Chronic treatment with the α2-adrenoceptor antagonist fluparoxan prevents age-related deficits in spatial working memory in APP×PS1 transgenic mice without altering ß-amyloid plaque load or astrocytosis.

Locus coeruleus degeneration and reduced central noradrenaline content is an early feature of Alzheimer's disease. In transgenic mouse models of Alzheimer's disease-like pathology, lesioning the locus coeruleus exacerbates ß-amyloid (Aß) pathology, neuroinflammation and memory deficits. Here we aimed to determine whether chronic treatment with the α(2)-adrenoceptor antagonist fluparoxan, that enhances noradrenaline release, can prevent the onset of Alzheimer's-like pathology and memory deficits in APP/PS1 transgenic mice (TASTPM). Fluparoxan (1mg/kg/day) was administered to TASTPM and wild type mice from 4 to 8 months of age. Memory was assessed at 4 and 8 months of age using the Morris water maze and contextual fear conditioning and at monthly intervals during the duration of treatment using the object recognition and spontaneous alternation task. Aß plaque load and astrocytosis were measured at 4 and 8 months of age by immunohistochemistry. Fluparoxan treatment prevented age-related spatial working memory deficits in the spontaneous alternation task but not spatial reference memory deficits in the Morris water maze. Aß plaque load and astrocytosis were unaltered by fluparoxan treatment in TASTPM mice. The findings suggest that fluparoxan treatment selectively prevent the decline of forms of memory where noradrenaline plays an integral role and that this beneficial effect is not due to altered Aß plaque pathology or astrocytosis.

Characterization of the sympathetic nerve responses to amphetamine: role of central alpha 2-adrenergic receptors.

Although amphetamine has profound cardiovascular actions, the role of the sympathetic nervous system in these responses is largely unknown. The purpose of this study was to characterize the sympathetic nerve responses to amphetamine and to determine whether these neural responses involve an action of amphetamine in the rostral ventrolateral medulla (RVLM). In sinoaortically denervated (SAD) and sham-SAD rats, amphetamine dose-dependently increased mean arterial pressure (MAP) and heart rate (HR), while decreasing (-87 +/- 5%, max) renal sympathetic nerve discharge (SND) for 57 +/- 5 min. Comparison of the SND responses in SAD and sham-SAD rats revealed a small but significant contribution of the baroreceptor reflex to the sympathoinhibitory response. In separate studies, the bilateral microinjection of amphetamine into RVLM decreased HR, MAP, and SND. The magnitude and duration of the decrease in SND elicited by amphetamine were significantly attenuated by the prior intravenous (i.v.) administration of idazoxan (alpha 2-adrenergic antagonist). The prior bilateral microinjection of idazoxan or piperoxan into RVLM significantly attenuated the duration of the sympathoinhibitory responses elicited by i.v. amphetamine. Idazoxan and piperoxan also tended to decrease the magnitude of the SND response; however, this reduction was significant at only the highest doses. The MAP and HR responses were unaffected by idazoxan treatment. The microinjection of terazosin (alpha 1-adrenergic antagonist) or propranolol (beta-adrenergic antagonist) into RVLM did not alter the HR, MAP, or SND responses to i.v. amphetamine. We conclude that i.v. amphetamine decreases SND in anesthetized rats, in large part, by a mechanism involving the activation of alpha 2-adrenergic receptors in RVLM.

Antagonism of the effects of clonidine by the alpha 2-adrenoceptor antagonist, fluparoxan.

1. The effects of fluparoxan, an alpha 2-adrenoceptor antagonist, on the pharmacodynamic changes induced by clonidine were investigated in this placebo-controlled, double-blind, two-period, cross-over study in 16 healthy male volunteers (aged 19 to 44 years). 2. Subjects received either fluparoxan or placebo, twice-daily for 5 1/2 days (11 doses). One hour after the first and last dose of each treatment period, clonidine (200 micrograms) was infused intravenously over 5 min. 3. Indices of clonidine-mediated pharmacodynamic responses (growth hormone secretion, bradycardia, hypotension, xerostomia and sedation) were taken before and after clonidine infusion. Growth hormone secretion was assessed by quantifying serum growth hormone concentrations; sedation was assessed by both visual analogue scales (VAS) and by a visual psychomotor response meter, measuring critical flicker fusion (CFF). 4. The majority of subjects reported minor adverse events such as lethargy, headache and dry mouth following clonidine infusion. All adverse events were likely to be related to clonidine, as they occurred consistently between treatment groups. Fluparoxan has, however, in previous studies been reported to cause headache and light-headedness. 5. Prior to the clonidine infusion, fluparoxan caused small but statistically significant increases in systolic blood pressure (4 mm Hg) and salivary flow (approximately 30%) after both single and repeated doses. A small increase in heart rate (2 beats min-1) was seen after a single dose which was also statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

The alpha-2 antagonists idazoxan and rauwolscine but not yohimbine or piperoxan are anxiolytic in the Vogel lick-shock conflict paradigm following intravenous administration.

The alpha 2 agonist clonidine has been shown to be anxiolytic in a number of preclinical anxiety models. Interestingly, intravenous infusion of the alpha 2 antagonists idazoxan at 10 mg/kg and rauwolscine at 2.24 mg/kg significantly disinhibited lick-shock conflict responding in rats similar to the alpha 2 agonist clonidine (0.022 mg/kg) and the benzodiazepine diazepam (0.5 mg/kg). However, the alpha 2 antagonists yohimbine and piperoxan, the alpha 2 agonists medetomidine, guanfacine, and guanabenz, the non-specific alpha antagonist phentolamine, and the alpha 1 antagonist prazosin did not disinhibit conflict responding in the Vogel lick-shock paradigm. In fact, yohimbine has been shown to be anxiogenic in both animals and man. This may be due to yohimbine's lack of specificity and its ability to inhibit GABAergic release. In addition, all of these agents, except idazoxan, did not increase water consumption in water deprived rats. Idazoxan (10 mg/kg) significantly decreased water consumption by 45%. Therefore, idazoxan increased conflict responding for water reward at a dose (10 mg/kg) which also decreased water consumption in a non-conflict paradigm. These data suggest that agents with selective antagonism at the alpha 2 receptor site may be anxiolytic while agents with less specificity at this site such as yohimbine, piperoxan, and phentolamine are not anxiolytic.

Brainstem mechanisms in the modulation of the sympathetic baroreflex by piperoxan.

Piperoxan (50-100 micrograms/kg) injected into the cisterna magna of anaesthetized dogs increased blood pressure, heart rate and resting rate of sympathetic nerve discharge. The baroreflex curve was shifted to the right with an elevation of the upper plateau (when blood pressure was lowered below resting values, renal sympathetic nerve activity rose to an upper plateau) and with no change in baroreflex sensitivity. Catecholamine depletion, produced by reserpine and alpha-methyl-p-tyrosine, did not change the effects of piperoxan on resting sympathetic nerve activity and on the baroreflex curve. Piperoxan (50 micrograms/kg i.c.) enhanced the rate of renal sympathetic nerve discharge in baroreceptor-denervated dogs. Piperoxan (5 micrograms) injected bilaterally into the nucleus tractus solitarii (NTS) increased blood pressure and resting sympathetic nerve activity with a shift of the sympathetic baroreflex curve to the right and no change in baroreflex sensitivity. Piperoxan (5 micrograms) injected bilaterally into the ventrolateral pressor area did not change blood pressure or the rate of sympathetic discharge. However, the baroreflex curve was shifted to the right with an elevation of the upper plateau level and the baroreflex sensitivity was increased. The present findings suggest that tonically active alpha 2-adrenergic mechanisms located within the NTS regulate resting and reflex sympathetic activity. An alpha 2-adrenergic mechanism in the rostral ventrolateral medulla modulates reflex sympathetic activity but has no influence on resting activity.