Response of central monoaminergic neurons to lisuride: comparison with LSD.

The response of brain serotonergic (dorsal raphe), noradrenergic (locus coeruleus) and dopaminergic (pars compacta, substantia nigra) neurons to lisuride hydrogen maleate, a non-hallucinogenic ergot, was studied in the rat using extracellular single cell recording techniques. As has been previously reported for LSD, minute intravenous infusions of lisuride (1–5 μg/kg) produced a complete but reversible suppression of raphe unit spontaneous firing. A similar depressant response was noted when lisuride was applied to raphe units by microiontophoresis. In contrast, locus coeruleus neurons were accelerated by the drug at somewhat higher doses (25–50 μg/kg). Pars compacta neurons demonstrated a predominately depressant response to lisuride but many of the cells tested were only partially suppressed and a few units were accelerated. It is suggested that the marked alterations in central monoamine turnover which have been observed with lisuride are directly paralled by changes in impulse flow in monoaminergic neurons. The fact that lisuride has powerful suppressant effects on central serotonergic neurons but no psychotomimetic actions in man challenges the “serotonin theory” of hallucinogensis; however, other pharmacological properties may account for lisuride's lack of hallucinogenic effects. Further studies with lisuride may provide insight into those drug characteristics critical to the presence or absence of hallucinogenic action.     

Semotiadil, a new calcium antagonist, is a very potent inhibitor of LDL-oxidation

The influence of semotiadil, a novel benzothiazine calcium antagonist on in-vitro copper-, 2,2àzo-bis-(2,4 dimethylvaleronitrile)[AMVN]-, and 2,2àzo-bis-(2-amidinopropane) [AAPH]-induced low-density lipoprotein (LDL) oxidation was assessed. The following parameters were measured: lag-time of oxidation, maximal rate of oxidation, dienes formed through continuous monitoring of developing conjugated dienes, thiobarbituric acid reactive substances, isoprostane(8-iso-PGF2alpha)-generation and relative electrophoretic mobility. The effect was compared with nifedipine, amlodipine and diltiazem. Besides the influence on isoprostane (8-iso-PGF2alpha)-generation where nifedipine was equipotent with semotiadil at 10(-3) M, semotiadil demonstrated a strong and significant effect in attenuating the indicated indices of LDL-oxidation, in particular, dose-dependently (10(-3) M to 10(-7) M). These results indicate that semotiadil may have the strongest antioxidant activity on LDL among the calcium antagonists examined.     

Sorbitol can fuel mouse sperm motility and protein tyrosine phosphorylation via sorbitol dehydrogenase

Energy sources that can be metabolized to yield ATP are essential for normal sperm functions such as motility. Two major monosaccharides, sorbitol and fructose, are present in semen. Furthermore, sorbitol dehydrogenase (SORD) can convert sorbitol to fructose, which can then be metabolized via the glycolytic pathway in sperm to make ATP. Here we characterize Sord mRNA and SORD expression during mouse spermatogenesis and examine the ability of sorbitol to support epididymal sperm motility and tyrosine phosphorylation. Sord mRNA levels increased during the course of spermatogenic differentiation. SORD protein, however, was first detected at the condensing spermatid stage. By indirect immunofluorescence, SORD was present along the length of the flagella of caudal epididymal sperm. Furthermore, immunoelectron microscopy showed that SORD was associated with mitochondria and the plasma membranes of sperm. Sperm incubated with sorbitol maintained motility, indicating that sorbitol was utilized as an energy source. Sorbitol, as well as glucose and fructose, were not essential to induce hyperactive motility. Protein tyrosine phosphorylation increased in a similar manner when sorbitol was substituted for glucose in the incubation medium used for sperm capacitation. These results indicate that sorbitol can serve as an alternative energy source for sperm motility and protein tyrosine phosphorylation.     

3,4-methylenedioxymethamphetamine (MDMA)-induced release of endogenous serotonin from the rat dorsal raphe nucleus in vitro: Effects of fluoxetine and tryptophan

The serotonin releasing action of 3,4-methylenedioxymethamphetamine on slices of dorsal raphe nucleus from rat was investigated. The slices were maintained in a gas-liquid interface perfusion chamber used for electrophysiological recording. Microdialysis probes designed for use on the slice surface were employed to measure the release of endogenous serotonin which was determined using liquid chromatography with electrochemical detection. Three minute duration exposure of the slices to 100 micromolar 3,4-methylenedioxymethamphetamine caused a long lasting release of endogenous serotonin. Fluoxetine, a serotonin transport inhibitor, reduced the amount of serotonin release. Tryptophan added to the perfusion solution increased both the duration and amount of serotonin released. These results further support earlier work on the mechanism of 3,4-methylenedioxymethamphetamine induced inhibition of serotonin neuronal firing.     

Functional supersensitivity of CNS α1-adrenoceptors following chronic antidepressant treatment

Chronic but not acute administration (21 days) of desipramine (10 mg/kg), amitriptyline (10 mg/kg) or iprindole (5 mg/kg) enhanced the stimulatory effect of the α₁-adrenergic agonist phenylephrine on the acoustic startle reflex when phenylephrine was infused into the subarachnoid space of the spinal cord. Comparable supersensitivity to phenylephrine also occurred 1 week after selective depletion of norepinephrine in the spinal cord via intrathecal administration of 6-hydroxydopamine. Behavioral supersensitivity to phenylephrine was associated with an increase in the number of ³H-prazosin binding sites following denervation but not following chronic antidepressant treatments. The results indicate that chronic antidepressant treatments may enhance functional α₁-adrenergic transmission through mechanisms different than those following denervation.     

An ultrastructural study on a new type of hepatic perisinusoidal cell in fish

Summary A new type of perisinusoidal cell containing numerous microfilaments is described for the first time. It is found in abundance in the livers of both marine and freshwater fish. These perisinusoidal cells are situated within the space of Disse and adhere firmly through desmosomes both to sinusoidal endothelial cells and to hepatocytes. The cytoplasmic microfilaments are striking and make these cells readily distinguishable from the perisinusoidal fat-storing cells of Ito. Although the function of these cells is not known, the observations presented here suggest that they may provide a supportive framework within the liver.Supported in part by Grants # GM92 and # ES07017