Garthe, William||Mittler, Sidney||Feyerherm, Harvey A.
M.S. (Master of Science)
Department of Biological Sciences
To test the postulate that chlorpromazine acts by inhibiting the binding of calcium to phospholipids within neuronal membranes, lanthanum chloride, which does inhibit the binding of calcium to phospholipids and axonal membrane, was run parallel to chlorpromazine in a series of four experiments: (1) an isolated myelin membrane preparation; (2) a conditioned avoidance response test; (3) an activity test; and (4) a diuretic test. If the postulate is true, the activity of these two compounds in these tests should be the same. A myelin fraction, freed of calcium by EDTA, was obtained through differential centrifugation from homogenized whole rat brain. The preparation was found to be contaminated, with a large number of the whole nuclei remaining. For each test, 1 ml of myelin-nuclei preparation, containing 6.5 mg protein, was mixed for one hour with 18,000 dpm Ca⁴⁵Cl and either 1 mM lanthanum chloride or 1 mM chlorpromazine at various pH levels. Control tubes were run without compound. Lanthanum chloride, at pH levels 5.4 through 9.4, and chlorpromazine, at pH levels 5.4 and 6.4, completely inhibit the binding of Ca⁴⁵. The conditioned avoidance response test consisted either of 100 or 200 trials in a two-way shuttle box. The conditioned stimuli were light and tone, the unconditioned stimulus footshock. Lanthanum chloride, at 1000 mg/kg ip, and chlorpromazine, at 3 mg/kg ip, decrease the number of avoids and increase the latency of response to conditioned stimuli without affecting latency of response to unconditioned stimulus. Natural activity was measured using a circular runway containing six photoelectric beams that when broken added a count to a cumulative counter. Each rat was observed for 20 minutes. Lanthanum chloride, at doses of 50, 100 and 200 mg/kg ip, and chlorpromazine, at 2, 4 and 8 mg/kg ip, significantly reduce total activity. For the diuretic test, groups of five rats were given 6 ml of 0.86% saline one-half hour before they were injected ip with either chlorpromazine, lanthanum chloride or saline. They were then immediately placed into a metabolism cage', which separated feces from urine, and urine collected for the next four hours. Lanthanum chloride, at 100 and 200 mg/kg, and chlorpromazine, at 8 and 16 mg/kg, dramatically reduce both concentration and total output of urine sodium and potassium. Lanthanum chloride, at 200mg/kg and chlorpromazine, at 2 and 8 mg/kg, increase urine concentration of calcium. Lanthanum chloride, at 200 mg/kg, and chlorpromazine, at 1 mg/kg, reduce urine volume. At 8 and 16 mg/kg, however, chlorpromazine increases urine volume. From these results it must be concluded that inhibition of calcium binding to neuronal membranes cannot be ruled out as a possible mechanism of action for chlorpromazine's CNS effects.
Hurley, Michael J., "A comparison of some pharmacological effects of lanthanum chloride with chlorpromazine in the rat" (1972). Graduate Research Theses & Dissertations. 188.
vii, 47 pages
Northern Illinois University
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