M. Barrios et al., ROLE OF L-TYPE CALCIUM CHANNELS ON YOHIMBINE-PRECIPITATED CLONIDINE WITHDRAWAL IN-VIVO AND IN-VITRO, Naunyn-Schmiedeberg's archives of pharmacology, 348(6), 1993, pp. 601-607
This study was designed to elucidate the possible participation of L-t
ype calcium channels in the expression of clonidine-withdrawal precipi
tated by yohimbine in clonidine-dependent animals. Mice implanted for
5 days with osmotic minipumps containing the alpha2-adrenoceptor agoni
st clonidine showed symptoms of a withdrawal syndrome (jerks, headshak
es, defecations and weight loss) when yohimbine, an alpha2-adrenocepto
r antagonist, was injected. Similarly, isolated rat ilea incubated wit
h clonidine in vitro showed a withdrawal contracture when yohimbine wa
s added to the organ bath. The effects of L-type calcium channel block
ers (verapamil and diltiazem) and the stimulant Bay K 8644 on these tw
o different types of withdrawal responses were evaluated. A dose-depen
dent decrease in yohimbine-precipitated clonidine withdrawal in vivo w
as observed when verapamil (10-40 mg/kg, sc. and 120 gg/mouse, i.cv.)
or diltiazem (5 - 20 mg/kg, sc. and 160 mug/mouse, i.c.v.) were admini
stered to mice dependent on clonidine. No effect was found after Bay K
8644 (0.5 - 5 mg/kg, s.c. and 1-5 mug/mouse) was injected under these
conditions. In vitro, both verapamil (0.1-5 muM) and D-CiS-diltiazem
(1 - 50 muM) concentration-dependently reduced the height of the yohim
bine-precipitated withdrawal contracture in rat ileum incubated with c
lonidine. Furthermore, the effect of diltiazem was stereospecific, as
D-cis-diltiazem 10 muM markedly inhibited clonidine withdrawal, wherea
s the same concentration of L-CiS-diltiazem had no effect. In contrast
, the calcium channel stimulant Bay K 8644 (0.1 - 1 muM) increased the
height of the ileum withdrawal contrature. These results confirm that
yohimbine-precipitated clonidine withdrawal can be obtained both in v
ivo 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 cal
cium channel-acting drugs on ethanol-, opiate- and benzodiazepine-with
drawal, suggest that L-type calcium channels play an important role in
the expression of the withdrawal responses to CNS depressant drugs.