Receptor Antagonist Prazosin Research Articles

Prejunctional facilitatory effect of a thiol-alkylating agent N -Ethylmaleimide on neurogenic contractions in rat prostate smooth muscle

The effect of a non-specific thiol-alkylating agent N-ethylmaleimide (NEM) was studied on neurogenic contractile mechanisms in rat ventral prostate gland. Male Wistar albino rats were used. The rats were killed by cervical dislocation under sevoflurane anesthesia and ventral prostate gland was removed. Two preparations were obtained from each lobe. Neurally evoked isometric contractions were induced using trains of electrical field stimulation (EFS; 0.5, 1, 4, or 8 Hz). The effect of NEM on the contractions to EFS was examined in the absence or presence of adrenergic and/or purinergic antagonists. NEM enhanced the EFS-evoked contractions without altering the basal tone. These effects were significantly suppressed by an α(1) -adrenergic receptor antagonist (prazosin), a P2-purinergic antagonist (suramin), a specific P2X-receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS), an ATP analog (α,β-methylene ATP), or a calcium channel blocker (verapamil). This facilitating effect of NEM did not occur following the administration of L-cysteine or glutathione which saturated NEM with excess thiols. However, a thiol-oxidant diamide failed to affect the contractions to EFS. An adrenergic neuron blocker (guanethidine) completely suppressed the responses to NEM. On the other hand, an α(2) -adrenergic receptor blocker (yohimbine), a nitric oxide synthase inhibitor (N(ω) -nitro-L-arginine) or a cholinergic muscarinic receptor antagonist (atropine) did not significantly affect the facilitatory response of NEM. These findings suggest that NEM has a prejunctional facilitatory action on the adrenergic nerves in rat prostate tissue to enhance release of transmitters, noradrenaline, and ATP. NEM sensitive proteins involved in transmitter release mechanisms can play a role in this effect.

α2- and β-adrenoceptors involvement in nortriptyline modulation of auditory sustained attention and impulsivity

The catecholamine innervation of the prefrontal cortex controls attentional focus and inhibits inappropriate behavioral responses. The mechanism of action with which norepinephrine (NE) reuptake inhibitors modulate these cognitive functions has not been fully investigated. We investigated the effect of systemic administration of the NE reuptake blocker nortriptyline (NT) on attention and impulsivity using an auditory sustained attention task. The task was designed to assess impulsive behavior and the maintenance of attentional focus to an auditory stimulus presented at interresponse time durations (IRT) between 5 and 80 s. NT (2.0 but not 3.0 mg/kg) improved sustained attention and decreased the percentage of premature responses without changing their latency. To better understand the adrenergic component of NT action, we tested the effect of noradrenergic receptor antagonists alone or together with NT. The α(2)-receptor antagonist yohimbine, the α(1)-receptor antagonist prazosin, or the β-receptor antagonist propranolol alone did not significantly affect attentive performance or premature responses. However, the beneficial effects of NT on sustained attention and premature responses were attenuated by pretreatment with either yohimbine or propranolol. On the contrary, prazosin did not affect the NT-mediated improvement in sustained attention. We conclude that sustained attention displays an inverse U-shaped dependence on NT, mediated-at least in part-by α(2)- and β-adrenoceptors. We speculate that low doses of NT improve performance by maximizing the phasic release of NE, while higher doses of NT would elevate tonic levels of NE, thus producing suboptimal levels of phasically released NE.

Neurotransmission of the antidepressant-like effects of the growth hormone-releasing hormone antagonist MZ-4-71

MZ-4-71 is an antagonist of growth hormone–releasing hormone (GH–RH) which suppresses the secretion of GH–RH. It has been shown that MZ-4-71 has antidepressive-like effects in a modified forced swimming test (FST) in mice, exerts anxiolytic effects in an elevated plus maze test, improves memory consolidation in passive avoidance learning, and corrects the impairment of memory consolidation caused by β-amyloid 25–35in mice. However, little is known about the mechanisms of action of MZ-4-71 on brain functions.The involvement of the adrenergic, serotonergic, cholinergic, dopaminergic or GABA-ergic receptors in the antidepressant-like action of MZ-4-71 (1.0μg/2μl, intracerebroventricular (i.c.v.)) was studied in a modified mouse forced swimming test (FST). Mice were pretreated with a non-selective α-adrenergic receptor antagonist, phenoxybenzamine, an α1/α2β-adrenergic receptor antagonist prazosin, an α2-adrenergic receptor antagonist, yohimbine, a β-adrenergic receptor antagonist, propranolol, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist methysergide, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a non-selective muscarinic acetylcholine receptor antagonist, atropine, a D2, D3, D4 dopamine receptor antagonist, haloperidol or a γ-aminobutyric acid subunit A (GABA-A) receptor antagonist bicuculline.Phenoxybenzamine, prazosin, methysergide, cyproheptadine and atropine prevented the effects of MZ-4-71 on the immobility, the climbing and the swimming times. Yohimbine, propranolol, haloperidol and bicuculline did not change the effects of MZ-4-71.The results demonstrated that the antidepressant-like effects of MZ-4-71 in this modified mouse FST are mediated, at least in part, by the an interaction of the α1-adrenergic, 5-HT1/5-HT2 serotonergic, and muscarinic acetylcholine receptors.

Blockade of CRF1 receptors in the central nucleus of the amygdala attenuates the dysphoria associated with nicotine withdrawal in rats

The majority of smokers relapse during the acute withdrawal phase when withdrawal symptoms are most severe. The goal of the present studies was to investigate the role of corticotropin-releasing factor (CRF) and noradrenergic transmission in the central nucleus of the amygdala (CeA) in the dysphoria associated with smoking cessation. It was investigated if blockade of CRF1 receptors, blockade of α1-adrenergic receptors, or stimulation of α2-adrenergic receptors in the CeA diminishes the deficit in brain reward function associated with nicotine withdrawal in rats. Nicotine dependence was induced by implanting minipumps that delivered a nicotine solution. Withdrawal was precipitated with the nicotinic acetylcholine receptor antagonist mecamylamine. A discrete-trial intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In all the experiments, mecamylamine elevated the brain reward thresholds of the rats chronically treated with nicotine and did not affect the brain reward thresholds of the saline-treated control rats. Intra-CeA administration of the CRF1 receptor antagonist R278995/CRA0450 completely prevented the mecamylamine-induced elevations in brain reward thresholds in the nicotine-treated rats and did not affect the brain reward thresholds of the saline-treated control rats. R278995/CRA0450 has also been shown to block sigma-1 receptors but there is no evidence that this could affect negative mood states. Intra-CeA administration of the α1-adrenergic receptor antagonist prazosin or the α2-adrenergic receptor agonist clonidine did not affect the brain reward thresholds of the nicotine or saline-treated rats. These studies suggest that CRF1 receptor antagonists may diminish the dysphoria associated with smoking cessation by blocking CRF1 receptors in the CeA.

Sympathetic nerve stimulation induces local endothelial Ca2+ signals to oppose vasoconstriction of mouse mesenteric arteries

It is generally accepted that the endothelium regulates vascular tone independent of the activity of the sympathetic nervous system. Here, we tested the hypothesis that the activation of sympathetic nerves engages the endothelium to oppose vasoconstriction. Local inositol 1,4,5-trisphosphate (IP(3))-mediated Ca(2+) signals ("pulsars") in or near endothelial projections to vascular smooth muscle (VSM) were measured in an en face mouse mesenteric artery preparation. Electrical field stimulation of sympathetic nerves induced an increase in endothelial cell (EC) Ca(2+) pulsars, recruiting new pulsar sites without affecting activity at existing sites. This increase in Ca(2+) pulsars was blocked by bath application of the α-adrenergic receptor antagonist prazosin or by TTX but was unaffected by directly picospritzing the α-adrenergic receptor agonist phenylephrine onto the vascular endothelium, indicating that nerve-derived norepinephrine acted through α-adrenergic receptors on smooth muscle cells. Moreover, EC Ca(2+) signaling was not blocked by inhibitors of purinergic receptors, ryanodine receptors, or voltage-dependent Ca(2+) channels, suggesting a role for IP(3), rather than Ca(2+), in VSM-to-endothelium communication. Block of intermediate-conductance Ca(2+)-sensitive K(+) channels, which have been shown to colocalize with IP(3) receptors in endothelial projections to VSM, enhanced nerve-evoked constriction. Collectively, our results support the concept of a transcellular negative feedback module whereby sympathetic nerve stimulation elevates EC Ca(2+) signals to oppose vasoconstriction.

A Novel Preclinical Strategy for Identifying Cardiotoxic Kinase Inhibitors and Mechanisms of Cardiotoxicity

Despite intense interest in strategies to predict which kinase inhibitor (KI) cancer therapeutics may be associated with cardiotoxicity, current approaches are inadequate. Sorafenib is a KI of concern because it inhibits growth factor receptors and Raf-1/B-Raf, kinases that are upstream of extracellular signal-regulated kinases (ERKs) and signal cardiomyocyte survival in the setting of stress. To explore the potential use of zebrafish as a preclinical model to predict cardiotoxicity and to determine whether sorafenib has associated cardiotoxicity, and, if so, define the mechanisms. We find that the zebrafish model is readily able to discriminate a KI with little or no cardiotoxicity (gefitinib) from one with demonstrated cardiotoxicity (sunitinib). Sorafenib, like sunitinib, leads to cardiomyocyte apoptosis, a reduction in total myocyte number per heart, contractile dysfunction, and ventricular dilatation in zebrafish. In cultured rat cardiomyocytes, sorafenib induces cell death. This can be rescued by adenovirus-mediated gene transfer of constitutively active MEK1, which restores ERK activity even in the presence of sorafenib. Whereas growth factor-induced activation of ERKs requires Raf, α-adrenergic agonist-induced activation of ERKs does not require it. Consequently, activation of α-adrenergic signaling markedly decreases sorafenib-induced cell death. Consistent with these in vitro data, inhibition of α-adrenergic signaling with the receptor antagonist prazosin worsens sorafenib-induced cardiomyopathy in zebrafish. Zebrafish may be a valuable preclinical tool to predict cardiotoxicity. The α-adrenergic signaling pathway is an important modulator of sorafenib cardiotoxicity in vitro and in vivo and appears to act through a here-to-fore unrecognized signaling pathway downstream of α-adrenergic activation that bypasses Raf to activate ERKs.

The role of adrenergic and cholinergic receptors on the antinociception of sildenafil in the spinal cord of rats

The role played by spinal adrenergic and cholinergic receptors in the antinociceptive effects of intrathecal sildenafil in formalin-induced nociception was examined. Intrathecal catheters were inserted into the subarachnoid space of male Sprague-Dawley rats, and nociception was assessed using the formalin test, consisting of a subcutaneous injection of 50μL of 5% formalin solution into the hind paw. We examined the effects of an alpha 1 adrenergic receptor antagonist (prazosin), an alpha 2 adrenergic receptor antagonist (yohimbine), a muscarinic acetylcholine receptor antagonist (atropine), and a nicotinic acetylcholine receptor antagonist (mecamylamine) on sildenafil-induced antinociception. Intrathecal sildenafil (3, 10, and 30μg) suppressed, in a dose-dependent manner, formalin-induced flinching during phases 1 and 2 of the test. Intrathecal sildenafil (30μg) could not show any effects against intrathecal prazosin (3μg), yohimbine (10μg), atropine (10μg), and mecamylamine (10μg) pretreatment during both phases of the formalin test. These results suggest that intrathecal sildenafil effectively attenuated the pain evoked by formalin injection. Additionally, spinal alpha 1, alpha 2, muscarinic and nicotinic receptors might play a role in sildenafil-induced antinociception.

Effects of catecholamines on hepatic and skeletal muscle mitochondrial respiration after prolonged exposure to faecal peritonitis in pigs

Use of norepinephrine to increase blood pressure in septic animals has been associated with increased efficiency of hepatic mitochondrial respiration. The aim of this study was to evaluate whether the same effect could be reproduced in isolated hepatic mitochondria after prolonged in vivo exposure to faecal peritonitis. Eighteen pigs were randomized to 27 h of faecal peritonitis and to a control condition (n = 9 each group). At the end, hepatic mitochondria were isolated and incubated for one hour with either norepinephrine or placebo, with and without pretreatment with the specific receptor antagonists prazosin and yohimbine. Mitochondrial state 3 and state 4 respiration were measured for respiratory chain complexes I and II, and state 3 for complex IV using high-resolution respirometry, and respiratory control ratios were calculated. Additionally, skeletal muscle mitochondrial respiration was evaluated after incubation with norepinephrine and dobutamine with and without the respective antagonists (atenolol, propranolol and phentolamine for dobutamine). Faecal peritonitis was characterized by decreasing blood pressure and stroke volume, and maintained systemic oxygen consumption. Neither faecal peritonitis nor any of the drugs or drug combinations had measurable effects on hepatic or skeletal muscle mitochondrial respiration. Norepinephrine did not improve the efficiency of complex I- and complex II-dependent isolated hepatic mitochondrial respiration [respiratory control ratio (RCR) complex I: 5.6 ± 5.3 (placebo) vs. 5.4 ± 4.6 (norepinephrine) in controls and 2.7 ± 2.1 (placebo) vs. 2.9 ± 1.5 (norepinephrine) in septic animals; RCR complex II: 3.5 ± 2.0 (placebo) vs. 3.5 ± 1.8 (norepinephrine) in controls; 2.3 ± 1.6 (placebo) vs. 2.2 ± 1.1 (norepinephrine) in septic animals]. Prolonged faecal peritonitis did not affect either hepatic or skeletal muscle mitochondrial respiration. Subsequent incubation of isolated mitochondria with norepinephrine and dobutamine did not significantly influence their respiration.

Pharmacological Stimulation of Locus Coeruleus Reveals a New Antipsychotic-Responsive Pathway for Deficient Sensorimotor Gating

Surprisingly little is known about the modulation of core endophenotypes of psychiatric disease by discrete noradrenergic (NE) circuits. Prepulse inhibition (PPI), the diminution of startle responses when weak prestimuli precede the startling event, is a widely validated translational paradigm for information-processing deficits observed in several mental disorders including schizophrenia, Tourette's syndrome, and post-traumatic stress disorder (PTSD). Despite putative NE disturbances in these illnesses, NE regulation of PPI remains poorly understood. In these studies, regulation of PPI by the locus coeruleus (LC), the primary source of NE to forebrain, was evaluated in rats using well-established protocols to pharmacologically activate/inactivate this nucleus. The ability of drugs that treat deficient PPI in these illnesses to reverse LC-mediated PPI deficits was also tested. Stimulation of LC receptors produced an anatomically and behaviorally specific deficit in PPI that was blocked by clonidine (Cataprese, an α2 receptor agonist that reduces LC neuronal firing after peri-LC delivery), a postsynaptic α1 NE receptor antagonist (prazosin), and second-generation antipsychotics (olanzapine, seroquel), but not by drugs that antagonized dopamine-1 (SCH23390), dopamine-2 (the first-generation antipsychotic Haloperidol), or serotonin-2 receptors (ritanserin). These results indicate a novel substrate in the regulation of PPI and reveal a novel functional role for the LC. Hence, a hyperactive LC-NE system might underlie a deficient sensorimotor gating endophenotype in a subset of patients suffering from psychiatric illnesses including schizophrenia, Tourette's syndrome, and PTSD, and the ability to normalize LC-NE transmission could contribute to the clinical efficacy of certain drugs (Cataprese, prazosin, and second-generation antipsychotics) in these conditions.

α 1-Noradrenegic receptor antagonism disrupts female songbird responses to male song

Female songbirds respond behaviorally to differences in male song structure. Past data suggest a complex role for norepinephrine in female responses to song. Here, we examined the effects of central infusions of the α 1-noradrenergic receptor antagonist prazosin on female European starling ( Sturnus vulgaris) responses to nest boxes broadcasting male song. Prazosin disrupted female preferential responses to male starling song over the less biologically relevant purple martin ( Progne subis) song. Prazosin decreased female responses to male starling song in a linear dose–response fashion; whereas, it affected responses to purple martin song in a U-shaped dose–response fashion. Results suggest that the role of norepinephrine in female responses to male song differs depending upon drug dose and the biological relevance of the song stimulus.

Progressive arteriolar vasoconstriction and fatigue during tetanic contractions of rat skeletal muscle are inhibited by α-receptor blockade

Voluntary muscle contractions activate sympathetic efferent pathways. Using a fatiguing electrical stimulation protocol designed specifically to enhance sympathetically-mediated vasoconstrictor tone, we explored the temporal profile and mechanistic bases of the evoked vasoconstrictor response and its role in muscle fatigue. Spinotrapezius muscles of Wistar rats were exteriorized and stimulated tetanically (100Hz, 6-8V, stimulus duration 700ms) every 3s for 2.5min. The extent and time course of diameter changes in arterioles (1A and 2A) and venules (1V and 2V) were determined after each of 10 discrete sets of muscle stimulation at 5-min intervals. At first, to compare the effect of stimulation parameters in this preparation, stimulations were performed with rectangular pulses of either 0.2- or 4-ms pulse duration. As expected the 0.2-ms pulse stimulation did not affect arteriolar diameter or muscle fatigability. In contrast, during and following 4-ms pulse stimulations, there was a surprising arteriolar vasoconstriction rather than the expected vasodilation. Arteriolar (but not venular) vasoconstriction (reduced arteriolar diameter by 38.6±2.6% in the 10th set) increased progressively with muscle fatigue (to 29±12% of initial tension in the 10th set) for the 4-ms pulse condition. Superfusion with the selective α1-adrenergic receptor antagonist prazosin (1μM) and/or α2-adrenergic receptor antagonist rauwolscine (10μM) abolished both the arteriolar vasoconstriction and significantly reduced fatigue (i.e., % initial tension, α1: 46.8±10.3%; α2: 39.0±5.8%; α1+α2: 48.7±16.3% in the 10th set; all P<0.05 vs. control). We conclude that sequential bouts of contractions induce a progressively greater degree of α-adrenergic receptor-induced arteriolar (but not venular) vasoconstriction which contributes significantly to fatigue in this model.

Melatonin inhibits tachykinin NK2 receptor-triggered 5-HT release from guinea pig isolated colonic mucosa

Melatonin is involved in the regulation of colonic motility, and sensation, but little is known about the influence of melatonin on 5-hydroxytryptamine (5-HT) release from colonic mucosa. A tachykinin NK₂ receptor-selective agonist, [β-Ala⁸]-neurokinin A(4-10) [βAla-NKA-(4-10)] can induce 5-HT release from guinea pig colonic mucosa via NK₂ receptors on the mucosal layer. The present study was designed to determine the influence of melatonin on 5-HT release from guinea pig colonic mucosa, evoked by the NK₂ receptor agonist, βAla-NKA-(4-10). The effect of melatonin was investigated on the outflow of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) from muscle layer-free mucosal preparations of guinea pig colon, using high-performance liquid chromatography with electrochemical detection. Melatonin caused a sustained decline in the βAla-NKA-(4-10)-evoked 5-HT outflow from the muscle layer-free mucosal preparations, but failed to affect its metabolite 5-HIAA outflow. The specific MT₃ receptor agonist, 5-methoxycarbonylamino-N-acetyltryptamine mimicked the inhibitory effect of melatonin on βAla-NKA-(4-10)-evoked 5-HT outflow. A MT₃ receptor antagonist prazosin shifted the concentration-response curve of melatonin to the right in a concentration-dependent manner and depressed the maximum effect, but neither a combined MT₁/MT₂ receptor antagonist luzindole, nor a MT₂ receptor antagonist N-pentanoyl-2-benzyltryptamine modified the concentration-response curve to melatonin. Melatonin inhibits NK₂ receptor-triggered 5-HT release from guinea pig colonic mucosa by acting at a MT₃ melatonin receptor located directly on the mucosal layer, without affecting 5-HT degradation processes. Possible contributions of MT₁/MT₂ melatonin receptors to the inhibitory effect of melatonin appear to be negligible. Melatonin may act as a modulator of excess 5-HT release from colonic mucosa.

Amitriptyline and Acute Inflammation: A Study Using Intravital Microscopy and the Carrageenan-Induced Paw Edema Model

Background/Aims: Antidepressants are reported to exhibit antiinflammatory effects. However, mechanisms involved in this action have not been elucidated. Thus, the objectives of the present study were (a) to evaluate the effects of amitriptyline on the acute inflammatory process, and (b) to investigate the participation of α₁-adrenergic receptors and glucocorticoids as possible mechanisms implicated in the amitriptyline action on inflammation. Methods and Results: Single and multiple doses of amitriptyline were administered to rats submitted to the carrageenan-induced paw edema model. The results showed a significant antiedematous reaction to amitriptyline, mainly when administered at each elimination half-life. The next step was to evaluate its effects on leukocyte behavior, using intravital microscopy. Amitriptyline produced a significant effect on leukocyte behavior. To investigate possible mechanisms involved, a glucocorticoid receptor antagonist (RU-486) and an α₁-adrenergic receptor antagonist (prazosin) were used. RU-486 administration lacked the ability to decrease the amitriptyline antiinflammatory effects in the carrageenan-induced paw edema model. Prazosin pretreatment potentiated the amitriptyline antiinflammatory effect without presenting an effect per se. Conclusion: The present study shows the ability of amitriptyline to decrease edema and affect leukocyte behavior in an acute inflammatory process; and, for the first time to our knowledge, we suggest the involvement of α₁-adrenoceptors in the antiinflammatory effects of amitriptyline.

Stimulation of α2-adrenergic receptors in the central nucleus of the amygdala attenuates stress-induced reinstatement of nicotine seeking in rats

Tobacco addiction is a chronic disorder that is characterized by craving for tobacco products, withdrawal upon smoking cessation, and relapse after periods of abstinence. Previous studies demonstrated that systemic administration of α2-adrenergic receptor agonists attenuates stress-induced reinstatement of drug seeking in rats. The aim of the present experiments was to investigate the role of noradrenergic transmission in the central nucleus of amygdala (CeA) in stress-induced reinstatement of nicotine seeking. Rats self-administered nicotine for 14–16 days and then nicotine seeking was extinguished by substituting saline for nicotine. The effect of the intra-CeA infusion of the α2-adrenergic receptor agonists clonidine and dexmedetomidine, the nonselective β1/β2-adrenergic receptor antagonist propranolol, and the α1-adrenergic receptor antagonist prazosin on stress-induced reinstatement of nicotine seeking was investigated. In all the experiments, exposure to footshocks reinstated extinguished nicotine seeking. The administration of clonidine or dexmedetomidine into the CeA attenuated stress-induced reinstatement of nicotine seeking. The administration of propranolol or prazosin into the CeA did not affect stress-induced reinstatement of nicotine seeking. Furthermore, intra-CeA administration of clonidine or dexmedetomidine did not affect operant responding for food pellets. This suggests that the effects of clonidine and dexmedetomidine on stress-induced reinstatement of nicotine seeking were not mediated by motor impairments or sedation. Taken together, these findings indicate that stimulation of α2-adrenergic receptors, but not blockade of α1 or β-adrenergic receptors, in the CeA attenuates stress-induced reinstatement of nicotine seeking. These findings suggest that α2-adrenergic receptor agonists may at least partly attenuate stress-induced reinstatement of nicotine seeking by stimulating α2-adrenergic receptors in the CeA.

Vesicoureteral Reflux and Primary Bladder Neck Dysfunction in Children: Urodynamic Evaluation and Randomized, Double-Blind, Clinical Trial on Effect of α-Blocker Therapy

Primary bladder neck dysfunction has been under diagnosed as a treatable cause of vesicoureteral reflux. We evaluated the effect of prazosin administration on vesicoureteral reflux resolution and urodynamic parameters in children with idiopathic primary reflux and primary bladder neck dysfunction. A total of 62 children (mean ± SD age 7.9 ± 2.4 years) with documented vesicoureteral reflux and urodynamics proved primary bladder neck dysfunction were randomized to receive either 0.025 mg/kg α-blocker (prazosin, 40 patients) or placebo (22) nightly for 1 week with a subsequent increase to 2 divided doses. Patients were followed for 12 months with clinical evaluation and uroflowmetry performed every 2 months, and each patient underwent complete urodynamic study at 6-month intervals. In the placebo group no uroflowmetry or urodynamic parameter changed significantly at 1-year followup. A 60% decrease in reflux grade was observed in the treatment group compared to 17% in the placebo group. Mean maximal detrusor pressure, post-void residual and opening time were significantly decreased in both followup sessions in the prazosin group (p <0.05). Average flow rate improved from 4.30 to 12.80 ml per second at 6 months and to 13.10 ml per second at 12 months (both p <0.05). Special attention should be given to secondary causes of vesicoureteral reflux (such as primary bladder neck dysfunction, an underdiagnosed entity in children), since conventional treatment will most likely fail if these conditions are not addressed promptly. In this study prazosin was effective therapy for children with vesicoureteral reflux and primary bladder neck dysfunction.

Horse chestnut extract contracts bovine vessels and affects human platelet aggregation through 5‐HT2A receptors: an in vitro study

Extract from seeds and bark of horse chestnut (Aesculus hippocastanum L) is used as an herbal medicine against chronic venous insufficiency. The effect and mechanism of action on veins, arteries, and platelets are not fully understood. The aim of this study was to investigate the effects and mechanisms of action of horse chestnut on the contraction of bovine mesenteric veins and arteries, and human platelet aggregation. Contraction studies showed that horse chestnut extract dose-dependently contracted both veins and arteries, with the veins being the most sensitive. Contraction of both veins and arteries were significantly inhibited by the 5-HT(2A) receptor antagonist ketanserin. No effect on contraction was seen with the cyclooxygenase inhibitor indomethacin, the alpha(1) receptor antagonist prazosin or the angiotensin AT(1) receptor antagonist saralasin neither in veins nor arteries. ADP-induced human platelet aggregation was significantly reduced by horse chestnut. A further reduction was seen with the extract in the presence of ketanserin. In conclusion, horse chestnut contraction of both veins and arteries is, at least partly, mediated through 5-HT(2A) receptors. Human platelet aggregation is reduced by horse chestnut. The clinical importance of these findings concerning clinical use, possible adverse effects, and drug interactions remains to be investigated.

Effects of prazosin, clonidine, and propranolol on the elevations in brain reward thresholds and somatic signs associated with nicotine withdrawal in rats

Tobacco withdrawal is characterized by a negative mood state and relatively mild somatic symptoms. Increased noradrenergic transmission has been reported to play an important role in opioid withdrawal, but little is known about the role of noradrenergic transmission in nicotine withdrawal. The aim of these experiments was to investigate the effects of prazosin, clonidine, and propranolol on the negative mood state and somatic signs associated with nicotine withdrawal in rats. A discrete-trial intracranial self-stimulation procedure was used to assess the negative affective state of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In all the experiments, the nicotinic acetylcholine receptor antagonist mecamylamine (3 mg/kg) elevated the brain reward thresholds of the nicotine-treated rats and did not affect those of the control rats. The α1-adrenergic receptor antagonist prazosin (0.0625 and 0.125 mg/kg) dose-dependently attenuated the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. The α2-adrenergic receptor agonist clonidine (10-40 μg/kg) and the nonselective β-adrenergic receptor antagonist propranolol (2.5-10 mg/kg) did not attenuate the elevations in brain reward thresholds associated with nicotine withdrawal. Furthermore, mecamylamine (2 mg/kg) induced more somatic signs in the nicotine-treated rats than in the control rats. Clonidine and propranolol, but not prazosin, decreased the total number of somatic signs associated with nicotine withdrawal. Blockade of α1-adrenergic receptors attenuates the deficit in brain reward function associated with nicotine withdrawal. Antagonism of β-adrenergic receptors or stimulation of α2-adrenergic receptors attenuates the somatic symptoms of nicotine withdrawal.

Erratum: Noradrenergic α1 Receptors as a Novel Target for the Treatment of Nicotine Addiction

Nicotine is the main psychoactive ingredient in tobacco and its rewarding effects are considered primarily responsible for persistent tobacco smoking and relapse. Although dopamine has been extensively implicated in the rewarding effects of nicotine, noradrenergic systems may have a larger role than previously suspected. This study evaluated the role of noradrenergic α1 receptors in nicotine and food self-administration and relapse, nicotine discrimination, and nicotine-induced dopamine release in the nucleus accumbens in rats. We found that the noradrenergic α1 receptor antagonist prazosin (0.25–1 mg/kg) dose dependently reduced the self-administration of nicotine (0.03 mg/kg), an effect that was maintained over consecutive daily sessions; but did not reduce food self-administration. Prazosin also decreased reinstatement of extinguished nicotine seeking induced by either a nicotine prime (0.15 mg/kg) or nicotine-associated cues, but not food-induced reinstatement of food-seeking, and decreased nicotine-induced (0.15 mg/kg) dopamine release in the nucleus accumbens shell. However, prazosin did not have nicotine-like discriminative effects and did not alter the dose-response curve for nicotine discrimination. These findings suggest that stimulation of noradrenergic α1 receptors is involved in nicotine self-administration and relapse, possibly via facilitation of nicotine-induced activation of the mesolimbic dopaminergic system. The findings point to α1 adrenoceptor blockade as a potential new approach to the treatment of tobacco dependence in humans.

Mechanisms mediating the ability of caffeine to influence MDMA (‘Ecstasy’)‐induced hyperthermia in rats

Caffeine exacerbates the hyperthermia associated with an acute exposure to 3,4 methylenedioxymethamphetamine (MDMA, 'Ecstasy') in rats. The present study investigated the mechanisms mediating this interaction. Adult male Sprague-Dawley rats were treated with caffeine (10 mg x kg(-1); i.p.) and MDMA (15 mg x kg(-1); i.p.) alone and in combination. Core body temperatures were monitored before and after drug administration. Central catecholamine depletion blocked MDMA-induced hyperthermia and its exacerbation by caffeine. Caffeine provoked a hyperthermic response when the catecholamine releaser d-amphetamine (1 mg x kg(-1)) was combined with the 5-HT releaser D-fenfluramine (5 mg x kg(-1)) or the non-selective dopamine receptor agonist apomorphine (1 mg x kg(-1)) was combined with the 5-HT(2) receptor agonist DOI (2 mg x kg(-1)) but not following either agents alone. Pretreatment with the dopamine D(1) receptor antagonist Schering (SCH) 23390 (1 mg x kg(-1)), the 5-HT(2) receptor antagonist ketanserin (5 mg x kg(-1)) or alpha(1)-adreno- receptor antagonist prazosin (0.2 mg x kg(-1)) blocked MDMA-induced hyperthermia and its exacerbation by caffeine. Co-administration of a combination of MDMA with the PDE-4 inhibitor rolipram (0.025 mg x kg(-1)) and the adenosine A(1/2) receptor antagonist 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-C]quinazolin-5-amine 15943 (10 mg x kg(-1)) or the A(2A) receptor antagonist SCH 58261 (2 mg x kg(-1)) but not the A(1) receptor antagonist DPCPX (10 mg x kg(-1)) exacerbated MDMA-induced hyperthermia. A mechanism comprising 5-HT and catecholamines is proposed to mediate MDMA-induced hyperthermia. A combination of adenosine A(2A) receptor antagonism and PDE inhibition can account for the exacerbation of MDMA-induced hyperthermia by caffeine.

Noradrenergic α1 Receptors as a Novel Target for the Treatment of Nicotine Addiction

Nicotine is the main psychoactive ingredient in tobacco and its rewarding effects are considered primarily responsible for persistent tobacco smoking and relapse. Although dopamine has been extensively implicated in the rewarding effects of nicotine, noradrenergic systems may have a larger role than previously suspected. This study evaluated the role of noradrenergic alpha(1) receptors in nicotine and food self-administration and relapse, nicotine discrimination, and nicotine-induced dopamine release in the nucleus accumbens in rats. We found that the noradrenergic alpha(1) receptor antagonist prazosin (0.25-1 mg/kg) dose dependently reduced the self-administration of nicotine (0.03 mg/kg), an effect that was maintained over consecutive daily sessions; but did not reduce food self-administration. Prazosin also decreased reinstatement of extinguished nicotine seeking induced by either a nicotine prime (0.15 mg/kg) or nicotine-associated cues, but not food-induced reinstatement of food-seeking, and decreased nicotine-induced (0.15 mg/kg) dopamine release in the nucleus accumbens shell. However, prazosin did not have nicotine-like discriminative effects and did not alter the dose-response curve for nicotine discrimination. These findings suggest that stimulation of noradrenergic alpha(1) receptors is involved in nicotine self-administration and relapse, possibly via facilitation of nicotine-induced activation of the mesolimbic dopaminergic system. The findings point to alpha(1) adrenoceptor blockade as a potential new approach to the treatment of tobacco dependence in humans.