Anxiety states—experience with an automated group treatment

Fifty patients drawn from a general practice were treated for manifest anxiety using relaxation techniques related to induction of hypnosis. The patients were instructed in groups of four to six with pretaped recordings.Forty-one patients completed the program which consisted of six one-hour recordings. Results indicated that 81% of those patients who subjectively evaluated their responses believed that they had been helped considerably. The impression gained from the study was that this method of treatment has useful application and that further study is warranted to assess more accurately the benefits of this approach to the psychotherapy of anxiety states.     

Multiple conductance states of the acetylcholine receptor channel complex

The acetylcholine-activated channel of vertebrate skeletal muscle, as manifested in cultured, developing cells, is able to adopt more than one conductance state. This paper briefly reviews the evidence for such multiple conductance channels and presents results showing that the amplitude of subconductance states does not depend on agonist size and (or) valence. This seems to rule out the possibility that subconductances occur during partial occlusion of the channel (by agonist molecules) and supports the idea that subconductances represent discrete, allosterically activated channel conformations.     

Photoaffinity labeling of functional states of the nicotinic acetylcholine receptor

The nicotinic acetycholine receptor was subjected to photoaffinity labeling in different conformational and functional states. The photolabel used was the ion-channel blocker [³H]-TPMP⁺. A procedure is described for isolating labeled -polypeptide chains from the receptor complex by preparative SDS-polyacrylamide gel electrophoresis. The photolabel was localized in the primary structure of the -chain. The site of labeling was found to be identical when photoaffinity labeling was performed in the resting, desensitized, or antagonist state, respectively.     

Theoretical conformation of the closed and open states of the acetylcholine receptor channel

We conduct a theoretical analysis to show the recently imaged structure of the acetylcholine receptor pore is in a non-conducting state. A hypothesised open state consistent with a lower resolution image is created and shown to have high conductance.     

Increase in muscarinic acetylcholine receptors in mouse intestine by hexamethonium treatment

The effects of hexamethonium (C6) administration on muscarinic acetylcholine receptors (mACh-R) in the intestine and brain of mice were investigated. Mice were treated with C6 with an osmotic mini-pump (330 mg/kg/day) for one week and then the binding of 3H-quinuclidinylbenzilate (3H-QNB) in the intestine and brain were assayed. This treatment increased the maximum specific binding (Bmax) of 3H-QNB from 160 to 320 fmoles/mg protein in the ileum and from 190 to 340 fmoles/mg protein in the rectum, without affecting the KD values in these regions. On the contrary, C6 treatment did not change the Bmax or KD value in brain tissues. This C6 treatment increased the sensitivity of the contractile response of the intestine to muscarinic agonists, possibly by increasing mACh-R.     

Electric organ polyamines and their effects on the acetylcholine receptor

1. The electric organ of Torpedo nobiliana contained putrescine (PUT), spermidine (SPD), spermine (SPM), and cadaverine (CAD). Traces of acetylated SPD and SPM were occasionaly seen. 2. Upon fractionation of the tissue by differential centrifugation, the polyamines (PA) were found predominantly in the soluble fraction. The postsynaptic membrane fraction, containing a high concentration of acetylcholine receptor (AChR), was proportionally enriched in SPM. The molar ratio of SPM to AChR was approximately two in these membranes. 3. The effect of exogeneous PA on AChR function was studied by two methods: carbamoylcholine (CCh)-dependent 86Rb+ influx into receptor-rich membrane vesicles and [alpha-125I]bungarotoxin (Bgt) binding to the AChR. 4. SPM inhibited both ion influx and the rate of Bgt binding at concentrations above 1 mM, and therefore it appears to act as a competitive antagonist of the AChR. 5. At submicromolar concentrations, and only after preincubation with the receptor-rich membrane, SPM and PUT increased the ion influx by about 20% over control values. 6. Preincubation with 100 nM SPM did not affect the equilibrium binding of iodinated toxin or the rate of toxin binding, and therefore SPM was not uncovering new receptors. 7. By measuring the initial rate of toxin binding after different periods of preincubation with 1 microM CCh, the rate of the slow phase of receptor desensitization was determined. This rate was not changed by 100 nM SPM. 8. Although these results suggest that at low concentrations SPM is a positive modulator of the AChR, the precise mechanism of action is not determined yet.     

The pathophysiology of hyperprolactinemic states and the role of newer ergot compounds in their treatment.

Studies of prolactin secretion in humans have confirmed the concept, derived originally from animal investigations, that prolactin is predominantly controlled by tonic inhibition from the hypothalamus. The locus of action of dopamine and dopaminergic agents such as the ergot alkaloids inhibiting prolactin secretion appears to be primarily at the pituitary level, though a hypothalamic action to increase secretion of prolactin inhibitory factor may also contribute. Prolactin hypersecretion, through any of several possible mechanisms, is frequently but not always found in patients with galactorrhea. Recent studies have shown that hyperprolactinemia is considerably more common than was previously appreciated among patients without galactorrhea. It is present in at least two-thirds of all patients with pituitary tumors and in a significant minority of patients with secondary amenorrhea. Its clinical measurement in these conditions is therefore of considerable diagnostic importance. Whatever the pathophysiology of its production, hyperprolactinemia of all forms is responsive to treatment with the newer ergot alkaloids. The potential use of these agents for therapeutic purposes, particularly in the treatment of infertility, appears to be wider than was originally anticipated.     

Oxidative metabolism and acetylcholine synthesis during acetylpyridine treatment

In order to clarify the mechanisms by which nicotinic acid deficiency impairs brain function, the effects of the nicotinic acid antimetabolite, 3-acetylpyridine, have been investigated on behavior, cerebral oxidative metabolism, and acetylcholine synthesis. In young rats (21–23 days old), 3-acetylpyridine caused dose- and time-related deficits in behavior, as measured by a neurological scale and by tight-rope performance, loss of body weight, and decreased survival. An intermediate dosage decreased cerebral glucose utilization in the inferior olivary nuclei, but increased it in the fastigial, interpositus, red, dentate, vestibular, posterior mamillary, and habenular nuclei. Selective alteration of metabolism was also observed in brain slices from 3-acetylpyridine-treated rats. Although forebrain slices were unaffected, in brainstem slices the synthesis of acetylcholine decreased by 34% with depolarizing (31 mM) concentrations of K⁺ (P<0.05). This dose of 3-acetylpyridine did not deplete the total pool of NAD in any of the 7 brain regions examined. Thus, the nicotinic acid deficiency which results from 3-acetylpyridine treatment appears to be yet another metabolic encephalopathy in which cholinergic systems are impaired.     

Cleistothecial states of Aspergillus and their taxonomic position

Mycopathologia - Twenty one ascosporic species belonging to the genus Aspergillus were studied by using freeze microtome sectioning, light microscopy and scanning electron microscopy. Out of...     

A conformational intermediate between the resting and desensitized states of the nicotinic acetylcholine receptor

The structural changes induced in the nicotinic acetylcholine receptor by two noncompetitive channel blockers, proadifen and phencyclidine, have been studied by infrared difference spectroscopy and using the conformationally sensitive photoreactive noncompetitive antagonist 3-(trifluoromethyl)-3-m-([(125)I]iodophenyl)diazirine. Simultaneous binding of proadifen to both the ion channel pore and neurotransmitter sites leads to the loss of positive markers near 1663, 1655, 1547, 1430, and 1059 cm(-)(1) in carbamylcholine difference spectra, suggesting the stabilization of a desensitized conformation. In contrast, only the positive markers near 1663 and 1059 cm(-)(1) are maximally affected by the binding of either blocker to the ion channel pore suggesting that the conformationally sensitive residues vibrating at these two frequencies are stabilized in a desensitized-like conformation, whereas those vibrating near 1655 and 1430 cm(-)(1) remain in a resting-like state. The vibrations at 1547 cm(-)(1) are coupled to those at both 1663 and 1655 cm(-)(1) and thus exhibit an intermediate pattern of band intensity change. The formation of a structural intermediate between the resting and desensitized states in the presence of phencyclidine is further supported by the pattern of 3-(trifluoromethyl)-3-m-([(125)I]iodophenyl)diazirine photoincorporation. In the presence of phencyclidine, the subunit labeling pattern is distinct from that observed in either the resting or desensitized conformations; specifically, there is a concentration-dependent increase in the extent of photoincorporation into the delta-subunit. Our data show that domains of the nicotinic acetylcholine receptor interconvert between the resting and desensitized states independently of each other and suggest a revised model of channel blocker action that involves both low and high affinity agonist binding conformational intermediates.     

Interaction of 18-methoxycoronaridine with nicotinic acetylcholine receptors in different conformational states

The interaction of 18-methoxycoronaridine (18-MC) with nicotinic acetylcholine receptors (AChRs) was compared with that for ibogaine and phencyclidine (PCP). The results established that 18-MC: (a) is more potent than ibogaine and PCP inhibiting (±)-epibatidine-induced AChR Ca²⁺ influx. The potency of 18-MC is increased after longer pre-incubation periods, which is in agreement with the enhancement of [³H]cytisine binding to resting but activatable Torpedo AChRs, (b) binds to a single site in the Torpedo AChR with high affinity and inhibits [³H]TCP binding to desensitized AChRs in a steric fashion, suggesting the existence of overlapping sites. This is supported by our docking results indicating that 18-MC interacts with a domain located between the serine (position 6′) and valine (position 13′) rings, and (c) inhibits [³H]TCP, [³H]ibogaine, and [³H]18-MC binding to desensitized AChRs with higher affinity compared to resting AChRs. This can be partially attributed to a slower dissociation rate from the desensitized AChR compared to that from the resting AChR. The enthalpic contribution is more important than the entropic contribution when 18-MC binds to the desensitized AChR compared to that for the resting AChR, and vice versa. Ibogaine analogs inhibit the AChR by interacting with a luminal domain that is shared with PCP, and by inducing desensitization.