Patterns of cerebrospinal fluid catechols support increased central noradrenergic responsiveness in aging and Alzheimer's disease.

BACKGROUND: High cerebrospinal fluid (CSF) norepinephrine (NE) concentrations in aging and Alzheimer's disease (AD) could reflect decreased NE clearance from central nervous system (CNS) extracellular fluid or increased release of NE into CNS extracellular fluid. Measuring CSF concentrations of the intraneuronal NE metabolite dihydroxyphenylglycol (DHPG), an estimate of NE clearance, and the NE precursor dihydroxyphenylacetic acid (DOPA), an estimate of NE biosynthesis, can help differentiate these mechanisms. METHODS: NE, DHPG, and DOPA were determined by HPLC in CSF and plasma obtained following yohimbine, clonidine, and placebo. Ten AD, 10 older, and 11 young subjects were studied. RESULTS: CSF DOPA following yohimbine was higher in older and AD than in young subjects. CSF DHPG did not differ among groups. Plasma DOPA following yohimbine was higher in AD than in young subjects. CONCLUSIONS: During alpha-2 adrenoreceptor blockade in both aging and AD, there are increased responses of CNS NE biosynthesis and release with unchanged CNS NE clearance. This pattern is consistent with partial loss of CNS noradrenergic neurons with compensatory activation of remaining CNS noradrenergic neurons. Given the marked loss of locus coeruleus (LC) noradrenergic neurons in AD, achievement of high CSF NE suggests particularly prominent compensatory activation of remaining LC neurons in this disorder.

Post-hypoxic frequency decline does not depend on alpha2-adrenergic receptors in the adult rat.

The aim of this study was to determine whether post-hypoxic frequency decline (PHFD) requires central activation of alpha2-adrenergic receptors. PHFD is defined as the undershoot in respiratory frequency that occurs immediately following brief hypoxic periods. Adult anesthetized, vagotomized rats were exposed to hypoxia (8% O2, mean=45 s) before and after intracerebroventricular (i.c.v.) infusion of vehicle or alpha2-antagonist. The efficacy of the i.c.v. antagonist was assessed by recording the response to intravenous injection of alpha2-agonist before and after the infusion. We compared breathing frequencies before, during, and after hypoxia, both before and after treatments. The decline in breathing frequency after hypoxia was not prevented by the alpha2-antagonists, RX 821002 or SK&F-86466. Guanabenz, an alpha2-agonist, prolonged baseline expiration and potentiated PHFD. Prior treatment with SK&F-86466 blocked the agonist-evoked response which was also reversed by subsequent administration of SK&F-86466. We conclude that PHFD does not require the activation of alpha2-adrenergic receptors, but that alpha2-adrenergic receptors can modulate resting and post-hypoxic respiratory frequency.

Cerebrospinal fluid and plasma disposition of yohimbine and 11-hydroxy-yohimbine in young and older healthy subjects, and Alzheimer's disease patients.

OBJECTIVE: The plasma and cerebrospinal fluid (CSF) disposition of yohimbine (YO) and 11-hydroxy-yohimbine (11-OH-YO), after oral administration of a single dose of YO (0.65 mg.kg-1) were studied in young and older healthy subjects and in patients with Alzheimer's disease (AD). RESULTS: Plasma disposition of YO displayed large variability; no significant differences among subject groups were observed. In contrast, 11-OH-YO Cmax and AUC were significantly lower in the older normal subjects than in the young normal or AD subjects. A strong positive correlation between CSF and plasma YO concentrations was observed. A weak positive correlation between CSF and plasma concentrations of 11-OH-YO was also observed. CSF to plasma concentration ratios for yohimbine and 11-OH-YO were low (approximately 2%).

Urapidil permeates the intact blood-brain barrier.

OBJECTIVE: To determine the plasma and cerebrospinal fluid (CSF) levels of urapidil after i.v. administration and the effect on CSF serotonin and 5-hydroxyindoleacetic acid (5-HIAA) concentrations. DESIGN: Open, single-dose study. SETTING: Post-surgery following neurosurgical removal of the hypophysis (n = 5) or aneurysm clipping (n = 1). PATIENTS: 6 patients, aged 32-71 years, with intact blood-brain barrier (BBB); 1 patient was studied twice. INTERVENTIONS: Single dose of 25 mg urapidil i.v. as prophylaxis of BP increase during extubation or as treatment of hypertensive episodes. MEASUREMENTS AND RESULTS: Urapidil, serotonin and 5-HIAA were measured by HPLC in CSF during 8 h after urapidil administration. Urapidil was detected in CSF as soon as 5 min after injection in 3 patients. The concentration ratio of plasma/CSF after the distribution phase was about 5:1. No significant effect on serotonin and 5-HIAA in CSF was seen. CONCLUSION: After administration of a therapeutic dose, urapidil permeates the BBB and may interact with central 5-HT1A-receptors.

Receptor occupancy in lumbar CSF as a measure of the antagonist activity of atenolol, metoprolol and propranolol in the CNS.

1. The antagonist activity of atenolol, metoprolol and propranolol in the CNS was estimated by determining the extent to which the drugs occupy animal beta 1- and beta 2-receptors in CSF ex vivo at the time of lumbar puncture. 2. Five CSF and plasma samples were obtained 4 h after drug intake from subjects treated for hypertension with atenolol, 100 mg once daily and five from subjects treated with metoprolol, 50 mg three times daily. Twenty-four samples were obtained 1, 2, 4 or 12 h after drug intake from subjects receiving a single 40 mg dose of propranolol. 3. The receptor occupancy in the samples was determined by adding beta 1-receptors of rabbit lung and beta 2-receptors of rat reticulocytes into the samples and labeling the receptors with a nonselective beta-adrenoceptor antagonist, (-)-[3H]-CGP-12177. 4. Atenolol and metoprolol occupied, as expected, larger fractions of beta 1- than beta 2-receptors in CSF and plasma samples. The receptor fraction occupied by atenolol in CSF was significantly (P < 0.05) lower than that occupied by metoprolol. The differences in occupancy between the drugs in plasma, however, were not statistically significant. 5. Propranolol occupied larger fractions of beta 2- than beta 1-receptors in the samples. Although propranolol concentrations in CSF were only 1/20-1/40 of those in plasma, the receptor occupancy of propranolol in CSF was similar to that in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)