Effect of Benzodiazepines Administered to Pregnant and Lactating Rats n the Reproductive Functions of their Offspring

Abstract

Newly born and developing individuals show essential differences when compared with the adult ones. They pass numerous anatomical and physiological changes to adapt themselves to the condition of extrauterine life as quickly as possible. In view of the differences in the physiological and morphological maturity of internal organs, receptors, membrane barriers, biochemical processes, ability of protein building etc., young individuals react differently than the adults on exposure to environmental factors, including the drugs. Central nervous system (CNS) constitutes one of important organs whose maturation and adaptation to peer environment is crucial to adequate functioning. Earlier investigations indicate that at birth, mammals including man, shows high functional immaturity in the CNS. In addition, the “blood-brain” barrier, which prevents numerous substances from entering the CNS, is more permeable for a variety of substances. For these a reasons a variety of drugs if administered during pregnancy, lactation and even in the postnatal period may exert differential bearing upon the development and behavior of adult. Neuro- and psychoactive drugs are used particularly frequently, sometimes for many years or even throughout life and enable mentally ill subjects to return to the society and normal life. However, they are required to be continuously on these medications. Therefore, the chances of their use exist during pregnancy and lactation. Up to now, the literature provides only a few reports as the basis for consideration is casual or, and all long-term applicants of neuro-and psychoactive drugs by pregnant women influences the development of CNS of their offspring. Previous investigation mainly dealt with the possible teratogenic action of mentioned substances. Benzodiazepines are the most common and well described anxiolytics. It exerts strong anti-depressant effect by easily passing through the placenta and the “blood-brain” barrier. It enters the milk of the mother. Fetuses and babies showed lower ability to metabolize and eliminate the anxiolytics than the adults. In view of these considerations the purpose of this work was to examine whether benzodiazepines administered to pregnant and lactating rat in doses that are therapeutic and even supra-therapeutic (in humans) affects the development, differentiation and functions of the CNS and then of their progeny by evaluating with behavioral, endocrine and corresponding structural changes. Our works demonstrates that exposure to long-acting benzodiazepine, diazepam and a short-acting benzodiazepine, clobazam from gestation day 15 through to postnatal life of the offspring up until day 5 to one group and day 20 to another group did not influence pregnancy outcome in any respect. Physical development, growth and the timing of sexual maturation also remained significantly unaffected by the two benzodiazepine agent. Sexual behavior in male and female rats was the first parameter during their development that registered a change which significantly differed. The most significant change noted was by the male progeny a result of diazepam exposure. This caused an increase in mounting and intromission frequencies as compared to controls. Accompanied changes I circulating testosterone concentrations and structural changes in the testes indicate a potential role for the testicular basis, beside modulation of central catecholaminergic mechanism/s in the behavioral alterations. Unlike diazepam, clobazam caused a marked reduction in mounting frequency but plasma and testicular testosterone concentrations did not correlate with the behavioral changes. The female progeny of both the benzodiazepines exposure caused a marked reduction in the lordotic quotient along with the corresponding endocrine changes in the ovarian tissue of the diazepam exposed group only. Unlike males, the basis for this consistency in effect of both the benzodiazepines derivatives observed in females is hard to speculate. Effects having been more convincing in the diazepam exposed male progeny led to investigate further the basis of enhanced sexual activity and testosterone concentrations in this group. For more insights into observation of perinatally exposed diazepam-induced enhanced copulatory activity a supplementary project was also developed to evaluate whether the observed effects are mediated by peripheral or central benzodiazepine receptors. The study revealed that central benzodiazepine agonists retained the increase effect on male sexual activity which was noy blocked by specific benzodiazepine antagonists. Further experiments showed that peripheral but not central antagonists do not block effects of diazepam on male sexual activity. A dose-dependent effect of a selective peripheral benzodiazepines agonists, on basal and hCG-stimulants androgen production by testicular interstitial cell suspensions was also revealed. It may be inferred that benzodiazepine has a direct effect on Leydig cells. Beyond the approved protocol of the study, catecholamine context and turnover in the specified CNS region, the hypothalamus, the amygdala and the cortex were also examined in order to assess neurochemical involvement of central mechanism/s. Elevated norepinephrine content and turnover in the hypothalamus outlined the involvement of central catecholaminergic basis for the enhanced sexual activity in the male progeny. 96