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THE COUNCIL FOR TOSACCO RESEARCH-U.S.A., INC. TO: Dr. S. C. Sommers and Staff FROM: D. H. Ford RE: Site visit with Dr. F,_._Stranct and colleagues, New York University, Washington Square, New York City, May 23, 1985. Grant No. 1656 R1 entitled, "Prenatal and Postnatal Effects of Nicotine and ACTH Peptides on Neuromuscular Development and Motor Behaviour." Progress in this grant has been excellent after only 6 months of support, as is reflected by the recent submission of a manuscript for publication in "Peptides" entitled "ACTH Peptides as Organizers of Neuronal Patterns in Development: Maturation of the Rat Neuromuscular Junction as Seen by Scanning Electron Microscopy," R. Frischer et al. Two abstracts for presentations at national meetings have also been submitted. All acknowledge CTR support. Results: Pups from mother rats given nicotine during pregnancy were found to weigh slightly more than pups from saline treated mothers. Question: Since nicotine is known to increase the release of ADH in adult rats, could it have an effect on the development of the supraoptic neurons, which release this hormone, in the young rats, which could possibly have caused an increased re- tention of body water and thus, weight gain? Muscle weights in the nicotine- treated group were slightly lower than normal, which would seem to have to be explained differently. In pups from nicotine-treated mothers there was an increase in the number of motor units in the extensor digitorum longus (EDL) muscle as compared to pups from-saline-treated control dams. The EDL muscle is the representative muscle studieJ. Contraction duration was shortened following prenatal and early postnatal exposure to nicotine in 14-15 day old rat pups. Relaxation time was shortened as well. Further, there seemed to be an increase in the number of nicotinic cholinergic neuromuscular receptors, thus paralleling what Lajtha observed in the CNS following prenatal exposure to nicotine (an increase in nicotine binding receptors). Since the EDL muscle under observation is initially a slow muscle which undergoes diff6Yentiation into a fast muscle, the shortened twitch and . relaxation times suggest an accelerated maturation. Other changes which occurred in relation to tetanic contractions also suggest that maturation rate is accelerated by prenatal nicotine exposure. ACTH peptide.4-9 and 4-10 accelerate the morphological changes occuring during maturation as observed by scanning electron microscopy. This was re- flected by an increase in the folds of theend.plate and an increase in end plate size, plus an increased occurrence of several other structural units at the end plate. This also occurred after prenatal and early postnatal ex- posure to nicotine. The question now is, does nicotine effect the neuro- muscular junction maturation directly or through AY- increase in ACTH release, such as described to occur in adult rats given nicotine (Fuxe)? Strand and her co-workers are planning studies to address this question.

Site Visit - Dr. F. Strand Grant #1656 R1 - P. 2 Behavioural studies indicate that nicotine has altered activity in the young 14 -15-day-old pups (increased restlessness and a decrease in ambulation). Other activity studies will be followed as the rats become older to evaluate grooming, rearing and other forms of behaviour. These behavioural changes are believed to be due to central effects of nicotine on the neurons of the CNS rather than an effect at the neuromuscular ; junction. Further, these behavioural effects all appeared to be due to prenatal exposure to nicotine, since postnatal exposure had little or no effect. Comment: This study is a basic investigation of the effect of nicotine on neuromuscular physiology in relation to maturation of the neuromuscular junction. The effects of nicotine may be mediated at the neuromuscular junction or be indirect and depend on nicotine's ability to increase the release of ACTH via stimulation of the hypothalamic neurons. (Note: It is not known if nicotine has any effect on the differentiation of the hypo- thalamic neurons involved in ACTH release. This is being currently evaluated by Fuxe). Further studies by Strand should answer this question. This study continues to be relevant to CTR's interest in the Maternal/Fetal Smoking problem. DF 5/30/85 W