Tissue blood flow reductions induced by remifentanil in rabbits and the effect of naloxone and phentolamine on these changes.

OBJECTIVES: The purpose of this study was to investigate the effects of naloxone and phentolamine on the blood flow changes in rabbit oral tissue induced by remifentanil during sevoflurane anesthesia. MATERIALS AND METHODS: Male Japan White rabbits were anesthetized with sevoflurane under mechanical ventilation. Remifentanil was continuously infused at a rate of 0.4 µg/kg/min. Naloxone 0.01 mg/kg or phentolamine 0.01 mg/kg was administered during remifentanil infusion. Observed variables were systolic and diastolic blood pressures, mean arterial pressure, heart rate, common carotid artery blood flow, tongue mucosal blood flow, mandibular bone marrow blood flow, masseter muscle blood flow, and upper and lower alveolar tissue blood flows. The common carotid artery blood flow was monitored continuously using an ultrasonic blood flowmeter. Tongue mucosal blood flow was monitored continuously using a laser Doppler blood flowmeter. Mandibular bone marrow blood flow, masseter muscle blood flow, and upper and lower alveolar tissue blood flows were measured using a hydrogen clearance tissue blood flowmeter. One-way analysis of variance for repeated measurements followed by the Student-Newman-Keuls test was used. RESULTS: Remifentanil produced decreases in the heart rate, systolic blood pressure, and common carotid artery blood flow by about 15% and mandibular bone marrow blood flow, masseter muscle blood flow, and upper and lower alveolar tissue blood flows by about 30%. In the naloxone group, all variables recovered after naloxone administration. In contrast, in the phentolamine group, tissue blood flow recovered, whereas heart rate, systolic blood pressure, and common carotid artery blood flow did not recover after phentolamine administration. CONCLUSIONS: Remifentanil deceased oral tissue blood flow and systemic hemodynamic variables. Naloxone and phentolamine produced a recovery of oral tissue blood flow with and without systemic hemodynamic recovery, respectively.

Local anesthetics: review of pharmacological considerations.

Local anesthetics have an impressive history of efficacy and safety in medical and dental practice. Their use is so routine, and adverse effects are so infrequent, that providers may understandably overlook many of their pharmacotherapeutic principles. The purpose of this continuing education article is to provide a review and update of essential pharmacology for the various local anesthetic formulations in current use. Technical considerations will be addressed in a subsequent article.

Concurrent glucocorticoid and noradrenergic activity shifts instrumental behavior from goal-directed to habitual control.

Stress modulates instrumental action in favor of habitual stimulus-response processes that are insensitive to changes in outcome value and at the expense of goal-directed action-outcome processes. The neuroendocrine mechanism underlying this phenomenon is unknown. Here, we tested the hypothesis that concurrent glucocorticoid and noradrenergic activity bias instrumental behavior toward habitual performance. To this end, healthy men and women received hydrocortisone, the alpha2-adrenoceptor antagonist yohimbine or both orally before they were trained in two instrumental actions leading to two distinct food outcomes. After training, one of the outcomes was devalued by inviting participants to eat that food to satiety. A subsequent extinction test revealed whether instrumental performance was goal-directed or habitual. Participants that received hydrocortisone or yohimbine alone decreased responding to the devalued action in the extinction test, i.e., they behaved goal-directed. The combined administration of hydrocortisone and yohimbine, however, rendered participants' behavior insensitive to changes in the value of the goal (i.e., habitual). These findings demonstrate that the concerted action of glucocorticoids and noradrenergic activity shifts instrumental behavior from goal-directed to habitual control.

Clozapine-induced salivation: interaction with N-desmethylclozapine and amisulpride in an experimental rat model.

Many drugs (e.g. amisulpride) have been used to treat troublesome clozapine-induced salivation; however, varying success has been achieved in this respect, probably because, until recently, the salivatory action of clozapine has been largely unexplained. In the rat, clozapine and its main metabolite, N-desmethylclozapine, were found to exert mixed secretory actions: excitatory, through muscarinic acetylcholine M1-receptors giving rise to a long-lasting, low-level flow of saliva; and inhibitory, through muscarinic M3-receptors and α(1) -adrenoceptors reducing the parasympathetically and sympathetically nerve-evoked flow of saliva. The aim of the present study was to define the interactions between clozapine and N-desmethylclozapine, and clozapine and amisulpride, with respect to the excitatory response. Submandibular glands, sensitized by chronic parasympathetic preganglionic denervation, were studied in pentobarbitone-anaesthetized rats. To prevent clozapine from being metabolized to N-desmethylclozapine by hepatic enzymes, the liver was, under terminal anaesthesia, excluded from the circulation. The weak receptor-stimulating clozapine prevented the strong receptor-stimulating N-desmethylclozapine, at specific ratios in humans and in rats, from exerting its full agonistic action. In conclusion, the contribution of N-desmethylclozapine to the clozapine-induced sialorrhoea was, at most, only partly additive. Furthermore, the present experimental set-up failed to demonstrate any anti-salivatory action of amisulpride on the clozapine-induced flow of saliva.

N-Desmethylclozapine exerts dual and opposite effects on salivary secretion in the rat.

N-Desmethylclozapine is a major metabolite of the atypical antipsychotic drug clozapine, used in the treatment of therapy-resistant schizophrenia. Patients under clozapine treatment report a troublesome sialorrhea. Recent experiments show clozapine to exert mixed agonist/antagonist actions on salivary secretion in rats. The present study was performed to define the secretory role of N-desmethylclozapine and to compare it with that of its parent compound. N-Desmethylclozapine evoked secretion by acting directly on the muscarinic acetylcholine M1-receptors of 'silent' duct-cannulated parotid and submandibular glands of the anaesthetized rat. In chronic surgically denervated glands, the secretory response was enlarged. The methacholine-evoked secretion, as well as the parasympathetic nerve-evoked secretion, were reduced by N-desmethylclozapine and involved blockade of M3-receptors, while the sympathetic nerve-evoked response was reduced, involving blockade of alpha(1)-adrenergic receptors. Synergistic interactions between N-desmethylclozapine and the beta-adrenergic receptor agonist, isoprenaline, occurred. Compared with clozapine, the excitatory efficacy of N-desmethylclozapine was higher and the inhibitory efficacy was lower (parasympathetic activity) or about the same (sympathetic activity). Theoretically, in humans treated with clozapine, an increase in the N-desmethylclozapine : clozapine ratio would contribute to salivation during the night and at rest, and, furthermore, the magnitude of the reduction in the reflexly elicited secretion is likely to diminish.

The use of phentolamine mesylate to evaluate mandibular nerve damage following implant placement.

High success rates and long-term predictability of implant therapy have been well documented in the literature. However, complications in implant treatment can arise and include sensory disturbances, especially in the posterior mandible in areas close to the inferior alveolar nerve. Treatment efficacy of sensory disturbances caused by implant placement in this area relies on the expeditious diagnosis of an induced paresthesia. Recently, phentolamine mesylate has been introduced as a reversal agent of local anesthesia with the ability to decrease the requisite time for a patient to return to normal sensation. This article introduces a method for faster detection of a potential paresthesia induced by implant placement in the posterior mandible.

Local anesthesia reversal.

PM (OraVerse) enables the dentist or dental hygienist (where permitted) to significantly decrease the duration of residual STA in patients where such numbness may prove to be potentially injurious (children, geriatric, and special needs patients), or a negative influence on their quality of life (speaking, eating, negative body image). (Note: As of August 3, 2009, dental hygienists are permitted to administer PM in the following states: Alaska, Arkansas, Hawaii, Idaho, Iowa, Louisiana, Montana, Nevada, New York, North Dakota, Oklahoma, Rhode Island, Tennessee, Utah, and Wisconsin.)

Activation of alpha(2)-adrenoceptors in the lateral hypothalamus reduces pilocarpine-induced salivation in rats.

Anti-hypertensive drugs that act on central alpha(2)-adrenoceptors and imidazoline receptors usually cause dry mouth in patients. A central area important for the control of salivary secretion and also for the effects of alpha(2)-adrenoceptor activation is the lateral hypothalamus (LH). Therefore, in the present study we investigated the effects of the injections of moxonidine (an alpha(2)-adrenoceptor and imidazoline agonist) alone or combined with RX 821002 (alpha(2)-adrenoceptor antagonist) into the LH on the salivation induced by intraperitoneal (i.p.) pilocarpine (cholinergic muscarinic agonist). Male Holtzman rats with stainless steel cannula implanted into the LH were used. Saliva was collected using pre-weighted small cotton balls inserted into the animal's mouth under ketamine anesthesia. Salivation induced by i.p. pilorcarpine (4micromol/kg of body weight) was reduced by the injection of moxonidine (10 and 20nmol/0.5microl) into the LH (222+/-46 and 183+/-19mg/7min, vs. vehicle: 480+/-30mg/7min). The inhibitory effect of moxonidine on pilocarpine-induced salivation was abolished by prior injections of RX 821002 (160 and 320nmol/0.5microl) into the LH (357+/-25 and 446+/-38mg/7min). Injections of the alpha(1)-adrenoceptor antagonist prazosin (320nmol/0.5microl) into the LH did not change the effects of moxonidine. The results show that activation of alpha(2)-adrenoceptors in the LH inhibits pilocarpine-induced salivation, suggesting that LH is one of the possible central sites involved in the anti-salivatory effects produced by the treatment with alpha(2)-adrenoceptor agonists.

Beta-adrenoceptor blockade delays granulation tissue formation in polyurethane sponge implants.

BACKGROUND: The role of adrenoceptors in granulation tissue formation is not well understood. The aim of this study was to investigate the effects of alpha- and beta-adrenoceptor blockade on granulation tissue development using polyurethane (PU) implants in the rat. METHODS: Animals were treated orally with propranolol (beta1- and beta2-antagonist), atenolol (beta1-antagonist) or phentolamine (alpha1- and alpha2-antagonist) until euthanasia. The control group received only water. All animals received subcutaneous implants of PU sponges. After 14 days, implants were collected, formalin-fixed and paraffin-embedded. Sections were stained with hematoxylin and eosin and Sirius red and immunostained for CD68 and alpha-smooth muscle actin. RESULTS: The number of inflammatory cells and the volume density of myofibroblasts and blood vessels were lower in the control group than in the propranolol- and atenolol-treated groups. The collagen fiber score was greater in the control group than in the propranolol- and atenolol-treated groups. The inflammatory infiltrate, collagen fiber score, blood vessel density or myofibroblast differentiation was not affected by phentolamine. The percentage of fibrovascular invasion was greater in the antagonist-treated groups than in the control group. CONCLUSIONS: Blockade of beta1- and beta2-adrenoceptors, but not alpha-adrenoceptors, impairs granulation tissue development in PU implants due to interference with the inflammatory response.

Effects of amphetamine on salivary secretion.

Amphetamine induces xerogenic effects, but its mechanism of action and xerogenic potency are unknown. In the current in vivo study on the rat parotid gland, the effects of amphetamine on reflex-evoked and acetylcholine-evoked salivation were examined in the absence and presence of adrenergic and dopaminergic antagonists. Under anaesthesia, amphetamine increased the secretion of salivary fluid and the amount of protein therein in response to acetylcholine. Phentolamine abolished the increase in salivary flow and had no effect on the salivary protein concentration, whereas propranolol only reduced the salivary protein concentration. Reflex activation of the secretion evoked a well-maintained level of secretion that was reduced by amphetamine [50% inhibitory dose (ID(50)) 1.9 +/- 0.1 mg kg(-1) intravenously); the salivary protein concentration was increased in the presence of amphetamine. Phentolamine and haloperidol reduced the amphetamine-inhibitory effect on the reflex-evoked fluid response, whereas propranolol had no effect on the fluid response. The xerogenic effect of amphetamine is mainly exerted by central mechanisms involving alpha-adrenoceptors, while, indirectly, amphetamine causes secretion of protein by inducing the release of noradrenaline from glandular nerve terminals.

What's new in local anaesthesia?

In this paper I have explored four areas of current interest to pain control in dentistry. Articaine HCl, the most recent addition to the dental LA armamentarium, has become a favoured drug in many, if not most, countries in which it is available. Rapid onset and improved hard- and soft-tissue penetration enable articaine HCl to be administered with great success as a mandibular infiltration, precluding the need, in most situations, to employ it by inferior alveolar nerve block. The 'question' about an increased risk of paresthesia following articaine administration via IANB has been answered by careful evaluation of case reports. C-CLAD systems have enabled the administration of LA to become much more comfortable, especially in the palate, and with accessory techniques such as the periodontal ligament injection (PDL, ILI). Two highly successful techniques, the AMSA and P-ASA, have been developed as a result of C-CLAD systems. Phentolamine mesylate (OraVerse) allows for the reversal of residual soft-tissue anaesthesia, decreasing its duration by approximately 50%. Reversal enables patients to 'feel normal' more quickly after dental treatment and should decrease the risk of traumatic injury to soft tissues. Knowledge of the maximum dosages of LAs to be administered to all patients, but to younger, lighter-weight patients in particular, is essential to safety. The prevention of LA overdose is more gratifying than managing this fear-inducing medical emergency. When used properly, local anaesthetics represent the safest and most effective drugs in all of medicine for the prevention and management of pain.

Characterization of the alpha1-adrenoceptor subtype activating extracellular signal-regulated kinase in submandibular gland acinar cells.

Alpha(1)-Adrenoceptors and extracellular signal-regulated kinases 1 and 2 (ERK1/2) regulate salivary secretion. However, whether alpha(1)-adrenoceptors couple to ERK1/2 activation and the specific alpha(1)-adrenoceptor subtypes involved in salivary glands is unknown. Western blotting of ERK1/2 phosphorylation showed phenylephrine activated ERK1/2 by 2-3-fold in submandibular gland slices and 3-4-fold in submandibular acinar (SMG-C10) cells with an EC(50) of 2.7+/-2 microM. ERK1/2 activation was blocked by either prazosin or HEAT, indicating alpha(1)-adrenoceptors stimulate ERK1/2 in native glands and SMG-C10 cells. Inhibition of [(125)I]HEAT binding by 5-methylurapidil (selective for alpha(1A) over alpha(1B/)alpha(1D)), but not BMY 7378 (selective for alpha(1D) over alpha(1A/)alpha(1B)), was biphasic and best-fit by a two-site binding model with K(i)(H) and K(i)(L) values for 5-methylurapidil of 0.64+/-0.3 and 91+/-7 nM, respectively, in SMG-C10 membranes. From these binding data, we obtained subtype-selective concentrations of 5-methylurapidil to determine the alpha(1)-adrenoceptor subtype/s activating ERK1/2 in SMG-C10 cells. 5-methylurapidil (20 nM) did not affect phenylephrine- or A-61603- (alpha(1A)-selective agonist) induced ERK1/2 activation; whereas, 30 microM chloroethylclonidine (alpha(1B)-selective antagonist) inhibited ERK1/2 activation by phenylephrine, indicating alpha(1B)-adrenoceptors, but not alpha(1A)-adrenoceptors, activate ERK1/2 in submandibular cells. We also examined alpha(1)-adrenoceptor location and dependence on cholesterol-rich microdomains for activating ERK1/2. Sucrose density gradient centrifugation showed 71+/-3% of alpha(1)-adrenoceptor binding sites were in plasma membranes. Cholesterol-disrupting agents filipin and methyl-beta-cyclodextrin inhibited phenylephrine-stimulated ERK1/2. These results show only alpha(1B)-adrenoceptors activate ERK1/2 and suggest subtype-specific ERK1/2 signaling by alpha(1B)-adrenoceptors may be determined by localization to cholesterol-rich microdomains in submandibular cells.

Randomized study of phentolamine mesylate for reversal of local anesthesia.

Local anesthetic solutions frequently contain vasoconstrictors to increase the depth and/or duration of anesthesia. Generally, the duration of soft-tissue anesthesia exceeds that of pulpal anesthesia. Negative consequences of soft-tissue anesthesia include accidental lip and tongue biting as well as difficulty in eating, drinking, speaking, and smiling. A double-blind, randomized, multicenter, Phase 2 study tested the hypothesis that local injection of the vasodilator phentolamine mesylate would shorten the duration of soft-tissue anesthesia following routine dental procedures. Participants (122) received one or two cartridges of local anesthetic/vasoconstrictor prior to dental treatment. Immediately after treatment, 1.8 mL of study drug (containing 0.4 mg phentolamine mesylate or placebo) was injected per cartridge of local anesthetic used. The phentolamine was well-tolerated and reduced the median duration of soft-tissue anesthesia in the lip from 155 to 70 min (p < 0.0001).

Pharmacokinetics of lidocaine with epinephrine following local anesthesia reversal with phentolamine mesylate.

Phentolamine mesylate accelerates recovery from oral soft tissue anesthesia in patients who have received local anesthetic injections containing a vasoconstrictor. The proposed mechanism is that phentolamine, an alpha-adrenergic antagonist, blocks the vasoconstriction associated with the epinephrine used in dental anesthetic formulations, thus enhancing the systemic absorption of the local anesthetic from the injection site. Assessments of the pharmacokinetics of lidocaine and phentolamine, and the impact of phentolamine on the pharmacokinetics of lidocaine with epinephrine were performed to characterize this potentially valuable strategy. The blood levels of phentolamine were determined following its administration intraorally and intravenously. Additionally, the effects of phentolamine mesylate on the pharmacokinetics of intraoral injections of lidocaine with epinephrine were evaluated. Sixteen subjects were enrolled in this phase 1 trial, each receiving 4 drug treatments: 1 cartridge lidocaine/epinephrine followed after 30 minutes by 1 cartridge phentolamine (1L1P), 1 cartridge phentolamine administered intravenously (1Piv), 4 cartridges lidocaine/epinephrine followed after 30 minutes by 2 cartridges phentolamine (4L2P), and 4 cartridges lidocaine/epinephrine followed by no phentolamine (4L). Pharmacokinetic parameters estimated for phentolamine, lidocaine, and epinephrine included peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve from 0 to the last time point (AUClast) or from time 0 to infinity (AUCinf), elimination half-life (t1/2), clearance (CL), and volume of distribution (Vd). The phentolamine Tmax occurred earlier following the intravenous administration of 1Piv (7 minutes than following its submucosal administration in treatment 1L1P (15 minutes) or 4L2P (11 minutes). The phentolamine t1/2, CL, and Vd values were similar for 1L1P, 1Piv, and 4L2P. The Tmax for lidocaine occurred later and the Cmax for lidocaine was slightly higher when comparing the 4L2P treatment and the 4L treatment. The phentolamine-induced delay of the lidocaine Tmax likely represents phentolamine's ability to accelerate the systemic absorption of lidocaine from oral tissues into the systemic circulation.

Salivary alpha-amylase levels after yohimbine challenge in healthy men.

CONTEXT: We and others have previously shown that standardized psychosocial stress significantly increases salivary alpha-amylase (sAA), but it remains unclear whether sAA reflects autonomic nervous system activation. OBJECTIVE: The aim of this study was to assess cardiovascular effects and sAA and catecholamine secretion after iv injection of yohimbine. DESIGN AND SETTING: We conducted a randomized double-blind placebo-controlled study at an academic research unit. PARTICIPANTS: Thirteen healthy males (aged 20-28 yr) were examined. INTERVENTION: Participants received iv injection of yohimbine (0.4 microg/kg) or placebo (0.9% NaCl). MAIN OUTCOME MEASURES: Eight saliva and blood samples were taken before and after injection for the assessment of salivary flow rate and sAA and catecholamine concentrations. In addition, blood pressure, mood, and anxiety were assessed repeatedly. RESULTS: Yohimbine induced increases of sAA activity and output in comparison to placebo (P = 0.034). Blood pressure (P < 0.001), salivary flow rate (P = 0.007), and catecholamines (P < 0.001) were also significantly increased. No significant correlations between alpha-amylase parameters and catecholamines were observed. CONCLUSIONS: The results indicate that yohimbine administration activates not only autonomic parameters but also sAA via adrenergic mechanisms, suggesting that sAA might be an indirect indicator of the central sympathetic system.

Alpha-adrenoceptor blockade by labetalol during long-term dosing.

The hypotensive effect of short-term labetalol, the alpha- and beta-adrenoceptor blocker, is greater in subjects in the orthostatic position, possibly because of the alpha-adrenoceptor blockade. During prolonged use the orthostatic blood pressure fall disappears. To verify whether or not this is due to reduction in alpha-blocking activity, phenylephrine-induced increase in blood pressure was studied in six subjects with mild essential hypertension before and after 3 and 6 days and 1 and 6 mo of continuous treatment with 200 mg labetalol three times a day by mouth. At the same intervals, isoproterenol-induced tachycardia was followed to assess beta-blockade. After 3 days on labetalol, the log dose-response curve of phenylephrine-induced increase in blood pressure shifted to the right and the dose of agonist required to elicit a 20% increase in systolic pressure was 1.7 times that before treatment. There was a progressive decline in the dose of agonist that induced the same increase in pressure so that after 6 mo of continuous labetalol it was the same as control. In contrast, the amount of isoproterenol needed to induce a 20% increase in heart rate was two to three times that before labetalol and did not change throughout 6 mo of therapy. These data indicate a decline in the alpha-adrenoceptor-blocking effect of oral labetalol without concomitant change in the degree of beta-adrenoceptor blockade. This might account for the disappearance of orthostatic hypotension early in the course of treatment and for some decrease in the antihypertensive efficacy of labetalol.

Doxazosin and cholestyramine similarly decrease fatty streak formation in the aortic arch of hyperlipidemic hamsters.

The effect of doxazosin, an alpha-1 adrenergic inhibitor, on atherosclerosis was determined in hyperlipidemic hamsters. Control hamsters fed chow plus 0.05% cholesterol and 10% coconut oil were compared to chow baseline animals, and to those receiving either 10 mg/kg/day doxazosin, or 245 mg/kg/day cholestyramine in the atherogenic diet. During 8 weeks of treatment, plasma lipids, mean arterial pressure (MAP) and heart rate (HR) were measured, then the ascending aortic arch was examined en face. Numbers of subendothelial macrophage-foam cells/mm2 and their average size (microns 2) were determined, and Oil red O staining (micrograms ORO/mm2) was quantitated to estimate lipid accumulation. Ultracentrifugation of control plasma demonstrate that low density lipoprotein (LDL) carried most of the cholesterol, and very low density lipoprotein (VLDL) was rich in triglycerides. Compared to controls, doxazosin and cholestyramine similarly decreased plasma total and LDL plus VLDL cholesterols, and total triglycerides on average by 46%, 61% and 45% respectively. High density lipoprotein cholesterol was unchanged. Doxazosin also reduced MAP by 18% without affecting HR. In all hamsters, foam cells and lipid accumulated in a lesion-prone area characterized by elevated endothelial cell density, and a thick intima of basement membrane-like material layered over "pads" of smooth muscle cells. Compared to controls, doxazosin and cholestyramine uniformly reduced the number of foam cells/mm2, foam cell size and ORO staining on average by 66%, 29% and 56%, respectively. We conclude that doxazosin decreases plasma lipids and inhibits the development of the fatty streak to a similar level as cholestyramine treatment.

Antihypertensive therapy and lipids. Paradoxical influences on cardiovascular disease risk.

It is generally acknowledged that hypertension is associated with an increased risk of cardiovascular morbidity and mortality, and that lowering elevated blood pressure is effective in reducing that risk. However, hypertension is more likely to cause cardiovascular disease in those with additional risk factors, such as cigarette smoking, hyperlipidemia, diabetes mellitus, hypokalemia, loft ventricular hypertrophy, or electrocardiographic abnormalities. The evidence to date indicates that not all patients with mild hypertension need to be treated with drugs; not all of those receiving drug therapy should be treated with the same drugs; and the benefit of the same degree of reduction in blood pressure may not be equivalent for different drugs. The use of traditional step 1 diuretic therapy is not uniformly appropriate. As an alternative, the vasodilator prazosin can be effective as monotherapy in the treatment of mild hypertension, and its addition to diuretic or beta blocker therapy appears to blunt or prevent the adverse effects of those agents on lipid levels. Since prazosin therapy is least likely to worsen existing risk factors or precipitate their occurrence, it should enhance the benefit of blood pressure reduction in delaying or preventing cardiovascular disease.

Effects of the alpha 2-adrenoreceptor antagonist dexefaroxan on neurogenesis in the olfactory bulb of the adult rat in vivo: selective protection against neuronal death.

A dysfunction of noradrenergic mechanisms originating in the locus coeruleus has been hypothesised to be the critical factor underlying the evolution of central neurodegenerative diseases [Colpaert FC (1994) Noradrenergic mechanism Parkinson's disease: a theory. In: Noradrenergic mechanisms in Parkinson's disease (Briley M, Marien M, eds) pp 225-254. Boca Raton, FL, USA: CRC Press Inc.]. alpha(2)-Adrenoceptor antagonists, presumably in part by facilitating central noradrenergic transmission, afford neuroprotection in vivo in models of cerebral ischaemia, excitotoxicity and devascularization-induced neurodegeneration. The present study utilised the rat olfactory bulb as a model system for examining the effects of the selective alpha(2)-adrenoceptor antagonist dexefaroxan upon determinants of neurogenesis (proliferation, survival and death) in the adult brain in vivo. Cell proliferation (5-bromo-2'-deoxyuridine labelling) and cell death associated with DNA fragmentation (terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling assay) were quantified following a 7-day treatment with either vehicle or dexefaroxan (0.63 mg/kg i.p., three times daily), followed by a 3-day washout period. The number of terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling-positive nuclei in the olfactory bulb was lower in dexefaroxan-treated rats, this difference being greatest and significant in the subependymal layer (-52%). In contrast, 5-bromo-2'-deoxyuridine-immunoreactive nuclei were more numerous (+68%) in the bulbs of dexefaroxan-treated rats whilst no differences were detected in the proliferating region of the subventricular zone. Terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling combination with glial fibrillary acidic protein or neuronal-specific antigen immunohistochemistry revealed that terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling-positive nuclei were associated primarily with a neuronal cell phenotype. These findings suggest that dexefaroxan increases neuron survival in the olfactory bulb of the adult rat in vivo, putatively as a result of reducing the apoptotic fate of telencephalic stem cell progenies.