Tobacco Documents Online

THE COUNCIL FOR TOBACCO RESLARCH-U.S.A., INC. 900 TIIIRI) AVENUE NEN' YORK. N. Y. 10022 Memorandum To: Dr. J. F. Glenn and Staff From: D.H.Ford Re: Site visit with Dr. Fleur Strand, NYU Washington Square, Jan. 30, 1989. Grant No.1656AR2 entitled "Long term effects of prenatal and postnatal administration of nicotine or ACTH 4-10 on selected adult parameters: neruomuscular maturation, reproduc- tion and sexual behaviour." Goals: To determine if the accelerated neuromuscular development induced by nicotine or ACTH 4-10 following pre- or postnatal administration is maintained in the adult. To determine if nicotine or ACTH 4-10 influence the devel- opment of the neuroendocrine axis. To determine if the effects of these two ligands are mediated through changes in neurotransmitter systems in the developing CNS. To determine if the changes evoked by nicotine are mediated by the release of ACTH. Results: The considerable results obtained by Dr. Strand and her students are more than adequately covered in her recent progress report No. 3 in her new Continuation application No. 1656B: I will only briefly cover what she has presented in detail. Summary of progress: Project reported by Mr. K. Rose. Mr Rose presented a mass of data showing that prenatal treatment with either nicotine or ACTH 4-10 accelerated neuromuscular maturation as evidenced by amplitide of contraction, ztime for relaxation, development of tetanus and contraction duration. The nicotine-treated mothers received 0.5 mg/kg/day throughout pregnancy. The response of the EDL muscle was measured on the 14th day after birth. What has occurred is that by this age, the maturation of the neuromuscular junction has achieved what is essentially an adult state, as there is no further change in maturation after 14 days, when the para- meters are at an adult level. About 1 year ago Dr. Strand and Mr. Rose felt that the effect of nicotine might be effected by the induction of a release of ACTH. A recent study just completed questions this hypythesis. When the gestation period is broken down into sub-periods, it turns out that the time when nicotine is most effective is duration gestation days 3-8, at least a week before there is any evidence of pituitary activity. Since lymph- oid elements are now known to synthesize and release many of the pituitary hormones, including ACTH and are known to possess nicotine receptors in adult animals, one may wonder if there are the beginnings of any lymphoid cells in what is about the first trimester of the rat which might be capable of synthesizing and releasing ACTH derived fragments. This is certainly a testable question. As a side study, they noted that nicotine at the dose used during pregnancy increased metabolic activity in the EDL muscle 100%. Mr. Rose will be presenting this material at his thesis defense in May 1989.

2 Results presented byDr. A. Segarra (PhD. awarded June, 1988). Dr. Segarra, like Mr. Rose presented a veritable mountain of data on the effect of prenatal and /or postnatal exposure to nicotine (0.25 mg/kg/day during pregnancy or to pups after birth) on sexual differentiation in Sprague-Dawley rats. Prenatal treatment of dams with ACTH 1-24 or with nicotine decreased sexual behaviour in males at adulthood, suggesting demasculinization (no significant differences in testosterone serum levels). Sex differences in salt preference were abolished, males shifting more to the female pattern. Further, ambulation and open field activity (rearing, grooming, defecating) in males tended to become more female in nature. There was also a decrease in the anogenital distance in the males treated with nicotine prenatally, all suggesting a feminization of the male progeny. Eye opening, as index of brain maturation was accelerated with both pre and post- natal nicotine and ACTH 1-24 administration. With the females, both nicotine and ACTH delayed vaginal opening, nicotine causing the longest delays. Estrous cycle lengths were shortened for both groups. These changes were accompanied by a significant decrease in preoptic area DA and DOPAC and 5-HT after nicotine prenatal treatment,.while ACTH- 1-24 increased these amine levels. Prolactin levels were decreased by nicotine. Sr. Segarra concludes that the data suggests that nicotine probably induces its effects on the maturation of behaviour via eff'ects on neuroendocrine function, while ACTH appears more likely to induce its effect mainly via other CNS pathways. Both, however, appear to act as neuromodualtors influencing sexual differentiation of the brain, having a major effect on the male progeny.. Dr. Segarra is pursuing these studies further to evaluate changes obsezved in the female as well as to follow up some of the changes observed in males (Further studies on catechol amine levels in other brain regions). Comment: Dr. Strand's program over the past 5 years has demon- strated that nicotine has effects on rieuromuscular maturation similar to those of ACTH 4-10, but which are clearly not mediated by a pituitary release of the peptide. The possibility of a lymph- oid origin for the peptide is an interesting possibility. There were also effects on males suggesting feminization, while the female progeny also present evidence of disruption in neuroendo- crine function. This remains a very interesting study of the effects of pre- and postnatal nicotine and ACTH on CNS maturation. So far, the result have raised many interesting questions, par- ticularly in the female which remain to be investigated (ie., significantly 6nlarged ovaries which may contain unruptured mature follicles) and additional investigations on neuroendocrine function in both sexes. DHF