INFLUENCE OF CERTAIN CALCIUM-CHANNEL BLOCKERS ON SOME ASPECTS OF LORAZEPAM-DEPENDENCE IN MICE

The effect of acute and chronic treatments of the calcium-channel bloc kers, isradipine, diltiazem and flunarizine in protecting against lora zepam dependence has been demonstrated in mice. Dependence was induced by twice-daily administration of lorazepam (1 mg kg(-1)) for 10 days, doubling the dose during the next 10 days. Withdrawal symptoms and ch anges in the noradrenaline, dopamine and 5-hydroxytryptamine content o f different regions of the brain were observed after either 24-h withd rawal or flumazenil administration. Isradipine inhibited lorazepam wit hdrawal symptoms, the effect being accompanied in the 24-h withdrawal group by significant decreases in the noradrenaline and dopamine conte nt of the thalamus and hypothalamus and in the noradrenaline content o f the mid-brain. In the flumazenil-treated group isradipine produced s ignificant decreases in mid-brain noradrenaline and dopamine levels an d in the dopamine content of the thalamus and hypothalamus. Diltiazem did not, on the other hand, afford significant protection against lora zepam withdrawal symptoms and did not induce any significant change in the neurotransmitters studied. Flunarizine significantly inhibited lo razepam withdrawal symptoms, an effect accompanied by significant redu ction in noradrenaline and dopamine levels in the thalamus and hypotha lamus. Dopamine was also significantly reduced in the cerebral cortex. Similar effects were produced in the flumazenil-treated group, and th e noradrenaline content was reduced in the medulla, pens and cerebellu m. It was concluded that isradipine and flunarizine might be of value in ameliorating lorazepam withdrawal symptoms.