Nonlinearity and ionization in Xe: experiment-based calibration of a numerical model.

Recently proposed universality of the nonlinear response is put to the test and used to improve a previously designed model for xenon. Utilizing accurate measurements resolving the nonlinear polarization and ionization in time and space, we calibrate the scaling parameters of the model and demonstrate agreement with several experiments spanning the intensity range relevant for applications in nonlinear optics at near-infrared and mid-infrared wavelengths. Applications to other species including small molecules are discussed, suggesting a self-consistent way to calibrate light-matter interaction models.

True versus effective Kerr nonlinear response in optical filamentation.

The optical Kerr effect, and the nonlinear polarization in general, represents an important light-matter interaction governing many regimes encountered in the nonlinear optics. We reason that in the context of optical filamentation one should distinguish the third-order Kerr effect occurring at relatively low light intensities from the effective Kerr nonlinearity relevant to higher intensity. While many properties of filaments can be captured well with a third-order nonlinear polarization model with a nonlinear index chosen somewhat higher than the true nonlinear index operative at low intensities, our comparative simulations indicate that some filamentation aspects carry significant signatures from the higher-order nonlinearity.

Neurotoxic and pharmacologic studies on enantiomers of the N-methylated analog of cathinone (methcathinone): a new drug of abuse.

These studies evaluated neurotoxic and pharmacologic properties of the R(+) and S(-) enantiomers of methcathinone, a psychostimulant drug that has surfaced in the illicit drug market, primarily in the S(-) form. Neurotoxic potential toward brain dopamine (DA) and serotonin (5-HT) neurons was assessed by measuring DA and 5-HT axonal markers and by means of silver degeneration studies; pharmacologic effects were evaluated by measuring locomotor stimulation. Methcathinone produced dose-related neurotoxic and locomotor stimulant effects which were species- and enantiomer-dependent. In mice, although both enantiomers produced toxic effects on DA neurons, the R(+) enantiomer was more potent, and neither enantiomer produced long-term effects on 5-HT neurons. By contrast, in behavioral studies, both enantiomers increased mouse locomotor activity, but the S(-) enantiomer was more potent, which suggests that methcathinone's neurotoxic and locomotor stimulant effects may be separable. Additional studies were done with rats, because mice are often refractory to 5-HT neurotoxicity induced by amphetamines. In the rat, both enantiomers produced toxic effects on DA neurons, only S(-)-methcathinone produced toxic effects on 5-HT neurons, and both enantiomers produced comparable locomotor stimulant effects. Together, these results indicate that: 1) Methcathinone has the potential to damage DA and 5-HT neurons; 2) Methcathinone neurotoxicity is enantiomer and species dependent; 3) Methcathinone's neurotoxic and locomotor stimulant effects are dissociable in mice but not rats; and 4) N-methylation confers 5-HT toxic activity onto cathinone, the N-desmethyl derivative of methcathinone, which is known to lack 5-HT neurotoxic activity.

Effects of dithiothreitol, a sulfhydryl reducing agent, on CA1 pyramidal cells of the guinea pig hippocampus in vitro.

The radioprotectant, dithiothreitol (DTT) has been shown to increase excitability in the hippocampal slice preparation. In the present study, intracellular recording techniques were used to further examine the actions of DTT. Electrophysiological recordings from CA1 pyramidal cells were obtained prior to, during and after DTT exposure. DTT caused a small depolarization without altering membrane resistance. DTT induced spontaneous firing and occasional burst firing in normally silent neurons. These effects were accompanied by a reduction in spike frequency adaptation but no change in the afterhyperpolarization following a train of action potentials. Following DTT exposure, orthodromic stimulation produced multiple firing. Subthreshold excitatory postsynaptic potentials (EPSPs) were significantly prolonged. Isolating the CA1 subfield, attenuated the prolongation of the EPSP by DTT. Recurrent inhibitory postsynaptic potentials were unaffected by DTT. The actions of DTT are likely to result from DTT-induced reduction of disulfide bonds since the reduced form of DTT does not cause a similar hyperexcitability.

Ionizing radiation alters neuronal excitability in hippocampal slices of the guinea pig.

To investigate the effects of ionizing radiation on an isolated neuronal network without complicating systemic factors, slices of hippocampus from the guinea pig were isolated and studied in vitro. Slices were irradiated with a 60Co source and compared to paired, sham-irradiated controls. Electrophysiological activity in the CA 1 population of pyramidal cells was evoked by stimulation of the stratum radiatum. Analysis of the somatic and dendritic responses suggested sites of radiation damage. Orthodromically evoked activity was significantly decreased in slices receiving greater than 75 Gy gamma radiation. The effects were dose and dose-rate dependent. At 20 Gy/min, doses of 50 Gy and greater produced synaptic impairment while doses of 75 Gy and greater also produced postsynaptic damage (i.e., the ability of the synaptic response to generate an action potential). A lower dose rate, 5 Gy/min, reduced the sensitivity of synaptic damage to radiation exposure; synaptic impairment required a dose of 100 Gy or greater at the lower dose rate. In contrast, postsynaptic damage was not sensitive to dose rate. This study demonstrates that ionizing radiation can directly affect the integrated functional activity of neurons.

Dithiothreitol elicits epileptiform activity in CA1 of the guinea pig hippocampal slice.

Dithiothreitol (DTT) is a sulfhydryl reducing agent used as a radioprotectant. Exposure of hippocampal slices for 30 min to 0.5 mM DTT irreversibly increased the orthodromic population spike amplitude, promoted repetitive firing and induced spontaneous epileptiform activity in the CA1 subfield. The same concentration of the oxidized form of DTT did not increase hippocampal excitability. Although the slope of the population synaptic response to afferent stimulation (popPSP) was unchanged by DTT, the duration of the popPSP was prolonged. Recurrent inhibition was unaffected. DTT probably exerts its effects through an irreversible chemical reaction with cellular components. Possible mechanisms of DTT-induced epileptiform activity are discussed.

Aminoglycoside-induced blockade of reflex activity in the isolated spinal cord from the neonatal rat.

The subarachnoid injection of gentamicin into rats causes a transient flaccid paralysis of the hindlimbs lasting 1 to 5 hrs followed by a permanent flaccid paralysis which develops after 24 to 36 hrs. Although the early transient paralysis could be attributed to a pharmacologic blockade of central synaptic transmission, the mechanism of the blockade was not apparent. This study examines the effects of gentamicin and two other aminoglycoside antibiotics, kanamycin and neomycin, on reflex transmission in the isolated, hemisected spinal cord of the neonatal rat and the interaction with calcium. Gentamicin produced a concentration-dependent depression of reflex activity with a 50% inhibitory concentration of 1.6 mM at an external calcium concentration ([Ca2+]o) of 2.5 mM. Reducing the [Ca2+]o by half (i.e., to 1.25 mM) lowered the 50% inhibitory concentration of gentamicin to 0.22 mM. Gentamicin also increased the magnitude of homosynaptic depression of reflex activity in a manner qualitatively similar to that of decreasing [Ca2+]o. Lowering the [Ca2+]o potentiated the effect of gentamicin on homosynaptic depression. The actions of neomycin, kanamycin and magnesium on reflex transmission were nearly identical to those of gentamicin. These findings demonstrate that the early paralysis seen after subarachnoid injection of gentamicin may result from a central blockade of transmission. It is most likely that the site for blockade of reflex activity by gentamicin is presynaptic.

Aminoglycoside-induced biphasic hindlimb paralysis in the rat: a histological and electrophysiological assessment.

The intrathecal injection of gentamicin into a human patient with gram-negative bacterial meningitis as well as its intracisternal injection into rabbits caused spongy-like lesions in the gray matter and tetraplegia in rabbits. To characterize this neurotoxic effect, gentamicin was injected into the subarachnoid space of the lumbar spinal cord of the rat. A biphasic hindlimb paralysis ensued which consisted at first of a transient flaccid paralysis lasting 1 to 5 hr followed by a permanent flaccid paralysis which developed after 24 to 36 hr. The initial paralysis occurred simultaneously with the transient loss of reflex transmission through the cord but in the absence of lesions in the spinal cord or physiological alterations of neuromuscular transmission and muscle contraction. The onset of the second phase of paralysis occurred concomitant with changes in reflex transmission and appearance of lesions. Loss of neuromuscular transmission and appearance of signs of denervation (e.g., depolarization, alteration in action potential parameters, and chemosensitivity) appeared after the second phase of paralysis was established. Both the initial transient and late permanent paralysis originated in the spinal cord. The early transient paralysis appears to be due to a central block of transmission while the late paralysis apparently resulted from neuronal damage. The neurotoxic effects of aminoglycosides on neuronal elements in the spinal cord resulted in secondary effects (signs of denervation) in hindlimb muscles.

Muscarinic receptors in the posterior pituitary gland.

The characteristics of atropine-sensitive binding of l-[3H]-quinuclidinyl benzilate ([3H]-QNB) to membrane suspensions of sheep posterior pituitary indicate that the binding sites represent muscarinic cholinergic receptors. Scatchard plots of 6 saturation experiments showed a single class of binding sites, with an equilibrium dissociation constant of 16 +/- 2 pM and a density equivalent to 1.8 +/- 0.2 pmol/g wet weight of tissue. Kinetic analysis of 2 association and 3 dissociation curves yielded mean association and dissociation rate constants of 3.9 x 10(8) M-1 min-1 and 4.3 x 10(-3) min-1, respectively. The binding had a detailed pharmacology for 12 drugs consistent with muscarinic receptor identification. In rat neurointermediate lobes, superior cervical ganglionectomy had no demonstrable effect on [3H]-QNB binding. The location(s) and functional role(s) of neurohypophyseal muscarinic receptors remain to be elucidated.