Tobacco Documents Online

TEIE COUNCIL FOR TOBACCO RE5EARCH-U.S.A., INC. Memorandum: To Dr. Harmon McAllister and Staff From: D.H.Ford Re: Site visit with Dr. Abel Lajtha and colleagues at the Nathan Kline Research Institute, Orangeburg, NY, June 20, 1991. Grant entitled "Mechanisms of regionally specific nicotine effects." Goals: To further their'understanding of the mechanisms involved in the regionally hetergeneous effects of nicotine in the CNS and to expand our knowledge of the nACh receptor diversity. Further, the group plans to expand their investigations of the effect of nicotine on the release of other neuro- transmitters. The move to 0rangeburg: During the past year the Center for Neurochemistry has moved from Ward's Island, NYC to become incorporated into the major center for the Nathan Kline Research Institute at the Rockland County Hospital in Orange- burg, NY. The new facilities appear to be excellent and well equipped, and as of this date, all the investigator's individual facilities were conducting on- going investigations. However, the impasse in Albany over funding of the Center has caused major morale problems and concern over the uncertainty of their future. Several Sceintists have left the Nathan Kline Center and several of the older members have taken early retirement. Unfortunately, even if the State does decide to continue funding of the center (about $18 million/year), there is considerable concern that the apparent lack of confidence in Albany for this type of work may have serious consequences in relation to.funding from Washington and other sources (about 1/3 of their budget). As of now, the politicians appear to be controlling the game. Results: A study reaching a conclusion measured the effect of local administration of`nicotine on the release of amino acids in the striatum and frontal cortex in the ratYin vivo by microdialysis. Nicotine stimulated the release of all 9 amino tested at both sites. The percent increase over basal levels was greater for -bo ~ transmitter amino acids than for the non transmitters. In the striatum, 5mM of ac ds produced an increase of 280-450% in Asp,Glu,Tau and GABA and only 10-90$ 7--'~y,Ser,Gn,Thr and Ala. 20mM of nicotine produced higher levels of release. In the frontal cortex, 5mM of nicotine increase the release of Asp, Glu, Tau and GABA by 600-1500%, while non-transmitters were increased much less. Kynurenic acid blocked nicotine's action on Asp, Glu and Tau as well as GABA in the striatum. Mecamylamine blocked the nicotine induced release of Asp and Glu slightly in the striatum, but had no effect on Tau or GABA release. Since it has been established that nicotine blocks GABA receptors in the Substantia nigra, it seems likely that the increase in GABA release induced by nicotine was associated with the 'down-regulation' of the GABA receptors, inducing a compen- satory increase release in transmitter. Whether or not nicotine has any effect on receptors for the other amino acid transmitters is not known and thus is an interesting question.. Other questions relate to effects in more specific areas of the striatum (nucleus accumbens, putamen) which appear to be associated -' specific relationships with dependence & Parkinson's disease respectfully. There is also the possibility that nicotine might have an effect on neuropeptide trans- mitters, since nicotine is known to effect a release of AVP and CRF in the hypothalamus. Another study conducted by Dr. Harsing is determining the effect of Acetylcarnitj on the release of DA and its metabolites in the striatum, again using the micro- dialysis technique. In the rat model, the ligand induced an increased release of DA without effecting levels of metabolites (Dopac and Hovac). Since this induced

2 release is blocked by reserpine, but not by amphetamine, Dr. Harsing concludes that the acetylcarnitine induced DA release is coming from the vesicular transmitter pool at the nerve termin ls. As with many other actions in the CNS and elsewhere, the effect of Ac was Ca+~ dependent. He is now undertaking to determine what occurs when calcium uptake across the neuronal membrane is blocked. Comment: The studies undertaken at the Center for Neurochemistry under the direction of Dr. Lajtha continue to be of considerable interest in determining how nicotine and other transmitter ligands interact with receptors to initiate a number of responses. At this time, one can but hope that Albany will recognize the value of the studies conducted at this site in relation to mental and various degernerative neurologic disorders and permit them to continue their investigations. DHF