Effect of chlorpromazine, imipramine and lithium on MAO-A and MAO-B activity in rat brain mitochondria

Drugs with efficacy in psychiatric disorders affect the function of central neurotransmitter amines, which are inactivated primarily by monoamine oxidase (MAO). Effect of these drugs on the two types of MAO (MAO-A and MAO-B) has been studied in rat brain. The result showed that chlorpromazine (CPZ) and imipramine (IMI) at concentrations of 1x10(-2), 5x10(-3) and 2.5x10(-3) M inhibited rat brain mitochondrial MAO-A activity in vitro by 82, 50, 39 and 86, 74, 38 %, respectively. CPZ at concentrations of 5x10(-3), 2.5x10(-3), 1x10(-3) M inhibited rat brain mitochondrial MAO-B activity in vitro by 83, 55, 39 %, respectively, while IMI at concentrations of 5x10(-4), 2.5x10(-4), 1x10(-4) M inhibited the in vitro enzyme activity by 43, 35, 21 %, respectively. Lithium at concentration of 5x10(-3) M could not either inhibit MAO-A or MAO-B in the mitochondrial fraction of rat brain.     

A comparison of the effects of chlorpromazine, 7-hydroxychlorpromazine and chlorpromazine sulfoxide on the activity of central dopaminergic neurons

Using single unit recording techniques, chlorpromazine and two of its naturally occuring metabolites in man, 7-hydroxychlorpromazine and chlorpromazine sulfoxide, were tested for their ability to reverse amphetamine-induced depression of rat dopaminergic ventral tegmental neurons (A10). Small equivalent doses of chlorpromazine and 7-hydroxychlorpromazine were found to readily reverse amphetamine-induced depression of these cells. Chlorpromazine sulfoxide was found to be 50–100 times less potent in this regard. Previous findings have demonstrated that only phenothiazines with antipsychotic properties reverse amphetamine-induced depression of A10 neurons. Thus, we would predict that 7-hydroxychlorpromazine would have anti-psychotic properties whereas chlorpromazine sulfoxide would not. A preliminary study by Sakalis et al., suggests that plasma levels of chlorpromazine and 7-hydroxychlorpromazine are possibly correlated with the therapeutic effects of chlorpromazine in schizophrenia. Chlorpromazine sulfoxide levels, on the other hand, are reported to be high in chlorpromazine treated non-responders. Thus there is a direct parallel between predictions of antipsychotic efficacy based on our test model and the possible clinical importance of these chlorpromazine metabolites. Both findings suggest that 7-hydroxychlopromazine might be a good antipsychotic agent.     

Effect of pentobarbital on unit activity of reticular and ventrolateral thalamic nuclei in cats

Responses of single units in the reticular and ventrolateral thalamic nuclei were studied in acute experiments on curarized cats before and after intravenous injection of small doses (0.5–15 mg/kg) of pentobarbital, with simultaneous derivation of activity by two electrodes. After injection of pentobarbital, unit activity in the reticular nucleus consisted of high-frequency grouped (52.5% of 40 neurons) or continuous (30%) discharges as long as barbiturate spindles were present in the electrocorticogram. Activity of only four neurons (10%) of this nucleus was inhibited during the presence of spindles. In all other neurons of the reticular nucleus (7.5%) the character of discharges was unchanged after injection of pentobarbital. The appearance of grouped discharges, repeated several times (66.5% of 40 neurons), or blocking of activity (30%) throughout the period of spindle recording was observed in neurons of the ventrolateral nucleus. The remaining neurons of that nucleus (3.5%) did not respond to intravenous pentobarbital. The appearance of high-frequency discharges in neurons of the reticular nucleus while spindles were recorded coincided with a period of silence in neurons of the ventrolateral nucleus (58.5% of 34 pairs of neurons). High-frequency electrical stimulation of the mesencephalic reticular formation led to asynchronous activation of neurons of the ventrolateral nucleus (82%) and inhibition of unit activity in the reticular nucleus (88%).I. S. Beritashvili Institute of Physiology, Academy of Sciences of the Georgian SSR, Tbilisi. Translated from Neirofiziologiya, Vol. 14, No. 5, pp. 517–524, September–October, 1982.     

Effect of pentobarbital dependence on adenylate cyclase activity and calmodulin levels in rat cerebral cortex

The effect of calcium (Ca2+) on the adenylate cyclase activity and calmodulin level of cerebral cortex was determined in pentobarbital dependent rats and age matched controls. Female Sprague-Dawley rats were made dependent and maintained on pentobarbital by eating a mixture of pentobarbital and rat chow (350 mg pentobarbital/30 g chow). Ca2+ activated then inhibited the adenylate cyclase activity associated with a 20,000 X g particulate fraction from pentobarbital dependent and age matched control rats. The values for one-half maximal stimulation and inhibition by Ca2+ did not differ significantly in either cortical preparation. However, the ability of Ca2+ to activate adenylate cyclase from pentobarbital dependent animals was significantly decreased (p less than 0.05) when compared to control animals. Pentobarbital (10(-4) - 10(-3) added to particulate fractions from naive control rats did not alter the ability of Ca2+ to activate adenylate cyclase. The calmodulin levels in the particulate fraction from pentobarbital dependent animals (30.2 +/- 6.7 ng calmodulin/mg protein) did not differ significantly when compared to control (33.0 +/- 4.7 ng/mg). By contrast, the calmodulin levels (37.9 +/- 5.9 ng/mg) in the 20,000 X g supernatant from cortex of pentobarbital dependent animals was significantly greater than the level in the supernatant from control animals (28.6 +/- 2.6 ng/mg). The ability of forskolin, dopamine, GTP or forskolin plus GTP (all at a concentration of 100 microM) to activate adenylate cyclase was significantly decreased in particulate preparations from pentobarbital dependent animals. In summary, our data show that alterations in calmodulin levels and a decreased responsivity of adenylate cyclase occur in animals physically dependent on pentobarbital.