Abstract
The aim of this study was to see how nifedipine counters the effects of cocaine on hepatic and brain enzymatic activity in rats and whether it affects urinary excretion of cocaine. Male Wistar rats were divided in four groups of six: control, nifedipine group (5 mg kg-1i.p. a day for five days); cocaine group (15 mg kg-1i.p. a day for five days), and the nifedipine+cocaine group. Twenty-four hours after the last administration, we measured neuronal nitric oxide synthase (nNOS) activity in the brain and cytochrome P450 quantity, ethylmorphine-N-demethylase, and anilinehydroxylase activity in the liver. Urine samples were collected 24 h after the last cocaine and cocaine+nifedipine administration. Urinary cocaine concentration was determined using the GC/MS method.Cocaine administration increased brain nNOS activity by 55 % (p<0.05) in respect to control, which indicates the development of tolerance and dependence. In the combination group, nifedipine decreased the nNOS activity in respect to the cocaine-only group.In the liver, cocaine significantly decreased and nifedipine significantly increased cytochrome P450, ethylmorphine-N-demethylase, and anilinehydroxylase in respect to control. In combination, nifedipine successfully countered cocaine effects on these enzymes.Urine cocaine excretion in the cocaine+nifedipine group significantly dropped (by 35 %) compared to the cocaine-only group.Our results have confirmed the effects of nifedipine against cocaine tolerance and development of dependence, most likely due to metabolic interactions between them.
Highlights
The aim of this study was to see how nifedipine counters the effects of cocaine on hepatic and brain enzymatic activity in rats and whether it affects urinary excretion of cocaine
In our earlier studies [5,6], we have demonstrated that nifedipine, co-administered with morphine, attenuates withdrawal symptoms, which correlate with changes in the activity of neuronal nitric oxide synthase [5]
We investigated the effect of cocaine on brain and liver cytochrome P450 after multiple administration in rats and found that the cumulative intraperitoneal (i.p.) dose of 15 mg kg-1 led to a significant increase in the quantity of cytochrome P450 [12] and in ethylmorphine-N-demethylase (CYP 3A) [13] and anilinehydroxylase (CYP 2E1) activity [14]
Summary
The aim of this study was to see how nifedipine counters the effects of cocaine on hepatic and brain enzymatic activity in rats and whether it affects urinary excretion of cocaine. We investigated the effect of cocaine on brain and liver cytochrome P450 after multiple administration in rats and found that the cumulative intraperitoneal (i.p.) dose of 15 mg kg-1 led to a significant increase in the quantity of cytochrome P450 [12] and in ethylmorphine-N-demethylase (CYP 3A) [13] and anilinehydroxylase (CYP 2E1) activity [14]. These findings suggest that cocaine and nifedipine interact in the brain and liver. The fourth group consisted of control animals, which were treated with saline, involved in the experiment from the very beginning, and housed under the same standard laboratory conditions as the treated animals
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