Transducing system operated by adenosine A(2A) receptors to facilitate acetylcholine release in the rat hippocampus

In spite of the increasing evidence concerning its neurotoxicity, young human individuals are often involved in the recreational use of amphetamine-type stimulants such as 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"). A study aimed to investigate short- and long-term consequences of a repeated and intermittent MDMA administration (0, 5 or 10 mg/kg i.p., 3 days treatment history) was conducted in mice. Mice were injected at different phases in development, namely at early (28 days old), middle (38 days old) or late (52 days old) adolescence. When assessed for nociceptive response, a dose-dependent analgesia was found in middle and late adolescent mice. Carryover consequences of previous MDMA treatment were then investigated at adulthood (80 days old). In a social interaction test, levels of environment exploration and social behaviour resulted markedly increased in drug-free state as a function of drug exposure during development, whereas others behaviours were reduced. MDMA challenge (5-mg/kg dose) produced the expected hyperactivity, as well as a marked increment of hypothalamic serotonin (5-hydroxyhyptamine, 5-HT) levels. Mice treated chronically with MDMA during middle and late adolescence were associated with important reductions of the indoleamine. As a whole, these results indicate a differential long-term vulnerability to behavioural and neurotoxicant effects of MDMA as a function of the developmental stage of exposure.     

Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia

Cyclooxygenase-2 is involved in the inflammatory component of the ischemic cascade, playing an important role in the delayed progression of the brain damage. The present study evaluated the pharmacological effects of the selective cyclooxygenase-2 inhibitor nimesulide on delayed neuronal death of hippocampal CA1 neurons following transient global cerebral ischemia in gerbils. Administration of therapeutically relevant doses of nimesulide (3, 6 and 12 mg/kg; i.p.) 30 min before ischemia and at 6, 12, 24, 48 and 72 h after ischemia significantly (P<0.01) reduced hippocampal neuronal damage. Treatment with a single dose of nimesulide given 30 min before ischemia also resulted in a significant increase in the number of healthy neurons in the hippocampal CA1 sector 7 days after ischemia. Of interest is the finding that nimesulide rescued CA1 pyramidal neurons from ischemic death even when treatment was delayed until 24 h after ischemia (34+/-9% protection). Neuroprotective effect of nimesulide is still evident 30 days after the ischemic episode, providing the first experimental evidence that cyclooxygenase-2 inhibitors confer a long-lasting neuroprotection. Oral administration of nimesulide was also able to significantly reduce brain damage, suggesting that protective effects are independent of the route of administration. The present study confirms the ability of cyclooxygenase-2 inhibitors to reduce brain damage induced by cerebral ischemia and indicates that nimesulide can provide protection when administered for up to 24 h post-ischemia.     

Explanations and unresolved issues pertaining to the development of the Nuclear Pharmacy Compounding Guidelines

OBJECTIVES: To provide background information related to the development of the Nuclear Pharmacy Compounding Guidelines, to discuss regulatory complexities related to radiopharmaceutical compounding practice, and to summarize the gaps in the current compounding regulations for radiopharmaceuticals. DATA SOURCES: The Guidelines closely follow the provisions of section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the monographs and chapters related to pharmacy compounding in the United States Pharmacopeia (USP), and the recommended guidelines published by the American Society of Health-System Pharmacists. SUMMARY: The Food and Drug Administration Modernization Act (FDAMA) of 1997 established parameters under which the compounding of drug products is appropriate and lawful, but these criteria expressly do not apply to radiopharmaceuticals. The Nuclear Pharmacy Compounding Practice Committee, a group of nuclear pharmacists convened by the American Pharmaceutical Association, developed the Nuclear Pharmacy Compounding Guidelines to establish a set of principles and guidelines for good radiopharmaceutical compounding practice. The intent of the new document is to provide guidance on radiopharmaceutical compounding practices that have evolved over the last 2 decades and to place them in an appropriate regulatory framework in accordance with previous enforcement policies and guidelines issued by the U.S. Food and Drug Administration (FDA) regarding the exemption of certain pharmacy practices from enforcement of adulteration, misbranding, and new drug requirements. CONCLUSION: The Nuclear Pharmacy Compounding Guidelines, recently released by APhA, is the first official document that provides realistic and practical compounding guidance for nuclear pharmacists. Even though the United States Court of Appeals for the Ninth Circuit recently ruled section 503A of the FD&C Act to be invalid in its entirety, and the Supreme Court upheld that ruling, the compliance policy guides issued by FDA in March 1992 and revised in May 2002 maintain guiding principles on pharmacy compounding similar to those stated in section 503A of the FD&C Act. The Nuclear Pharmacy Compounding Practice Committee is optimistic that the practical information contained in the Guidelines will assist state boards of pharmacy, FDA, and the United States Pharmacopeial Convention in setting appropriate standards for nuclear pharmacy compounding practice that will ensure the continued availability of high-quality compounded radiopharmaceuticals at reasonable cost.     

Altered expression of small-conductance Ca2+-activated K+ (SK3) channels modulates arterial tone and blood pressure

The endothelium is a critical regulator of vascular tone, and dysfunction of the endothelium contributes to numerous cardiovascular pathologies. Recent studies suggest that apamin-sensitive, small-conductance, Ca2+-activated K+ channels may play an important role in active endothelium-dependent vasodilations, and expression of these channels may be altered in disease states characterized by vascular dysfunction. Here, we used a transgenic mouse (SK3T/T) in which SK3 expression levels can be manipulated with dietary doxycycline (DOX) to test the hypothesis that the level of expression of the SK subunit, SK3, in endothelial cells alters arterial function and blood pressure. SK3 protein was elevated in small mesenteric arteries from SK3T/T mice compared with wild-type mice and was greatly suppressed by dietary DOX. SK3 was detected in the endothelium and not in the smooth muscle by immunohistochemistry. In whole-cell patch-clamp experiments, SK currents in endothelial cells from SK3T/T mice were almost completely suppressed by dietary DOX. In intact arteries, SK3 channels contributed to sustained hyperpolarization of the endothelial membrane potential, which was communicated to the arterial smooth muscle. Pressure- and phenylephrine-induced constrictions of SK3T/T arteries were substantially enhanced by treatment with apamin, suppression of SK3 expression with DOX, or removal of the endothelium. In addition, suppression of SK3 expression caused a pronounced and reversible elevation of blood pressure. These results indicate that endothelial SK3 channels exert a profound, tonic, hyperpolarizing influence in resistance arteries and suggest that the level of SK3 channel expression in endothelial cells is a fundamental determinant of vascular tone and blood pressure.     

Psychotic depression and mortality

OBJECTIVE: Major depressive disorder is associated with elevated mortality rates that increase with the severity of depression. The authors hypothesized that patients with psychotic depression would have higher mortality rates than patients with nonpsychotic depression. METHOD: Survival analytic techniques were used to compare the vital status of 61 patients with psychotic major depression with that of 59 patients with nonpsychotic major depression up to 15 years after hospital admission. Medical status was assessed with the Cumulative Illness Rating Scale. Dexamethasone suppression test (DST) data were available for 101 patients. RESULTS: The mortality rate for subjects with psychotic depression was significantly greater than that for those with nonpsychotic depression, with 41% versus 20%, respectively, dying within 15 years after hospital admission. A proportional hazards model with age and medical status entered as covariates confirmed a significantly higher mortality rate in patients with psychotic depression (hazards ratio=2.31). A positive DST result was associated with psychotic depression but was not related to vital status. CONCLUSIONS: Patients with psychotic depression have a two-fold greater risk of death than do patients with severe, nonpsychotic major depression.     

Subcellular localization of adenosine A(1) receptors in nerve terminals and synapses of the rat hippocampus

Adenosine is a neuromodulator in the CNS that mainly acts through pre- and postsynaptic A(1) receptors to inhibit the release of excitatory neurotransmitters and NMDA receptor function. This might result from a highly localized distribution of A(1) receptors in the active zone and postsynaptic density of CNS synapses that we now investigated in the rat hippocampus. The binding density of the selective A(1) receptor antagonist, [3H]1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX), was enriched in membranes from Percoll-purified nerve terminals (B(max)=1839+/-52 fM/mg protein) compared to total membranes from the hippocampus (B(max)=984+/-31 fM/mg protein), the same occurring with A(1) receptor immunoreactivity. [3H]DPCPX binding occurred mainly to the plasma membrane rather than to intracellular sites, since the binding of the membrane permeable A(1) receptor ligand [3H]DPCPX to intact hippocampal nerve terminals (B(max)=1901+/-192 fM/mg protein) was markedly reduced (B(max)=321+/-30 fM/mg protein) by the membrane impermeable adenosine receptor antagonist, 8-sulfophenyltheophilline (25 microM). Further subcellular fractionation of hippocampal nerve terminals revealed that A(1) receptor immunoreactivity was strategically located in the active zone of presynaptic nerve terminals, as expected to understand the efficiency of A(1) receptors to depress neurotransmitter release. A(1) Receptors were also present in nerve terminals outside the active zone in accordance with the existence of a presynaptic A(1) receptor reserve. Finally, A(1) receptor immunoreactivity was evident in the postsynaptic density together with NMDA receptor subunits 1, 2A and 2B and with N-and P/Q-type calcium channel immunoreactivity, emphasizing the importance of A(1) receptors in the control of dendritic integration.