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).

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.

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.

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.

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.

Electrophysiological actions of neurotensin in rat cerebellum.

The electrophysiological actions of neurotensin (NT) and its analog D-Arg9-NT were studied in rat cerebellar Purkinje neurons. NT applied by pressure ejection was a potent depressant of Purkinje (P) neuron firing. In contrast, iontophoretically applied NT was a weak depressant. Pressure-ejected D-Arg9-NT, which is largely inactive in peripheral systems, had little effect on P neurons. The depressant effects of pressure-ejected NT were blocked by intraperitoneally administered haloperidol, iontophoretically applied magnesium or 6-OHDA pretreatment. After such treatments, locally applied NT evoked only excitations. The results of this study suggest that NT, when applied by pressure ejection, produces two effects on the Purkinje neuron. The potent inhibitory effects of locally applied NT appear to result from release of the inhibitory transmitter, norepinephrine from locus coeruleus-derived afferents. We postulate that the excitations, which appear when postsynaptic effects of norepinephrine are antagonized or release is reduced, may be the direct result of NT action at the postsynaptic P neuron membrane.

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.

Age-related electrophysiological changes in rat cerebellum.

The spontaneous discharge of cerebellar Purkinje neurons was studied in 3-, 12-, 15-, and 20-month-old rats. Fluphenazine and haloperidol administered intraperitoneally produced a dose-dependent increase in the spontaneous discharge in 3-month-old animals, but were ineffective in 12-, 15- and 20-month-old rats. Intraperitoneal administration of amphetamine resulted in a dose-dependent decrease in spontaneous Purkinje neuron discharge in 3-month-old rats without affecting neurons from the older animals. Discrution of norepinephrine afferents by 6-OHDA or reserpine increased spontaneous discharge rate in 3-month-old animals. This treatment did not affect Purkinje neurons in 12-, 15- and 20-month-old rats. Local application of drug with the same multibarreled electrode revealed that neurons from older rats were significantly less sensitive to inhibition by norepinephrine than were Purkinje neurons from 3-month-old animals. Similar application of GABA did not reveal a differential sensitivity. For locus coeruleus activation to produce 50% inhibition in Purkinje neuron discharge, significantly higher stimulation currents were required in 15-month-old rats than in 3-month-old animals. Our results suggest a decreased postsynaptic sensitivity to norepinephrine in 12-, 15- and 20-month-old rats as compared to 3-month-old animals.

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.

Candidate mechanisms for inhibition of neurotransmitter release by narcotic analgesics and endorphins.

Some neurones are endowed with receptors for endorphins and narcotic analgesics. Activation of these receptors results in a depression of the release of transmitter per impulse. It is currently believed that narcotic analgesics and endorphins depress the stimulus-induced influx of calcium (Ca2+) into the terminal and thereby modify the amount of the ion which triggers the release of the transmitter from intracellular stores. The influx of Ca2+ is largely governed by the Ca2+ "channel", which opens during depolarization of the neuronal membrane either after an action potential (electrical stimulus) or in the presence of high extracellular potassium (K+) or nicotinic stimulants (chemical stimulus). The evoked influx of Ca2+ can be affected by a direct action on the Ca2+ "channel" or by primary actions on other membrane properties that subsequently regulate the Ca2+ "channel". In many tissues narcotic analgesics and endorphins fail to inhibit transmitter release. This may be accounted for by the possibility that either such neurones lack presynaptic opiate receptors or that the function of existing receptors remains latent under the experimental conditions employed. Currently, there is insufficient evidence for endorphins physiologically modulating transmitter release.

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.

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 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.

Some mechanisms underlying actions of ketamine on electromechanical coupling in skeletal muscle.

The effects on excitation contraction coupling (ECC) of ketamine (a dissociative general anesthetic) were investigated using the sartorius muscle of the frog. Extracellular studies revealed that ketamine depressed action potential production in a concentration-dependent manner. Ketamine decreased both the conduction velocity and the compound action potential while concomitantly increasing the threshold current. Intracellular studies showed that ketamine caused a slight non-significant decrease in the membrane potential and also decreased the threshold potential (mechanical threshold). Ketamine (1.5 X 10(-4) M and 3.0 X 10(-4) M) initially potentiated and then blocked the twitch response elicited by direct muscle stimulation. Both of these effects were statistically different from control values. These findings suggest that ketamine alters action potential production in frog skeletal muscle. This property of ketamine contributes in part to the disruption of ECC observed with this drug. The results suggest the ketamine probably interferes with calcium binding, its release and/or its fluxes which may contribute to the intial potentiation and subsequent depression of twitch tension.

Effects of acute and chronic amphetamine treatment on Purkinje neuron discharge in rat cerebellum.

The spontaneous discharge of the cerebellar Purkinje neuron in urethane-anesthetized rats is used as an indicator of central noradrenergic activity during the acute and chronic administration of d-amphetamine. Acute parenteral administration of amphetamine causes a dose-dependent slowing of the discharge. Since this effect is not seen in animals in which the catecholaminergic innervation has been selectively removed by previous treatment with 6-hydroxydopamine, it is hypothesized that the slowing is caused by the increased release and/or blocked reuptake of endogenous norepinephrine. Acute administration of amphetamine also increases the response of the Purkinje neurons to its afferent inputs: the excitatory climbing fibers and the inhibitory basket and stellate cells. These effects of amphetamine on spontaneous and evoked activity are similar to the effects of microiontophoretically applied norepinephrine. After daily treatment for 5 days with amphetamine, there is no change in the response to acutely administered amphetamine. After 21 days of treatment, discharge rates before and after acute administration are both significantly lower than in acutely treated controls. Administration of the beta adrenergic antagonist propranolol returns the discharge rate to control levels in these chronically treated animals. Chronic amphetamine treatment may thus cause an increase in response to endogenous norepinephrine, both when spontaneously released and when released after acute amphetamine administration.

An investigation of the activity of opiate drug receptors located on frog skeletal muscle fibre membrane.

Extracellular and intracellular microelectrode studies were conducted to test the actions and interactions of opiate agonists, antagonists, and procaine on action potentials in frog sartorius muscles. Extracellular studies showed that morphine, methadone, propoxyphene, and procaine all depressed action potential production. Low concentrations of naloxone or naltrexone antagonized the excitability depression produced by the three opiate agonists but not the depression produced by procaine. Intracellular studies revealed that certain concentrations of the opiate agonists produced a biphasic decline in the stimulus-induced increase in sodium conductance (gNa). Naloxone or naltrexone antagonized only the second phase of this decline. These results show that part of the excitability depression produced by opiate agonists is due to an action on opiate drug receptors.