed morphine-induced CPP and this reversal was blocked by naloxone (2 mg/kg). Clonidine and prazosin reversed, while yohimbine decreased morphine-induced CPP. Phenylephrine did not alter the morphine response. Furthermore, yohimbine and prazosin reversed the imipramine effect. None of the drugs influenced locomotion. However, prazosin or yohimbine in combination with morphine altered locomotor activity during the acquisition of CPP. Yohimbine by itself increased locomotion. It is concluded that imipramine can induce CPA through an opioid receptor mechanism and alpha-adrenoceptor agents may influence morphine CPP.     

Effect of alpha-adrenoceptor agents on imipramine-induced antinociception in nerve-ligated mice.

In this study, the effects of adrenoceptor agonists and antagonists on antinociception induced by imipramine in sciatic-nerve-ligated mice were investigated. The response of different doses of morphine, imipramine and adrenoceptor agonists and antagonists was examined 14 days after unilateral nerve-ligation in the hot-plate test. Intraperitoneal injection of different doses of morphine (3, 6 and 9 mg/kg), imipramine (10, 20 and 40 mg/kg), the alpha(2)-adrenoceptor agonist, clonidine (0.05, 0.1 and 0.2 mg/kg) or the alpha(1)-adrenoceptor agonist, phenylephrine (2, 4 and 8 mg/kg) induced dose-related antinociception in both intact and nerve-ligated mice. The antinociception induced by morphine but not that of imipramine, clonidine or phenylephrine, in nerve-ligated mice was significantly less than that induced in intact animals. Imipramine in combination with clonidine tends to induce a higher response, but the combination of imipramine with phenylephrine did not lead to significant potentiation. The alpha(2)-adrenoceptor antagonist, yohimbine, reduced the response induced by imipramine or imipramine plus clonidine in intact and nerve-ligated animals. However, the alpha(1)-adrenoceptor antagonist, prazosin, did not alter imipramine response. It may be concluded that imipramine induced antinociception in both intact and nerve-ligated mice through an alpha(2)-adrenoceptor mechanism(s).     

Effects of adrenoceptor agents on apomorphine-induced licking behavior in rats

In the present study, intraperitoneal (IP) administration of the dopaminergic receptor agonist apomorphine (0.1, 0.25, and 0.5 mg/kg) induced a dose-dependent licking in rats. The intraperitoneal injection of the alpha1'adrenoceptor agonist phenylephrine (1-8 mg/kg) but not the alpha2-adrenoceptor agonist clonidine (0.025-0.05 mg/kg) decreased licking induced by apomorphine. The alpha-adrenoceptor antagonists prazosin, phenoxybenzamine, and yohimbine also reduced the apomorphine response significantly. The response induced by phenylephrine was decreased by a dose of prazosin. The beta1-adrenenocepor agonist dobutamine and beta2-adrenenocepor agonist salbutamol did not alter the apomorphine response. However, beta2-adrenenocepor antagonists atenolol and propranolol reduced the apomorphine effect. It may be concluded that alpha1- and possibly beta1-adrenoceptor mechanisms may be involved in modulation of licking behavior.     

Influence of alpha-adrenoceptor agonists and antagonists on imipramine-induced hypothermia in mice

Effects of adrenoceptor agonists and antagonists on imipramine-induced hypothermia in mice were studied. Intraperitoneal injection of imipramine (10-40 mg x kg(-1)), alpha2-adrenoceptor agonist clonidine (0.05-0.1 mg x kg(-1)), alpha1-adrenoceptor agonist phenylephrine (6 mg x kg(-1)) and alpha1-adrenoceptor antagonist prazosin (1-4 mg x kg(-1)) but not alpha2-adrenoceptor antagonist yohimbine (1-4 mg x kg(-1)) induced significant hypothermia. The hypothermic response induced by imipramine (10-30 mg x kg(-1)) was not altered by clonidine (0.05-0.1 mg x kg(-1)) or phenylephrine (2-6 mg x kg(-1)). The response of imipramine (10-30 mg x kg(-1)) was reduced significantly by yohimbine (2 mg x kg(-1)) and was potentiated by prazosin (1 mg x kg(-1)). The hypothermic effect of clonidine (0.1 mg x kg(-1)) and imipramine (20 mg x kg(-1)) were also decreased significantly by different doses of yohimbine (1-4 mg x kg(-1)). The hypothermia induced by different doses of prazosin (1-4 mg x kg(-1)) was not altered by yohimbine (2 mg x kg(-1)) or by low dose of imipramine (10 mg x kg(-1)). It is concluded that alpha2-adrenoceptor mechanism may be involved in the hypothermic effect of imipramine.     

Alpha-2 agonists decrease expression of morphine-induced conditioned place preference

Opioidergic system can interact with different transmission such as dopaminergic and adrenergic system. It has been shown that alpha-adrenergic system is involved in some effects of opioid including reward. In this study, alpha-2 agonists were used before testing on day 6 to evaluate their effects on the expression of morphine-induced conditioned place preference (CPP). Our results showed that intraperitoneal (i.p.) injections of morphine (5 mg/kg) induced CPP. Administration of alpha(2)-agonists clonidine (0.01, 0.02 and 0.04 mg/kg, i.p.), tizanidine (0.1, 0.2 and 0.4 mg/kg, i.p.) and xylazine (2.5, 5 and 10 mg/kg, i.p.) decreases the expression of morphine-induced CPP. Yohimbine (0.5 mg/kg, i.p.) reversed the inhibitory effect of alpha(2)-agonists. The comparison of potency of inhibitory effect of three agonists showed that ID(50) values for clonidine, tizanidine and xylazine were 0.013, 0.32 and 1.86 mg/kg respectively. Therefore, it is concluded that alpha(2)-agonists decrease the morphine-induced CPP in mice and clonidine is more potent than tizanidine and xylazine. The relative potency of clonidine with respect to tizanidine and xylazine was 30 and 180 respectively.     

Effects of adrenoceptor agonists and antagonists on morphine-induced Straub tail in mice

Straub-tail behavior was induced by subcutaneous injection of different doses (10-60 mg/kg) of morphine to mice. The maximum response was obtained with 20-40 mg/kg of the drug. The response induced by morphine (40 mg/kg) was decreased by intraperitoneal administration of different doses of clonidine (0.05-0.1 mg/kg). Pretreatment of animals with yohimbine (1-4 mg/kg i.p.) reversed the inhibitory action of clonidine. Yohimbine did not elicit any response by itself. Administration of prazosin (0.25, 0.5, and 1 mg/kg) reduced the morphine response. The combination of prazosin with yohimbine (1 mg/kg), but not with clonidine (0.05 mg/kg), caused a potentiated inhibition of the morphine effect. Phenylephrine (2-6 mg/kg i.p.) did not elicit any effect by itself and also did not alter the response induced by morphine or morphine plus clonidine. Dobutamine (2.5-10 mg/kg i.p.), atenolol (2.5-10 mg/kg i.p.), salbutamol (2.5-10 mg/kg i.p.), and propranolol (2.5-10 mg/kg i.p.) did not alter morphine-induced Straub-tail behavior in mice. In conclusion, activation of alpha2-adrenergic pathways contributes to morphine-induced Straub tail, while alpha1- and beta2-adrenergic may not be involved in this phenomenon.     

Effect of alpha-adrenoceptor agonists and antagonists on imipramine-induced antinociception in the rat formalin test

In this study, the effect of central administration of the alpha-adrenoceptor agents on the antinociception induced by imipramine in the formalin test has been investigated. Intraperitoneal (IP) administration of different doses of imipramine (10-80 mg/kg) and intracerebroventricular (ICV) administration of the alpha(2)-adrenoceptor agonist clonidine (0.05-0.8 microg/rat) elicited a dose-dependent antinociception in the both phases of the test. Furthermore, different doses of clonidine (0.05-0.2 microg/rat) increased the antinociception induced by imipramine (10 and 20 mg/kg). The alpha(2)-adrenoceptor antagonist yohimbine (2 microg/rat, ICV) reduced the response of a low dose imipramine (10 mg/kg, IP) plus different doses of clonidine (0.05, 0.1 and 0.2 microg/rat, ICV), but did not alter the response induced by higher doses of imipramine (20 and 40 mg/kg) alone or in combination with clonidine. Yohimbine by itself elicited no effect. The alpha(1)-adrenoceptor agonist phenylephrine (0.07-1.5 microg/rat) induced antinociception in both phases of the formalin test, but did not alter the imipramine-induced antinociception. The alpha(1)-adrenoceptor antagonist prazosin neither elicited antinociception nor altered the imipramine response. Yohimbine (2 microg/ rat, ICV) in combination with prazosin (0.5 microg/rat, ICV) caused more inhibition of the response of imipramine or imipramine plus clonidine. Therefore, it is concluded that alpha(2)-adrenoceptor mechanism may be involved in the imipramine-induced antinociception.     

The antinociceptive effect of FR140423 in mice: involvement of spinal alpha(2)-adrenoceptors

We investigated the role of the spinal noradrenergic system in the antinociceptive effect of FR140423, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]py razole, by using the tail-pinch test in mice and various adrenoceptor antagonists. The antinociceptive effect of FR140423 injected i.t. was completely abolished by co-administration of the non-selective alpha-adrenoceptor antagonist phentolamine and the alpha(2)-adrenoceptor antagonist yohimbine but not by the alpha(1)-adrenoceptor antagonist prazosin or the beta-adrenoceptor antagonist propranolol. Oral administration of FR140423, at doses of 5-80 mg/kg, produced a dose-dependent antinociceptive effect with an ED(50) value of 19 mg/kg. This antinociception was abolished by i.t., but not i.c.v., injection of phentolamine and yohimbine (10 microg/mouse). These results suggest that alpha(2)-adrenoceptors in the spinal cord are involved in the antinociceptive effect of FR140423 against mechanical noxious stimulus as they are in the effect of morphine and clonidine.     

Pharmacological characterization of the postsynaptic alpha-adrenoceptors in human uterine artery

Prazosin and yohimbine were used to differentiate postjunctional alpha-adrenoceptors in the human uterine artery in-vitro. Two postjunctional alpha-adrenoceptor subtypes were distinguished by the affinities of the receptor for yohimbine and prazosin. The pA2 for prazosin was 8.91 against phenylephrine with a slope not significantly different from unity (0.91), and the pA2 for yohimbine was 7.25 against naphazoline and 8.70 against clonidine, with slopes not significantly different from unity (1.11 and 1.18, respectively). Yohimbine was not very active against phenylephrine, while prazosin was very active against the mixed and selective alpha 2-adrenoceptor agonist noradrenaline and clonidine; the intercepts of the Schild plot were 8.80 and 8.82 but with slopes significantly less than unity (0.77 and 0.67, respectively). Prazosin competitively antagonized phenylephrine at the alpha 1-adrenoceptor, whereas yohimbine competitively antagonized naphazoline and clonidine at the alpha 2-adrenoceptor. It is concluded that both alpha 1- and alpha 2-adrenoceptors are present in the human uterine artery.     

Adrenoceptor mechanisms underlying imipramine-induced memory deficits in rats

The post-training administration of tricyclic antidepressant imipramine impairs memory consolidation in the passive avoidance task. The present study investigated the effects of intrahippocampal (i.h.) injection of adrenoceptor agents on imipramine-induced (2-8 microg/rat) amnesia. The administration of the alpha1-adrenoceptor agonist phenylephrine (0.05 microg/rat) and the alpha1-adrenceptor antagonist prazosin (0.5 microg/rat) did not alter the effect of imipramine. The lower doses of phenylephrine (0.005 and 0.015 microg/rat) impaired, while the higher dose of the drug (0.025 and 0.05 microg/rat) improved retention. The effect of phenylephrine was not altered by prazosin (0.5 and 1 microg/rat) pretreatment, although prazosin alone decreased retention latencies. The alpha2-adrenoceptor antagonist yohimbine (0.5 and 1 microg/rat) decreased the response induced by imipramine. However, the alpha2-adrenoceptor agonist clonidine (0.08 microg/rat) did not alter the effect of the drug. Clonidine (0.15 and 0.3 microg/rat) by itself decreased, while yohimbine (1 and 2 microg/rat) increased retention latencies. Yohimbine pretreatment attenuated the effect of clonidine. It is concluded that alpha2-adrenoceptor mechanism(s) may be involved in imipramine-induced impairment of memory.     

Norepinephrine modulates seizures induced by quinolinic acid in rats: selective and distinct roles of alpha-adrenoceptor subtypes

We investigated in rats whether alterations in noradrenergic function caused by 6-hydroxydopamine or alpha- and beta-adrenoceptor agonists and antagonists would modify the susceptibility of the brain to electroencephalographic seizures induced by intrahippocampal infusion of quinolinic acid. 6-Hydroxydopamine depletion of norepinephrine facilitated the expression of seizures while alpha-adrenoceptor stimulation by clonidine had either proconvulsant (0.1 mg/kg) or anticonvulsant (from 0.5 to 2 mg/kg) effects. Clonidine's anticonvulsant activity (0.5 mg/kg) was mimicked by methoxamine given intrahippocampally (10 micrograms), and antagonized by prazosin (1 mg/kg), whereas both yohimbine (5 and 10 mg/kg) and piperoxane (5 mg/kg) had no significant effect. Seizure facilitation induced by clonidine (0.1 mg/kg) was blocked by yohimbine (10 mg/kg). Systemic (0.25 and 0.5 mg/kg) or intrahippocampal (10 and 20 micrograms) isoproterenol and propranolol (10 mg/kg) had no effect. Spiking activity and neurotoxicity induced by quinolinic acid were unaltered by treatments which protected against convulsions. Modulation of quinolinic acid-convulsive activity by alpha-adrenoceptor subtypes appears to be selective and complex, since alpha 1-type activation reduces seizures while alpha 2-type stimulation has proconvulsant effects.     

Effects of alpha-adrenoceptor agonists and antagonists on insulin secreting cells and pancreatic blood vessels: comparative study

The effects of alpha-adrenergic drugs were studied on glucose-induced insulin secretion and effluent flow rate on the same preparation: the isolated perfused rat pancreas. An alpha 1-adrenoceptor agonist, phenylephrine 0.05 microM slightly decreased insulin secretion (-25%); this inhibition was counteracted by an alpha 2-adrenoceptor antagonist, yohimbine 0.6 microM. Phenylephrine evoked a fall in liquid flow rate (-13%) which was reversed by an alpha 1-adrenoceptor antagonist, prazosin 6 microM, but not by yohimbine. An alpha 2-adrenoceptor agonist, clonidine 0.01 and 0.05 microM decreased insulin secretion (-80%). This inhibition was reversed by yohimbine 0.6 and 6 microM respectively. Only the concentration of 0.05 microM clonidine evoked a fall (-25%) in liquid flow rate; this fall was counteracted by yohimbine 0.6 microM. In conclusion our results show that adrenergic inhibition of insulin secretion is mediated only by alpha 2-receptors whereas both types of adrenoceptors are implicated in the vasoconstrictor effect. The insulin inhibitory effect of adrenoceptor agonists is not related to vasoconstriction.     

Alpha-adrenoceptor blocking action of terazosin

alpha-Adrenoceptor blocking activities and vascular relaxation activities of terazosin, a new antihypertensive agent, were studied. Terazosin had no effect on Ba2+, serotonin, angiotensin II and Ca2+ induced contractions in the isolated rat aorta. Terazosin competitively inhibited norepinephrine (NE) and phenylephrine (PE) induced contractions of the isolated rat aorta, and their pA2 values were 9.28 and 8.74, respectively. The potency of terazosin in the NE induced contraction was about 0.11, 8 and 176 times more than prazosin, phentolamine and yohimbine, respectively. The potency of terazosin in the PE induced contraction was about 0.09, 6 and 60 times more than prazosin, phentolamine and yohimbine. Terazosin (i.v.) competitively inhibited the PE induced pressor response. The "pA2" values of postsynaptic alpha-adrenoceptor blocking activity was 5.22, and its potency was about 0.05, 5 and 62.5 times more than prazosin, phentolamine and yohimbine, respectively. Terazosin (0.3 mg/kg, i.v. or less) did not show any significant effect on clonidine induced bradycardia during electrical stimulation of cardiac sympathetic nerve, whereas prazosin (0.3 mg/kg), phentolamine (0.1 mg/kg) and yohimbine (0.1 mg/kg) antagonized the effect of clonidine by 37%, 80.6% and 63.3%, respectively. Terazosin, 0.3 and 1 mg/kg, p.o., antagonized the PE (3 micrograms/kg, i.v.) induced pressor response in conscious unrestrained rats. This effect lasted for 8 hr in the case of 0.3 mg/kg and lasted for 12 hr in the case of 1 mg/kg. Thus, it is strong suggested that the antihypertensive effect of terazosin is based on the postsynaptic alpha-adrenoceptor blocking action.     

The effects of simultaneous administration of alpha(2) -adrenergic agents with L-NAME or L-arginine on the development and expression of morphine dependence in mice

Both alpha(2)-adrenoceptors and the L-arginine/nitric oxide (NO) pathway have been implicated in the modulation of morphine dependence. This study examined the effects of simultaneous administration of the alpha(2)-adrenoceptor agonist clonidine or the antagonist yohimbine together with the NO precursor L-arginine or the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on the induction and expression of morphine dependence as assessed by naloxone-precipitated withdrawal jumping and diarrhoea. Male NMRI mice weighing 20-30 g were used. In the induction phase, clonidine (0.01-0.1 mg/kg) intensified and yohimbine (0.5-2 mg/kg) attenuated the degree of morphine dependence. Yohimbine reversed the effect of clonidine. L-NAME (5 and 10 mg/kg) did not affect the development of morphine dependence, but significantly potentiated the effects of both subeffective (0.01 mg/kg) and effective (0.03 mg/kg) doses of clonidine. L-Arginine did not alter morphine dependence but inhibited the effect of clonidine. The effects of yohimbine in the induction phase were attenuated by L-NAME, but were not significantly affected by L-arginine. In the expression phase, clonidine attenuated and yohimbine intensified the signs of dependence. The effect of clonidine was inhibited by yohimbine. In the expression phase, L-NAME attenuated the withdrawal syndrome at 10 mg/kg and showed potentiation with clonidine in suppressing withdrawal signs. L-Arginine did not alter morphine dependence, but at 20 mg/kg inhibited and at 100 mg/kg potentiated the attenuating effect of clonidine on the expression of withdrawal syndrome. The effect of yohimbine on the expression phase was also attenuated by L-NAME, but was not significantly affected by L-arginine. In conclusion, alpha(2)-adrenergic and NO pathways seem to be functionally linked in the modulation of opioid dependence.     

The role of alpha-adrenoceptors in the amnestic effect of intracerebroventricular dexamethasone.

Corticosteroids exert dual enhancing or impairing effects on cognitive functions. While their memory-enhancing effects have been well investigated, the mechanisms involved in their amnestic effects are not completely understood. Thus, we examined the role of alpha-adrenoceptors on dexamethasone-induced amnesia using step-through passive avoidance test in rat. Intracerebroventricular (i.c.v.) injection of dexamethasone (5 and 10 microg per rat) decreased the retention latencies. Likewise, intraperitoneal administration of alpha(2)-adrenoceptor agonist clonidine (0.1-0.3 mg kg(-1)) but not alpha(2)-adrenoceptor antagonist yohimbine (0.5-2 mg kg(-1)) decreased the retention latency. Yohimbine pre-treatment decreased the amnestic effects of dexamethasone or dexamethasone plus clonidine. On the other hand, intraperitoneal administration of alpha(1)-adrenoceptor agonist phenylephrine (0.5-2 mg kg(-1)) per se increased, while prazosin at 2 mg kg(-1) decreased the retention latency. Administration of phenylephrine before dexamethasone completely reversed the amnestic effect of the latter, while prozosin did not affect dexamethasone-induced amnesia. These data suggest that dexamethasone may induce its amnestic effect through activation of alpha(2)-adrenoceptors, leading to decreased alpha(1)-adrenergic activity.     

Morphine state-dependent learning: interactions with alpha2-adrenoceptors and acute stress

The interactions of -adrenoceptors and acute restraint stress with morphine state-dependent memory of passive avoidance were examined in mice. Memory acquired following pre-training morphine administration (5 mg/kg, i.p.) was dose- and time-dependently retrieved by pre-test morphine; this effect was reversible by yohimbine (1 mg/kg). Pre-test clonidine (0.005-0.1 mg/kg) was also effective in restoring morphine-induced memory. Pre-training clonidine (2 mg/kg) induced an amnestic effect that was restorable by pre-test clonidine or morphine; this effect was also blocked by yohimbine. Acute pre-training stress for 2 h induced an amnestic effect that was reversible by pre-test morphine (1 and 5 mg/kg) or clonidine (0.01 and 0.1 mg/kg). Finally, acute pre-test stress could restore the impairment of memory induced by pre-training morphine. The data are suggestive of a functional interaction between -opioid, -adrenergic receptors and stress in modulating state-dependent learning and memory.     

Influence of α‐Adrenoceptor Agonists and Antagonists on Imipramine‐Induced Hypothermia in Mice

Abstract: Effects of adrenoceptor agonists and antagonists on imipramine‐induced hypothermia in mice were studied. Intraperitoneal injection of imipramine (10–40 mg kg^?1), α₂‐adrenoceptor agonist clonidine (0.05–0.1 mg kg^?1), α₁‐adrenoceptor agonist phenylephrine (6 mg kg^?1) and α₁‐adrenoceptor antagonist prazosin (1–4 mg kg^?1) but not α₂‐adrenoceptor antagonist yohimbine (1–4 mg kg^?1) induced significant hypothermia. The hypothermic response induced by imipramine (10–30 mg kg^?1) was not altered by clonidine (0.05–0.1 mg kg^?1) or phenylephrine (2–6 mg kg^?1). The response of imipramine (10–30 mg kg^?1) was reduced significantly by yohimbine (2 mg kg^?1) and was potentiated by prazosin (1 mg kg^?1). The hypothermic effect of clonidine (0.1 mg kg^?1) and imipramine (20 mg kg^?1) were also decreased significantly by different doses of yohimbine (1–4 mg kg^?1). The hypothermia induced by different doses of prazosin (1–4 mg kg^?1) was not altered by yohimbine (2 mg kg^?1) or by low dose of imipramine (10 mg kg^?1). It is concluded that α₂‐adrenoceptor mechanism may be involved in the hypothermic effect of imipramine.     

Changes in catecholaminergic pathways innervating the rat heart ventricle during morphine dependence. Involvement Of alpha(1)- and alpha(2)-adrenoceptors

In the present study, we examined the effects of alpha(1)- and the alpha(2)-adrenoceptors blockade on the changes in the ventricular content of catecholamines in rats withdrawn from morphine. Rats were given morphine by s.c. implantation of morphine pellets for 5 days. On the seventh day, morphine withdrawal was induced by s.c. administration of naloxone (1 mg/kg), and rats were killed 30 min later. Pretreatment with yohimbine (alpha(2)-adrenoceptor) or prazosin (alpha(1)-adrenoceptor) 15 min prior to naloxone administration attenuated some of the behavioural signs of morphine withdrawal. In addition, biochemical analysis indicated that yohimbine completely abolished the withdrawal-induced increase in noradrenaline and dopamine turnover in the right ventricle. By contrast, prazosin did not block the hyperactivity of catecholaminergic neurons in the heart during withdrawal. These data suggest that the hyperactivity of catecholaminergic neurons in the heart during morphine withdrawal is dependent upon alpha(2)-adrenoceptor activation. In addition, the present results rule out the involvement of alpha(1)-adrenoceptors.     

α-Adrenergic receptors in auditory cue detection: α2 receptor blockade suppresses false alarm responding in the rat

Numerous studies have suggested a facilitatory role of the noradrenergic system in attention. Cognitive functions relating to attentive states--arousal, motivation, behavioral flexibility, and working memory--are enhanced by norepinephrine release throughout the brain. The present study addresses the role of the adrenergic system on stimulus validity and sustained attention within the auditory system. We examined the effects of adrenoceptor stimulation via systemic injection of α1 and α2-adrenoceptor antagonist and agonist drugs, prazosin (1 mg/kg), phenylephrine (0.1 mg/kg), yohimbine (1 mg/kg), and clonidine (0.0375 mg/kg), respectively. Our results indicate that α1-adrenergic stimulation is ineffective in modulating the biological assessment of auditory signal validity in the non-stressed rat, while α2-adrenoceptor antagonist and agonist drugs were effective in modulating both accuracy and response latencies in the habituated animal. Remarkably, blockade of α2-adrenoceptors significantly improved the animal's ability to correctly reject non-signal events. These findings indicate not only a state dependent noradrenergic component of auditory attentional processing, but a potential therapeutic use for drugs targeting norepinephrine release in neurological disorders ranging from Alzheimer's disease to schizophrenia.     

Antagonism of clonidine-induced hypothermia by alpha adrenoceptor antagonists in electrically stimulated mice

The involvement of receptor subtypes in clonidine-induced hypothermia in electrically stimulated mice was studied using various alpha-adrenoceptor antagonists. Yohimbine, the selective alpha 2-adrenoceptor antagonist significantly blocked the action of low dose (50 micrograms/kg i.p.) of clonidine pretreated with Minimal Threshold Shock (12 mA, 0.2 Sec), while prazosin, selective alpha 1-adrenoceptor antagonist partially blocked the action, suggesting predominant involvement of alpha 2 and partial involvement of alpha 1-adrenoceptors. Under similar conditions when clonidine was used in higher dose (500 micrograms/kg i.p.), its action was blocked by prazosin, phenoxybenzamine and yohimbine suggesting involvement of both alpha 1 and alpha 2-adrenoceptors. In case of animals pretreated with Maximal Threshold Shock (36 mA, 0.2 Sec) the hypothermic action of clonidine in lower dose was blocked by all the three antagonists viz. prazosin, phenoxybenzamine and yohimbine, suggesting involvement of both alpha 1 and alpha 2-adrenoceptors, however, when clonidine was used in the higher dose, the action was significantly antagonised by prazosin and partially by yohimbine, suggesting predominant involvement of alpha 1 and partial involvement of alpha 2-adrenoceptors.