alpha(1)-Adrenoceptors in the lateral septal area modulate food intake behaviour in rats

Background and purpose: Control of food intake is a complex behaviour which involves many interconnected brain structures. The present work assessed if the noradrenergic system in the lateral septum (LS) was involved in the feeding behaviour of rats. Experimental approach: In the first protocol, the food intake of rats was measured. Then non-food-deprived animals received either 100 nL of 21 nmol of noradrenaline or vehicle unilaterally in the LS 10 min after local 10 nmol of WB4101, an alpha(1)-adrenoceptor antagonist, or vehicle. In the second protocol, different doses of WB4101 (1, 10 or 20 nmol in 100 nL) were microinjected bilaterally into the LS of rats, deprived of food for 18 h and food intake was compared to that of satiated animals. Key results: One-sided microinjection of noradrenaline into the LS of normal-fed rats evoked food intake, compared with vehicle-injected control animals, which was significantly reduced by alpha(1)-adrenoceptor antagonism. In a further investigation, food intake was significantly higher in food-deprived animals, compared to satiated controls. Pretreatment of the LS with WB4101 reduced food intake in only food-deprived animals in a dose-related manner, suggesting that the LS noradrenergic system was involved in the control of food intake. Conclusion and implications: Activation by local microinjection of noradrenaline of alpha(1)-adrenoceptors in the LS evoked food intake behaviour in rats. In addition, blockade of the LS alpha(1)-adrenoceptors inhibited food intake in food-deprived animals, suggesting that the LS noradrenergic system modulated food intake behaviour and satiation.

Insular cortex alpha(1)-adrenoceptors modulate the parasympathetic component of the baroreflex in unanesthetized rats

The insular cortex (IC) has been reported to modulate the cardiac parasympathetic activity of the baroreflex in unanesthetized rats. However, which neurotransmitters are involved in this modulation is still unclear. In the present study, we evaluated the possible involvement of local IC-noradrenergic neurotransmission in modulating reflex bradycardiac responses. Bilateral microinjection of the selective alpha(1)-adrenoceptor antagonist WB4101 (15 nmol/100 nL), into the IC of male Wistar rats, increased the gain of reflex bradycardia in response to mean arterial pressure (MAP) increases evoked by intravenous infusion of phenylephrine. However, bilateral microinjection of equimolar doses of either the selective alpha(2)-adrenoceptor antagonist RX821002 or the non-selective beta-adrenoceptor antagonist propranolol into the IC did not affect the baroreflex response. No effects were observed in basal MAP or heart rate values after bilateral microinjection of noradrenergic antagonists into the IC, thus suggesting no tonic influence of IC-noradrenergic neurotransmission on resting cardiovascular parameters. In conclusion, these data provide evidence that local IC-noradrenergic neurotransmission has an inhibitory influence on baroreflex responses to blood pressure increase evoked by phenylephrine infusion through activation of alpha(1)-adrenoceptors. (C) 2009 Elsevier B.V. All rights reserved.

Involvement of central alpha(1)-adrenoceptors on renal responses to central moxonidine and alpha-methylnoradrenaline

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Functional effects of castration on alpha(1)-adrenoceptors in rat vas deferens

The effects of castration on alpha(1)-adrenoceptors in rat vas deferens were investigated by determining the actions of selective antagonists against the contractions induced by noradrenaline. The results obtained in vas deferens from control rats suggest participation of alpha(1A)-adrenoceptors as judged by the pA(2) values for prazosin (9.6), benoxathian (9.5), 2(2,6-dimethoxyphenoxyethyl) amino-methyl-1,4-benzodioxone hydrochloride) (WB 4101) (9.6), phentolamine (8.4), 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5] decane-7,9-dionedihydrochloride (BMY 7378) (6.7) and by the insensitivity to chloroethylclonidine (100 mu M, 45 min). In vas deferens from castrated rats, WE 4101 and spiperone showed slopes lower than 1.0 in the Schild plots, suggesting participation of multiple receptors. In these organs, noradrenaline contractions were partially inhibited by chloroethylclonidine (100 mu M, 45 min), indicating participation of alpha(1B)-adrenoceptors. After chloroethylclonidine treatment, WE 4101 showed a slope not different from 1.0 in the Schild plot, resulting in a pA(2) of 9.4, which indicates an interaction with alpha(1A)-adrenoceptors. It is suggested that castration modifies the functional alpha(1)-adrenoceptors subtypes in rat vas deferens. (C) 1998 Elsevier B.V. B.V. All rights reserved.

Functional characterisation of alpha(1)-adrenoceptors in denervated rat vas deferens

We investigated whether or not surgical denervation of the rat vas deferens changes the alpha(1)-adrenoceptor subtypes involved in the contractions to noradrenaline. Denervated vas deferens was approximate to22 times more sensitive to noradrenaline (pD(2)=7.35 +/- 0.04) than control vas (pD(2)= 6.01 +/- 0.03). This difference in noradrenaline potency was eliminated when cocaine (6 muM) was added to control vas (pD(2)=7.22 +/- 0.04). The noradrenaline-induced contractions of control and denervated vas deferens were insensitive to the alpha(1B)/alpha(1D)-adrenoceptor alkylating agent chloroethylclonidine (100 muM, 45 min). The concentration-response curves to noradrenaline in control and denervated vas deferens were competitively antagonised by prazosin (pA(2)approximate to9.6), WB-4101 (pA(2)approximate to9.5), 5-methyl urapidil (pA(2)approximate to8.4), phentolamine (pA(2)approximate to8.7), yohimbine (pA(2)approximate to6.9), BMY 7378 (pA(2)approximate to6.9) and indoramin (pA(2)approximate to8.7). After the treatment of control and denervated vas deferens with phenoxybenzamine, the partial agonist oxymetazoline antagonised competitively the concentration-response curves to noradrenaline showing pA(2) values approximate to7.4 in both groups. We conclude that noradrenaline-induced contractions in control and denervated rat vas deferens are mediated by alpha(1A)-adrenoceptors and that surgical denervation of the rat vas deferens is not able to change the alpha(1)-adrenoceptor subtypes involved in the contractions to noradrenaline.

alpha(1)-Adrenoceptors in proximal segments of tail arteries from control and reserpinised rats

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Denervation supersensitivity to phenylephrine in guinea-pig vas deferens in vivo and in vitro - Functional studies on alpha(1)-adrenoceptors

The objective was to estimate alterations in adrenergic receptor sites of guinea pig vas deferens, in vivo and in vitro, induced by chronic denervation. The denervation process induced an increased sensitivity (3-fold at the EC50 level) without alteration in the maximum response to phenylephrine in vitro. The sensitivity alteration was characterized by the decrease in the dissociation constant of phenylephrine for alpha-adrenoceptor [K-A: normal tissue 3.50 (0.75-16.21) x 10(-5) and denervated tissue 0.43 (0.11-1.67) x 10(-5) M, p < 0.05] without changing the dissociation constant of prazosin. A decrease in pD(2)' value for phenylephrine-phenoxybenzamine, probably due to a qualitative rather than a quantitative alteration in the alpha-adrenoceptor, was also shown in vitro [pD(2)': normal tissue (8.2776 +/- 0.0402) and denervated tissue (8.0051 +/- 0.0442), p < 0.05]. No change in sensitivity and maximum response to phenylephrine was observed in vivo after denervation, although an increased resistance of vas deferens to phenoxybenzamine blockade has been evidenced in this condition. (C) 1999 Elsevier B.V. All rights reserved.

Involvement of central alpha(1)- and mu(2)-adrenoceptors on cardiovascular responses to moxonidine

In the present study we compared the effects produced by moxonidine (alpha(2)-adrenoceptor/imidazoline agonist) injected into the 4th cerebral ventricle and into the lateral cerebral ventricle on mean arterial pressure, heart rate and on renal, mesenteric and hindquarter vascular resistances, as well as the possible action of moxonidine on central alpha(1)- or alpha(2)-adrenoceptors to produce cardiovascular responses. Male Holtzman rats (n = 7-8) anesthetized with urethane (0.5 g/kg, intravenously - i.v.) and alpha-chloralose (60 mg/kg, i.v.) were used. Moxonidine (5, 10 and 20 nmol) injected into the 4th ventricle reduced arterial pressure (-19 +/- 5, -30 +/- 7 and -43 +/- 8 mmHg vs. vehicle: 2 +/- 4 mmHg), heart rate (-10 +/- 6, - 16 +/- 7 and -27 +/- 9 beats per minute - bpm, vs. vehicle: 4 +/- 5 bpm), and renal, mesenteric and hindquarter vascular resistances. Moxonidine (5, 10 and 20 nmol) into the lateral ventricle only reduced renal vascular resistance (-77 +/- 17%, - 85 +/- 13%, -89 +/- 10% vs. vehicle: 3 +/- 4%), without changes on arterial pressure, heart rate and mesenteric and hindquarter vascular resistances. Pre-treatment with the selective alpha(2)-adrenoceptor antagonist yohimbine (80, 160 and 320 nmol) injected into the 4th ventricle attenuated the hypotension (-32 +/- 5, -25 +/- 4 and -12 +/- 6 mmHg), bradycardia (-26 +/- 11, -23 +/- 5 and -11 +/- 6 bpm) and the reduction in renal, mesenteric and hindquarter vascular resistances produced by moxonidine (20 nmol) into the 4th ventricle. Pretreatment with yohimbine (320 nmol) into the lateral ventricle did not change the renal vasodilation produced by moxonidine (20 nmol) into the lateral ventricle. The alpha(1)-adrenoceptor antagonist prazosin (320 nmol) injected into the 4th ventricle did not affect the cardiovascular effects of moxonidine. However, prazosin (80, 160 and 320 nmol) into the lateral ventricle abolished the renal vasodilation (-17 +/- 4, -6 +/- 9 and 2 +/- 11%) produced by moxonidine. The results indicate that the decrease in renal vascular resistance due to moxonidine action in the forebrain is mediated by alpha(1)-adrenoceptors, while the cardiovascular effects produced by moxonidine acting in the brainstern depend at least partially on the activation of coadrenoceptors. (c) 2007 Elsevier B.V. All rights reserved.

Both alpha(1)- and alpha(2)-adrenoceptors in the Insular Cortex Are Involved in the Cardiovascular Responses to Acute Restraint Stress in Rats

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alpha 1 and alpha 2-adrenoceptors in the medial amygdaloid nucleus modulate differently the cardiovascular responses to restraint stress in rats

Medial amygdaloid nucleus (MeA) neurotransmission has an inhibitory influence on cardiovascular responses in rats submitted to restraint, which are characterized by both elevated blood pressure (BP) and intense heart rate (HR) increase. In the present study, we investigated the involvement of MeA adrenoceptors in the modulation of cardiovascular responses that are observed during an acute restraint. Male Wistar rats received bilateral microinjections of the selective alpha 1-adrenoceptor antagonist WB4101 (10, 15, and 20 nmol/100 nL) or the selective alpha 2-adrenoceptor antagonist RX821002 (10, 15, and 20 nmol/nL) into the MeA, before the exposure to acute restraint. The injection of WB4101 reduced the restraint-evoked tachycardia. In contrast, the injection of RX821002 increased the tachycardia. Both drugs had no influence on BP increases observed during the acute restraint. Our findings indicate that alpha 1 and alpha 2-adrenoceptors in the MeA play different roles in the modulation of the HR increase evoked by restraint stress in rats. Results suggest that alpha 1-adrenoceptors and alpha 2-adrenoceptors mediate the MeA-related facilitatory and inhibitory influences on restraint-related HR responses, respectively. (C) 2012 Elsevier Ltd. All rights reserved.

Bed nucleus of the stria terminalis alpha(1)-adrenoceptor modulates baroreflex cardiac component in unanesthetized rats

The bed nucleus of stria terminalis (BST) has a tonic modulating role on the baroreflex parasympathetic component. In the present study, we verified that local BST-adrenoceptors modulate baroreflex-evoked bradycardiac responses in unanesthetized rats. Bilateral microinjection of the selective alpha(1)-adrenoceptor antagonist WB4101 (15 nmol/100 nL) into the BST increased the gain of reflex bradycardia in response to mean arterial pressure increases caused by intravenous (i.v.) infusion of phenylephrine, suggesting that BST alpha(1)-adrenoceptors modulate baroreflex bradycardiac response. Bilateral microinjection of either the selective alpha(2)-adrenoceptor antagonist RX821002 (15 nmol/100 nL) or the non-selective beta-adrenoceptor antagonist propranolol (15 nmol/100 nL) into the BST had not affected baroreflex bradycardia. Animals were pretreated intravenously with the cholinergic muscarinic receptor antagonist homatropine methyl bromide (HMB, 1.5 mg/Kg) to test the hypothesis that activation of alpha(1)-adrenoceptors in the BST would modulate the baroreflex parasympathetic component. Baroreflex bradycardiac responses evoked before and after BST treatment with WB4101 were no longer different when rats were pretreated with HMB. These results suggest that parasympathetic activation accounts for the effects saw after BST pharmacological manipulation and ruling out the possibility of a sympathetic withdraw. In conclusion, our data point out that local alpha(1)-adrenoceptors mediate the BST tonic influence on the baroreflex bradycardiac response modulating parasympathetic cardiac activity. (C) 2008 Elsevier B.V. All rights reserved.

Two new classes of conopeptides inhibit the alpha 1-adrenoceptor and noradrenaline transporter

Cone snails use venom containing a cocktail of peptides ('conopeptides') to capture their prey. Many of these peptides also target mammalian receptors, often with exquisite selectivity. Here we report the discovery of two new classes of conopeptides. One class targets alpha (1)-adrenoceptors (rho -TIA from the fish-hunting Conus tulipa), and the second class targets the neuronal noradrenaline transporter (chi -MrIA and chi -MrIB from the mollusk-hunting C. marmoreus). rho -TIA and chi -MrIA selectively modulate these important membrane-bound proteins. Both peptides act as reversible non-competitive inhibitors and provide alternative avenues for the identification of inhibitor drugs.

Effects of castration on alpha(1)-adrenoceptor subtypes in the rat aorta

The expression of alpha(1)-adrenoceptor subtypes in several tissues is regulated by gonadal hormones. In this study, we investigated whether castration regulates the alpha(1)-adrenoceptor subtypes mediating the contractions of the aorta from male rats to noradrenaline. Noradrenaline induced similar concentration-dependent contractions in the aorta from control and castrated rats. Treatment of the aorta from both control and castrated rats with the alpha(1B)/alpha(1D)-adrenoceptor alkylating agent chloroethylclonidine resulted in approximate to1600-fold rightward shift in the concentration-response curves to noradrenaline. The pA(2) values found for WB 4101, benoxathian (alpha(1A)-selective) and BMY 7378 (alpha(1D)-selective) indicate that alpha(1D)-adrenoceptors are involved in the contractions of the aorta from control and castrated rats to noradrenaline. However, there was a 15-fold difference between the pK(B) estimated through the lowest effective concentrations of the alpha(1A)-adrenoceptor selective antagonist 5-methyl-urapidil in the aorta from control and castrated rats. The pK(B) estimated in aorta from control rats is consistent with the interaction with alpha(1D)-adrenoceptors (7.58 +/- 0.06), while that calculated in organs from control rats is consistent with alpha(1A)-adrenoceptors (8.76 +/- 0.09). These results suggest that castration induces plasticity in the alpha(1)-adrenoceptor subtypes involved in the contractions of the aorta to noradrenaline. (C) 2003 Elsevier B.V. All rights reserved.

Effects of indoramin in rat vas deferens and aorta: concomitant alpha(1)-adrenoceptor and neuronal uptake blockade

1 the actions of the alpha(1)-adrenoceptor antagonist indoramin have been examined against the contractions induced by noradrenaline in the rat vas deferens and aorta taking into account a putative neuronal uptake blocking activity of this antagonist which could. result in self-cancelling actions.2 Indoramin behaved as a simple competitive antagonist of the contractions induced by noradrenaline in the vas deferens and aorta yielding pA(2) values of 7.38 +/- 0.05 (slope = 0.98 +/- 0.03) and 6.78 +/- 0.14 (slope = 1.08 +/- 0.06), respectively.3 When the experiments were repeated in the presence of cocaine (6 mu M) the potency (pA(2)) of indoramin in antagonizing the contractions of the vas deferens to noradrenaline was increased to 8.72 +/- 0.07 (slope = 1.10 +/- 0.05) while its potency remained unchanged in the aorta (pA(2) = 6.69 +/- 0.12; slope = 1.04 +/- 0.05).4 In denervated vas deferens, indoramin antagonized the contractions to noradrenaline with a potency similar to that found in the presence of cocaine (8.79 +/- 0.07; slope = 1.09 +/- 0.06).5 It is suggested that indoramin blocks alpha(1)-adrenoceptors and neuronal uptake in rat vas deferens resulting in Schild plots with slopes not different from unity even in the absence of selective inhibition of neuronal uptake. As a major consequence of this double mechanism of action, the pA(2) values for this antagonist are underestimated when calculated in situations where the neuronal uptake is active, yielding spurious pK(B) values.

The tricyclic antidepressants amitriptyline, nortriptyline and imipramine are weak antagonists of human and rat alpha(1B)-adrenoceptors

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