Paul S. Guth

THE PHENOTHIAZINETRANQUILIZERS: BIOCHEMICAL AND BIOPHYSICAL ACTIONS.

Publisher Summary This chapter discusses biochemical and biophysical actions of the phenothiazine tranquilizers. The alteration of membrane permeability is one of the major effects of and constitutes the major mode of action of the phenothiazine tranquilizers. The phenothiazines produce changes in membraneless systems. For example, certain purified enzymes are inhibited by chlorpromazine (CPZ ). The enzyme inhibitions and the alterations in membrane function have a common cause at the molecular level. The chapter discusses the similarity between Wilsons disease and certain actions of the phenothiazines. The qualitative similarity of pharmacodynamic actions among phenothiazine derivatives extending to chemical relatives, such as methylene blue, is discussed. The chapter also discusses the antagonism in some systems and between the phenothiazines and Rauwolfia alkaloids. There is also a discussion regarding how this antagonism underscores the difference in basic action of the two major tranquilizer groups. There is evidence provided that the phenothiazines, in apparent contrast to other drugs, act in the central nervous system at those sites where they concentrate in the brain.

The vestibular hair cells: post-transductional signal processing.

Hair cells in mechanosensory systems transduce mechanical stimuli into biological signals to be presented to and analyzed by the brain. Vestibular hair cells transduce stimuli primarily associated with the organisms orientation and motion in space. When examined superficially it may appear that the hair cells act as passive transducers whereby mechanical stimulation of their hair bundle results in transmitter release at their afferent synapses. In fact, hair cell functions are more complicated, and the mechanical signals are heavily processed even before being encoded in afferent nerve activity. Hair cells are different from one another in morphology, biophysics, transmitter and transmitter receptor complements, not only across different organs (as one might expect), but even in the same organ. This review focuses on hair cell morpho-physiological properties, ionic conductances, neurotransmitters/modulators and their receptors, second messengers and effectors. Special features of hair cell neurotransmission, as the synaptic body and the presence of autoreceptors and local circuits, are also discussed, as is the possibility of a differential modulation of hair cell transmitter release in the resting and mechanically-stimulated states.

The effect of glutamate on the frog semicircular canal.

L-glutamate (Glu) has at least two sites of action in the frog semicircular canal: the hair cell (presynaptic) and the primary afferent nerve fibres (postsynaptic). Glus action on the hair cell results in an increased release of the natural transmitter which is responsible for a substantial increase in the frequency of firing in primary afferents. The presynaptic action of Glu is antagonized by D-alpha-aminoadipate (D alpha AA). Glu produces a long-lasting depolarization on the afferent nerve fibres which does not by itself elicit any afferent discharge of impulses when the release of the natural transmitter is prevented. Glu-induced nerve depolarization is only partially antagonized by D alpha AA. The difficulty of reconciling some of the observations made of the effects of Glu in semicircular canals with its presumed role as an afferent transmitter in this organ is discussed, but this role is not definitely rejected.

Electrophysiological properties and morphology of hair cells isolated from the semicircular canal of the frog

Hair cells isolated from the crista ampullaris of the frog (Rana pipiens) remained viable for up to 5 h and were studied using whole cell voltage- and current clamp recordings. Morphological characteristics of isolated crista hair cells were compared with hair cells studied in situ using light- and electron microscopy. While other labyrinthine hair cells such as mammalian inner and outer hair cells of the cochlea, saccular hair cells of the frog, and cochlear hair cells of the turtle typically have a cylindrical shape, the crista hair cells in the frog are predominantly bulbous, having a thin elongated trunk projecting from a spherical base just large enough to enclose the nucleus. This shape correlates well with the compressed packing configuration of hair cells of the crista ampullaris observed in situ in the histological material. The support cells often failed to separate adjacent hair cells, particularly the apical ends of the hair cells. Maximal cell density on the sensory epithelial ridge appears to be achieved by this arrangement. The mean resting membrane potential (Vz) of isolated crista hair cells was -44.8 mV. Cells with smooth surfaces and apparent opacity had the most negative Vz potentials. As the cells appeared to deteriorate, there was development of transparency and cell surface granulation. Such cells had more positive initial Vz values. Cells with Vz values more positive than -15 mV exhibited a distinct, contoured nucleus. Cells lacking these indicators of deterioration were characterized by input resistances of 1.9 +/- 0.31 G omega and membrane time constants of 13 +/- 2.5 ms. A large complex outwardly rectifying current was identified which was abolished by substituting Cs+ for K+ in the internal solution. The outward K+ current had two major components: a fast tetraethylammonium (TEA)-insensitive, voltage dependent I(A)-type current which showed voltage dependent inactivation; and a TEA sensitive current which had characteristics of a calcium dependent IK(Ca)-type current. Transient changes (20 ms duration) in membrane potential mimicking that which could be produced by the transduction current during cilial displacement potently modulated the I(A) current. Depolarizing current pulses of greater than 63800 pA were required to elicit membrane voltage oscillations. The resulting membrane potential offset of at least 40 mV is well beyond the magnitude of hair cell receptor potentials making it unlikely that these oscillations would play a role in enhancing frequency selectivity.(ABSTRACT TRUNCATED AT 400 WORDS)

Differential modulation of spontaneous and evoked neurotransmitter release from hair cells: Some novel hypotheses

It has been generally accepted that even in the absence of mechanical stimulation of the transductional elements, a resting depolarizing current exists which is ultimately responsible for the spontaneous release of neurotransmitter. Movement of the transductional elements modulates this resting current and thereby the evoked release of neurotransmitter occurs. Recent data from our laboratory and others have led us to question whether the relationship between spontaneous and evoked neurotransmitter release is as simple as stated. Indeed, a variety of experimental manipulations appear to influence the two modes of release differently. Examination of our results and the results of others has led us to four hypotheses: 1. the two modes of neurotransmitter release are processed differently by the hair cells; 2. cyclic AMP is involved in spontaneous but not evoked neurotransmitter release; 3. there is a positive feedback step involving an excitatory amino acid and its receptor on the hair cell in evoked neurotransmitter release and; 4. different pools of calcium are involved according to the mode of release. Accordingly, there may be several biochemical steps between the transductional movement of the stereocilia at the apex of the hair cells and the ultimate release of the neurotransmitter at the base of these cells. Some of these biochemical steps are different depending on whether the mode of release is spontaneous or evoked. These biochemical steps may amplify or at least interact with the biophysical processes previously described in the hair cells.

The hair cell acetylcholine receptors: a synthesis

In this article the evidence concerning the nature of the acetylcholine (ACh) receptors on hair cells is reviewed. A schematic organization of these receptors is offered, based on the evidence as follows. (1) There are two kinds of ACh receptors on hair cells: muscarinic-like and nicotinic-like. (2) The nicotinic-like receptor mediates a hyperpolarizing response to ACh and a consequent reduction in afferent firing. (3) The muscarinic-like receptors mediate both a depolarization and a hyperpolarization of hair cells. (4) The hyperpolarization results in a reduction in afferent firing and (5) the depolarization results in an increase in afferent firing.

Histamine and related substances influence neurotransmission in the semicircular canal

Histamine and other imidazole-containing substances were found to increase ampullar nerve afferent firing rate while both H1 and H2 histamine antagonists effectively inhibited ampullar nerve activity. A specific inhibitor of histidine decarboxylase, the enzyme which catalyses the synthesis of histamine, reduced ampullar nerve firing in a dose-dependent manner. These observations suggest a physiological role for histamine in the inner ear. Maintenance of a response to histamine after de-efferentation of the crista ampullaris supports the hypothesis that the site of action is the hair cell; antagonism of the histamine response by a cholinergic antagonist, atropine, and antagonism of a cholinergically mediated facilitation by the histaminergic antagonist pyrilamine, indicate that the site of action may involve the acetylcholine receptor complex on the crista ampullaris hair cells. The observation that imidazole-containing compounds cause significant effects on semicircular canal neurotransmission provides an important finding with regard to the site of action of antihistamines used for the treatment of vertigo and motion sickness.

An explanatory note.

employment-population ratio returned to its February-March record level of 59.4 percent. 2 The en t i r e July increase in employment took place among adult women, as both white and black women posted strong ga ins . Adult males of both races had about the same employment leve ls as they had in June; teenage employment was also about unchanged. The c iv i l i an labor force grew by 530,000 over the month to 103.1 mi l l ion, 2.4 mil l ion above i t s yea r ea r l i e r l e v e l . Most of t h i s labor force growth occurred before March. At 63.8 percent , the c iv i l i an labor force pa r t i c ipa t ion ra t e was a half point above a year e a r l i e r . Adult women accounted for most of the over-the-year increase in labor force pa r t i c ipa t ion ; the i r pa r t i c ipa t ion ra te in July was a record 50.7 percent . (See table A-l . )

The effect of proteolytic enzymes on the α9-nicotinic receptor-mediated response in isolated frog vestibular hair cells

In frog vestibular organs, efferent neurons exclusively innervate type II hair cells. Acetylcholine, the predominant efferent transmitter, acting on acetylcholine receptors of these hair cells ultimately inhibits and/or facilitates vestibular afferent firing. A coupling between alpha9-nicotinic acetylcholine receptors (alpha9nAChR) and apamin-sensitive, small-conductance, calcium-dependent potassium channels (SK) is thought to drive the inhibition by hyperpolarizing hair cells thereby decreasing their release of transmitter onto afferents. The presence of alpha9nAChR in these cells was demonstrated using pharmacological, immunocytochemical, and molecular biological techniques. However, fewer than 10% of saccular hair cells dissociated using protease VIII, protease XXIV, or papain responded to acetylcholine during perforated-patch clamp recordings. When present, these responses were invariably transient, small in amplitude, and difficult to characterize. In contrast, the majority of saccular hair cells ( approximately 90%) dissociated using trypsin consistently responded to acetylcholine with an increase in outward current and concomitant hyperpolarization. In agreement with alpha9nAChR pharmacology obtained in other hair cells, the acetylcholine response in saccular hair cells was reversibly antagonized by strychnine, curare, tetraethylammonium, and apamin. Brief perfusions with either protease or papain permanently abolished the alpha9-nicotinic response in isolated saccular hair cells. These enzymes when inactivated became completely ineffective at abolishing the alpha9-nicotinic response, suggesting an enzymatic interaction with the alpha9nAChR and/or downstream effector. The mechanism by which these enzymes render saccular hair cells unresponsive to acetylcholine remains unknown, but it most likely involves proteolysis of alpha9nAChR, SK, or both.

Studies in vitro and in vivo of the effects of chlorpromazine on rat liver lysosomes

Abstract Evidence is presented demonstrating a stabilization of the rat liver lysosomal membrane by chlorpromazine both in vivo and in vitro . The lysosomal membrane is labilized in vitro by various incubation manipulations and in vivo by injection of vitamin A or Escherichia coli endotoxin. These data bear implications for some previously advanced hypotheses concerning the phenothiazine mode of action and may explain the protective effect of chlorpromazine in certain shock states.