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Rate of L-type calcium channels on yohimbine-precipitated clonidine withdrawal in vivo and in vitro

Naunyn-Schmiedeberg's Archives of Pharmacology volume 348, pages 601–607 (1993)Cite this article

Summary

This study was designed to elucidate the possible participation of L-type calcium channels in the expression of clonidine-withdrawal precipitated by yohimbine in clonidine-dependent animals. Mice implanted for 5 days with osmotic minipumps containing the α2-adrenoceptor agonist clonidine showed symptoms of a withdrawal syndrome (jerks, headshakes, defecations and weight loss) when yohimbine, an α2-adrenoceptor antagonist, was injected. Similarly, isolated rat ilea incubated with clonidine in vitro showed a withdrawal contracture when yohimbine was added to the organ bath. The effects of L-type calcium channel blockers (verapamil and diltiazem) and the stimulant Bay K 8644 on these two different types of withdrawal responses were evaluated. A dose-dependent decrease in yohimbine-precipitated clonidine withdrawal in vivo was observed when verapamil (10–40 mg/kg, s.c. and 120 μg/mouse, i.cv.) or diltiazem (5–20 mg/kg, s.c. and 160 μg/mouse, i.c.v.) were administered to mice dependent on clonidine. No effect was found after Bay K 8644 (0.5–5 mg/kg, s.c. and 1–5 μg/mouse) was injected under these conditions. In vitro, both verapamil (0.1–5 μM) and d-cis-diltiazem (1–50 μM) concentration-dependently reduced the height of the yohimbine-precipitated withdrawal contracture in rat ileum incubated with clonidine. Furthermore, the effect of diltiazem was stereospecific, as d-cis-diltiazem 10 μM markedly inhibited clonidine withdrawal, whereas the same concentration of l-cis-diltiazem had no effect. In contrast, the calcium channel stimulant Bay K 8644 (0.1–1 μM) increased the height of the ileum withdrawal contrature. These results confirm that yohimbine-precipitated clonidine withdrawal can be obtained both in vivo and in vitro, and suggest that the expression of these abstinence responses involves activation of L- type calcium channels. The present results, together with those of previous studies of the effects of calcium channel-acting drugs on ethanol-, opiate- and benzodiazepine-withdrawal, suggest that L-type calcium channels play an important role in the expression of the withdrawal responses to CNS depressant drugs.

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  1. Department of Pharmacology and Neurosciences Institute, Medical School, University of Granada, E-18012, Granada, Spain

    Manuel Barrios, Ignacio Robles & José M. Baeyens

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  1. Manuel Barrios
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  2. Ignacio Robles
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  3. José M. Baeyens
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Correspondence to: J. M. Baeyens at the above address

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Barrios, M., Robles, I. & Baeyens, J.M. Rate of L-type calcium channels on yohimbine-precipitated clonidine withdrawal in vivo and in vitro. Naunyn-Schmiedeberg's Arch Pharmacol 348, 601–607 (1993). https://doi.org/10.1007/BF00167236

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  • DOI: https://doi.org/10.1007/BF00167236

Key words

  • Verapamil
  • Diltiazem
  • Bay K 8644
  • Calcium channels
  • Clonidine withdrawal
  • Yohimbine