The protection afforded by the outer layer to procercoids of Schistocephalus solidus during passage through the stomach lumen of their vertebrate host (Gasterosteus aculeatus).

Intestinal cestodes with complex life cycles have to pass through the acid stomach lumen of their vertebrate host(s) in order to reach their preferred site of development. The cestode's tegument is the only organ in constant contact with this hostile environment. Procercoids of Schistocephalus solidus (order Diphyllobothriidea) lose their outer layer on passing through the acidic stomach of their second intermediate host (Gasterosteus aculeatus). We wanted to investigate if the outer layer is an adaptation that enables passage through this hostile environment. We used fish bile to force the procercoid larvae to shed their outer layer. This allowed us to compare the survival of the normal procercoids and the transformed ones when exposed to hydrochloric acid. We observed that the presence of the outer layer significantly improved the survival and active period of the procercoid larvae. Thus we conclude that in cestodes which inhabit the digestive tracts of vertebrates, the outer layer is an adaptation which enables them to pass through the acidic stomach environment of their vertebrate host(s).

A novel procedure for generating both nitric oxide and superoxide in situ from chemical sources at any chosen mole ratio. First application: tyrosine oxidation and a comparison with preformed peroxynitrite.

The first method for generating (*)NO and O(2)(*)(-) at any known, constant ratio has been developed. Spermine NONOate and di(4-carboxybenzyl)hyponitrite decay with first-order kinetics and exactly equal rate constants (half-lives of 80 min) at 37 degrees C and pH 7.5 to give 200 and 40 mol % (*)NO and O(2)(*)(-), respectively. Tyrosine oxidation to dityrosine and 3-nitrotyrosine (the major and minor products under the conditions used in these experiments) has been studied (mainly in the presence of CO(2)) using various different ratios of the rates of formation of (*)NO and O(2)(*)(-). The (*)NO/O(2)(*)(-) = 1.0 product profiles are very similar to those of the products derived from equal amounts of (*)NO and O(2)(*)(-) generated at a (*)NO/O(2)(*)(-) ratio of 1.0 from SIN-1 but are very different from those derived from preformed peroxynitrite. All the experimental results can be explained in terms of free radical chemistry. The product profiles at all the (*)NO/O(2)(*)(-) ratios could be satisfactorily simulated provided an important group of reactions which lead to the consumption of dityrosine was included.

Electrophysiological assay and characterization of central adrenoceptors: techniques and neuropharmacology.

Several single unit electrophysiological studies that have investigated central adrenoceptors are reviewed. The techniques and paradigms employed to electrophysiologically assay such adrenoceptors are discussed. Several regions of the brain, e.g., the nucleus locus coeruleus, the dorsal raphe nucleus, the lateral geniculate nucleus, and the cerebellar Purkinje neurons, are examined in detail, with reference to the nature of the adrenoceptor(s) located on these neurons. From the studies reviewed, it can be concluded that single unit electrophysiological recordings provide a valuable and powerful assay for adrenoceptors. Modification of this technique to study adrenoceptors from awake (behaving) or chronically treated animals is likely to result in significant advances in our understanding of mechanisms contributing to neuroreceptor plasticity.

Supersensitivity of analgesic responses to alpha 2-adrenergic agonists in genetically hypertensive rats.

This study compared the responsivity of alpha 2-adrenoceptors to agonists in normotensive (WKY) and genetically hypertensive (SH) rats. Clonidine produced a greater degree of analgesia in SH as compared to WKY rats. This analgesia was antagonized by yohimbine. Neither naphazoline nor 4-hydroxy-clonidine produced analgesia in SH or WKY rats. Our results suggest that the analgesic effects of clonidine in SH rats are probably mediated by supersensitive central alpha 2-adrenoceptors.

Spinal clonidine inhibits neural firing in locus coeruleus.

Intrathecally-administered clonidine inhibited the spontaneous firing of single neurons in the pontine nucleus locus coeruleus of rats. Such inhibition of neuron firing was not observed when the non-lipophilic alpha 2 adrenoceptor agonist (oxymetazoline) was administered intrathecally. It is concluded that lipophilic drugs like clonidine, when administered intrathecally, can have profound supraspinal actions and thus caution should be exercised in interpreting the sites of action of such drugs.

Typical and atypical neuroleptics are potent antagonists at alpha 1-adrenoceptors of the dorsal lateral geniculate nucleus. An electrophysiological study.

The present electrophysiology studies examined the actions of neuroleptics at central alpha 1-adrenoceptors in the rat. In single-cell recording experiments, typical and atypical neuroleptics, when administered systemically or locally (iontophoresis and pressure ejection), were found to be potent antagonists of activating alpha 1-adrenoceptor responses in the dorsal lateral geniculate nucleus (dLGN). Doses of neuroleptics effective as antagonists at alpha 1-adrenoceptors had very weak effects at muscarinic receptors in the dLGN. Since doses of neuroleptics employed in the present study were within the clinical range, it appears likely that central alpha 1-adrenoceptors would be blocked during a neuroleptic therapy in humans.

Relative potencies of alpha-1 and alpha-2 antagonists in the locus ceruleus, dorsal raphe and dorsal lateral geniculate nuclei: an electrophysiological study.

The actions of some adrenoceptor antagonists were examined in single unit studies at alpha-1 adrenoceptors of the dorsal raphe nucleus and the dorsal lateral geniculate nucleus and alpha-2 adrenoceptors of the nucleus locus ceruleus. Prazosin, WB-4101 and corynanthine were found to be effective central alpha-1 adrenoceptor antagonists and piperoxane, yohimbine and rauwolscine were found to be effective central alpha-2 adrenoceptor antagonists. Prazosin, WB-4101 and corynanthine had no activity at alpha-2 adrenoceptors. However, piperoxane, yohimbine and rauwolscine in addition to their alpha-2 adrenoceptor actions, also displayed significant alpha-1 adrenoceptor antagonist properties. Thus, the latter drugs are not as selective for central alpha-2 adrenoceptors as in some other systems. This supports the suggestion that alpha adrenoceptor subtypes are not identical across all species and tissues.

Candidate mechanisms underlying phencyclidine-induced psychosis: an electrophysiological behavioral, and biochemical study.

The central effects of phencyclidine (PCP) were investigated using electrophysiological, biochemical, and behavioral techniques. PCP produced depressions of neuronal firing of several brain regions when applied locally or parenterally. At the cerebellar locus coeruleus Purkinje neuron pathway PCP produced depressions of spontaneous firing. Use of lesion techniques and receptor antagonists revealed that at this synapse PCP acted as an agonist, i.e., an indirect sympathomimetic in that it caused release and or blocked reuptake of norepinephrine. PCP also produce alterations in behavioral measures such as stereotypy and rotarod performance. In addition PCP, like norepinephrine, produced increases in cyclic AMP levels in cerebellar slices. Inhibition of central neuron firing, and alterations in behavior were correlated with brain and blood levels of PCP. Many effects of PCP were antagonized by neuroleptics. It can be concluded that PCP has profound effects on several indices of central neuron function and such changes can be related to the psychosis and other effects of this drug.

Hypothyroidism elicits electrophysiological noradrenergic subsensitivity in rat cerebellum.

discharge rats of Purkinje neurons were compared in control and hypothyroid adult rats. Purkinje neurons in hypothyroid rats fired significantly faster and were less sensitive to iontophoretically applied norepinephrine than those in control rats. The subsensitivity of the Purkinje neurons appeared to be primarily due to an alteration in the beta-receptor--adenylate cyclase complex, because the sensitivity of these cells to locally applied N6-monobutyryl adenosine 3'-5'-monophosphate (N6 cyclic AMP) did not change significantly. The sensitivity of the Purkinje neurons to norepinephrine could be restored in hypothyroid rats by administration of triiodothyronine.

Electrophysiologic interactions of antipsychotic drugs with central noradrenergic pathways.

The pathway from the nucleus coeruleus to Purkinje neurons in rat cerebellar cortex was used to analyze effects of antipsychotic neuroleptic drugs on a central noradrenergic pathway. Fluphenazine and haloperidol produced a dose-dependent increase in Purkinje neuron spontaneous discharge. This effect was not seen in animals in which the noradrenergic input had been removed by the neurotoxin 6-hydroxydopamine. In contrast, the effects of neuroleptics were still present in animals which had received neonatal X-ray irradiation, which destroys intrinsic inhibitory and excitatory pathways in cerebellar cortex. Chlorpromazine produced the same increase in discharge rate, but was significantly less potent. alpha-Flupenthixol was equipotent with fluphenazine, but beta-flupenthixol, a behaviorally inactive stereoisomer, was without effect. The dose-response curves showed potencies similar to those in several animal behavioral paradigms. In addition, the rank order of potency was identical to that in clinical tests of antipsychotic activity. Three-week chronic administration of fluphenazine resulted in complete blockage of noradrenergic activity, with no further increase in Purkinje neurons spontaneous discharge rate by additional doses of drug. Thus, tolerance does not develop to the noradrenergic blocking effect of the neuroleptic. Taken together, this evidence suggests that antipsychotic neuroleptic drugs block noradrenergic neurotransmission in the CNS.

Changes in noradrenergic neurotransmission in rat cerebellum during aging.

This study compared the electrophysiological effects of locally applied cyclic adenosine-mono-phosphate (N6cAMP) between Purkinje neurons from young (4-month) and old rats (15-months and older). Purkinje neurons from young rats were significantly more sensitive to locally applied norepinephrine and N6cAMP than neurons from old rats. GABA sensitivity between the two groups was unaltered. Our results suggest that the locus of the adrenergic subsensitivity observed in older animals may reside to a large extent at or beyond the level of cAMP generation.

Differential electrophysiological and behavioral responses to optically active derivatives of phencyclidine.

Dextro- and levorotatory isomers of 1-(1-phenylcyclohexyl)-3-methylpiperidine (PCMP) were synthesized. Both isomers inhibited spontaneous cerebellar Purkinje neuron firing when applied locally by pressure ejection. This effect was dose-dependent, with the (+)-isomer about 5--7 times more potent than the (-)-isomer. Both isomers also depressed rotarod performance in mice. Again, the (+)-isomer was about 5 times more potent than the (-)-isomer. Both rotarod performance and Purkinje cells discharge were depressed maximally 10--15 min after i.p. injection of drug. Our results suggest a correlation between behavioral performance and central neuron electrophysiological activity and suggest that the central actions of PCP or its derivatives are probably mediated at one locus, by a stereospecific mechanism.

Electrophysiological evidence for presynaptic actions of phencyclidine on noradrenergic transmission in rat cerebellum.

The actions of the psychotomimetic drug phencyclidine (PCP) were studied using Purkinje neurons in the cerebellum of urethane-anesthetized rats. PCP, applied by micropressure ejection through multibarreled micropipettes, depressed the spontaneous activity of these neurons as recorded by extracellular electrophysiological techniques. This depressant effect was blocked by neuroleptic drugs and lithium, both of which also block the depressant effects of norepinephrine, but not those of gamma-aminobutyric acid. PCP-elicited depressions could not be obtained in rats in which the cerebellar noradrenergic terminals had been lesioned selectively by pretreatment with the neurotoxin 6-hydroxydopamine. However, PCP was still an effective depressant in animals after destruction of non-noradrenergic intrinsic excitatory and inhibitory interneurons which synapse on the Purkinje cell by neonatal X-irradiation. Further treatment of the X-irradiated animal with 6-hydroxy-dopamine resulted in Purkinje neurons which were not responsive to PCP. Administration of magnesium ions, which reduces the release of neurotransmitters from afferent terminals, also blocked the depressant effects of PCP. The results of this study suggest that PCP acts in the cerebellum by a presynaptic mechanism involving the release of norepinephrine from intact, functioning noradrenergic terminals.