Cholinergic involvement in mental disorders.
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Biomedical subjects
Publications and source records attributed to K L Davis.
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Lethality of orally administered oxotremorine for female mice required 250 times the dose that was effective for inhibiting methylphenidate-induced stereotypy. A number of lines of evidence indicate that increasing central cholinergic activity may be useful in various psychiatric syndromes and movement disorders. A relatively safe oral cholinomimetic would be clinically useful. Oxotremorine may be such an agent.
Seven men and one woman with primary affective disorder, mania, were given a slow intravenous infusion of physostigmine salicylate. In six patients, mood and thought content changed from mania toward depression as evaluated by either a visual analog mood scale or the Pettersen scale. Two other patients, who were the only predominantly irritable manics in the study, demonstrated little change in their hostility, although one became somewhat depressed. These findings are consistent with earlier reports of suppression of manic symptoms after physostigmine infusion in some but not all patients with mania. The pharmacologic mechanism of physostigmine reversal of manic symptoms may be the direct result of increased cholinergic activity or a result of the effect of increased cholinergic activity on other brain neurotransmitters.
Exretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured repeatedly in 17 normal subjects. The amount of MHPG excreted over a 24-hour period was fairly stable over a period of three consecutive 24-hour samplings, but stability was rather poor over subsequent periods of several weeks, suggesting that execretory patterns are not traits. A normal range of MHPG excretion was estimated to be 900 to 3,500 micrograms/24 hr. This range covers the majority of persons with affective disorders whose excretion patterns have been measured, although comparisons of absolute values between laboratories must be made cautiously. Further, substantial changes within this range may occur in normal subjects with no accompanying change in affect. A slight but definite diurnal pattern of excretion was found, with a peak at the period of 1600 to 1800 hours. No clear relationship to MHPG excretion to state of physical activity, recent consumption of foods or beverages, or prevailing affective state was defined in those subjects living under normal conditions. While MHPG excretion may yet prove useful for categorizing depressed patients and predicting response to drugs, any inferences drawn regarding the pathogenesis of affective disorders must be guarded.
A case of possible organophosphate-induced parkinsonism is presented. The patient was a crop duster with numerous episodes of acute organophosphate intoxication and chronic organophosphate exposure. The etiology of parkinsonism is discussed in terms of a balance hypothesis between cholinergic and dopaminergic neurotransmission in the striatum. A possible relationship between chronic organophosphate exposure and alterations in central cholinergic or dopaminergic activity is suggested. The course of this patient raises the possibility that agricultural workers may be at risk for the late development of parkinsonism.
The hypotheses of relative cholinergic underactivity in Huntington's disease, tardive dyskinesia, mania, and schizophrenia were pharmacologically investigated, using physostigmine and choline chloride. Intravenous physostigmine improved the involuntary movements of all of four patients with tardive dyskinesia and three of six patients with Huntington's disease. Physostigmine infusion also decreased manic symptoms in six of nine patients with mania, but had no beneficial effects in three patients with schizophrenia. Precursorloading with choline chloride may increase brain acetylcholine levels and central cholinergic activity. In patients with movement disorders a transient improvement during physostigmine infusion predicted a positive response to a trial of oral choline chloride. One manic patient may have been improved by choline chloride, however choline chloride did not improve symptoms in four of six schizophrenix patients. Chronic treatment with oral choline chloride increases plasma levels of choline during administration and for approximately 48 hr after discontinuation of treatment. A single 5-g dose of choline chloride also transiently raises plasma choline levels. These results with physostigmine support the hypotheses of cholinergic underactivity in Huntington's disease, tardive dyskinesia, and mania. Agents which might chronically increase cholinergic activity such as choline chloride should be further tested in these disorders.
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Forty-one Telomian, beagle, and F1 hybrid puppies were tested in the presence and absence of a sound-producing stimulus under 2 social conditions, single and paired, at 6, 7, and 8 weeks of age. The sound stimulus definitely produced fearful reactions, as measured by tail carriage, which were not affected by social condition and accompanying differences in distress vocalization. Nor was distress vocalization significantly altered by the sound stimulus. We conclude that sound-induced fear and separation distress are separate and independent affective states. Social condition and the presence of the sound stimulus produced interactive effects at the behavioral level in that paired animals showed longer latencies to contact and maintained greater distances from the sound stimulus.
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Nineteen subjects completed a 12-week double-blind crossover study comparing phenytoin with placebo in the treatment of severe binge eating. In the placebophenytoin sequence the number of binges decreased during phenytoin treatment from both placebo and pretreatment levels. However, in the phenytoin-placebo sequence, not only did phenytoin reduce the number of binges from pretreatment levels, but there was no reversal of this effect during the placebo period. This sequential effect was unexpected and is still unexplained. The mechanism of phenytoin action and the significance of EEG abnormalities found in 7 of the subjects remain uncertain.
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A case report is presented of a patient with remitting tardive dyskinesia coexistent with neuroleptic-induced parkinsonism. The patient received benztropine and physostigmine challenges on successive days and the effects on both syndromes are described. The clinical course of both diseases is discussed in terms of a balance hypothesis between dopaminergic and cholinergic neurotransmission.
Physostigmine was given intravenously to a total dose of 3 mg to 13 subjects; a placebo of 0.25 N saline was given intravenously to 10 other subjects; both groups received 1 mg of methscopolamine bromide subcutaneously preceding the intravenous infusions. A "physostigmine syndrome" consisting of decreased speech, slowed thoughts, mild sedation, expressionless faces, nausea, and decreased spontaneous activity was evident following doses of 1.5 to 2.0 mg of physostigmine. The capacity of short-term memory (STM) as measured by digit span tasks was significantly less for the subjects who received physostigmine than for the subjects who received placebo. No difference was observed between the two groups on tasks of consolidation from STM to long-term memory (LTM). Subjects who received physostigmine did not significantly differ from subjects who received placebo in their mood. However, two subjects in the physostigmine group, and no subjects in the saline group became tearful and depressed.