The major objective of this research will be to determine brain area sites an cholinergic mechanisms important to nicotine's effects on behavior. Previous research conducted in this laboratory has indicated that neurons in the hippocampus (Hp) and midbrain reticular formation (MRF) are somehow involved in the ability nicotine (400 microgram/kg, s.c.) to exert discriminative stimulus (DS) control of behavior. In addition the nicotine- induced DS appeared to have a non-cholinergic component as we were unable to mimic the nicotine DS by increasing brain acetylcholine (ACh) levels via the administration of phsostigmine (250 microgram/kg, s.c.) muscarinic receptors were blocked by atropine. The major direction of the research to be conducted will further define the nature of the nicotine-induce DS. Thus, we will initially study the role of the HP and MRF further using different nicotine training doses (100 and 200 microgram/kg) and will study the generalization of the peripherally-induced DS to each brain site by perfusing a given site with nicotine and other cholinergic agonists using an EMIT perfusion apparatus. This central perfusion approach will be used to evaluate other brain area sites in relation to the peripherally-mediated nicotine DS and will also be utilized to study the effects of nicotinic and muscarinic stimulation on other operant behaviors as well. Thus, in addition to studying the importance of a given brain area site to the DS properties of nicotine we will also attempt to characterize each brain area site as it relates to the effects of nicotinic/muscarinic stimulation and/or inhibition on simple operant behaviors. Such an approach will provide information important to both nicotine's effects on behavior and the importance of specific cholinergic neurons (muscarinic and nicotinic) to behavior. A major goal of this research will be to identify nicotinic sites sensitive to ACh using in vivo behavioral approaches. To date few investigators have demonstrated that ACh-elicited effects can be antagonized by nicotinic receptor antagonist such as mecamylamine; most direct or indirect-elicited ACh effects are antagonized the muscarinic antagonists atropine. This aspect of the research will be studied using the perfusion of brain area sites with ACh analogs such as methacholine with the goal of demonstrating that a given behavioral effect can be selectively antagonized by muscarinic and/or nicotinic antagonists.
