Effects on Brain Biogenic Amines of Repeated Treatments with Calcium Antagonists.

Abstract

Discrete brain sections were obtained from rats once or repeatedly (once a day for 5 days) given i.p. nifedipine, verapamil or diltiazem at doses ranging from 5 to 20 mg/kg. The biogenic amines and metabolites in the hypothalamus, brain stem, hippocampus, striatum, cortex and thalamus-midbrain were determined by high performance liquid chromatography with electrochemical detection. The drug-induced changes, displaying regional specificity and differences according to the various com pounds, suggested that: (a) serotonergic systems were activated, especially in fasted rats or after repeated treatment; (b) the dopaminergic system of the striatum was inhibited by nifedipine which did reduce the HVA levels and the HVA/DA, as well as the DOPAC/DA, ratio. These effects disappeared after repeated treatment. It was also speculated that the data obtained could be of great interest in view of the possi ble use of calcium antagonists to treat disorders of the central nervous system.

Effects of Nimodipine on Biogenic Amines in Discrete Brain Areas

“…This discrepancy could be ex plained with a 'nimodipine-fasting' interac tion because, in the same conditions, the 'ni fedipine-fasting' interaction had previously been observed [4], In particular, since food ingestion is known to increase the splanchnic blood flow, the hepatic extraction and metab olism of the drugs could be decreased in fasted rats [19], On the other hand. 8 h food deprivation, in comparison with 2 h, had been found [4] to reduce the 5-HIAA/5-HT ratio in all the brain areas because of little changes in amine and metabolite content. The reduced working load of the serotonergic sys tem could potentiate the drug-induced effect.…”

“…In any case nimodipine, when administered to rats fasted for 8 h. enhanced the levels of 5-HIAA and the activation signs of the serotonergic system in all the brain areas, except for the cortex. These fact [4] suggested that central effects of calcium antagonists could greatly differ ac cording to the functional state of CNS at the time of their administration. In this regard, some authors [2] had argued that these drugs could have an effect on neuronal functions, but only subsequent to certain forms of VSCC activation.…”

“…These recepto-time [2], However, in previous studies, we showed that nifedipine, verapamil and diltiazem, once [3] or repeatedly [4] administered to rats, were able to both activate serotonergic and inhibit dopaminergic systems. These ef fects displayed regional specificity and differ ences according to the various compounds, likewise because of their different selectivity [5][6][7] or specificity [8.…”

“…9] for the various brain area VSCC. However, especially after re peated administration of nifedipine [4], the greatest effects were observed in the hippo campus and in the thalamus-midbrain (i.e. in brain areas with a high density of [3H]-nitrendipine binding sites [10]).…”

Differences in effects of Ca 2+ channel antagonists on dopamine metabolism in the limbic and extrapyramidal dopaminergic structures

“…Several authors suggest that Ca 2+ entry blockade inhibits rather than activates the dopaminergic systems. Most of the studies, however, were carried out using a single injection and were limited to the striatum, a structure that in the present study was shown to be unaffected by Ca 2+ channel antagonists (Gaggi and Gianni 1991;Kato et al 1992;Brouard et al 1994). On the other hand, Tsuda et al (1992Tsuda et al ( , 1993 have described a significant increase in [ 3 H]dopamine basal and stimulation-evoked release from rat striatal slices exposed to verapamil and diltiazem, while nicardipine produced no effect.…”