Rats were trained to discriminate an injection of cocaine, 5.0 mg/kg, from an injection of saline, using a two-lever choice paradigm: one lever was correct after cocaine injection, the other lever was correct after a saline injection. After training, cocaine and methamphetamine were generalized to the cocaine lever, but phenethylamine (PEA) was only partially generalized. Cocaine was injected every 8 hrs, 20.0 mg/kg, and the discriminability of 5.0 mg/kg was tested every other day. Redetermination of the cocaine generalization curve after 6 days of chronic administration showed a shift to the right, from an ED50 of 4.1 mg/kg in the pre-chronic condition to 10.0 mg/kg. Tolerance did not develop to the behavioral effects of cocaine, measured by time to the first reinforcement and response rate. There was cross-tolerance to methamphetamine; however, no evidence for cross-tolerance to PEA was obtained. Following the acquisition of tolerance, chronic administration of cocaine was terminated, and the discriminability of 5.0 mg/kg was tested every other day for loss of tolerance. After 8 days the ED50 returned to 5.0 mg/kg.

The muscarinic agonist carbachol stimulates a rapid increase in ^32Pi incorporation into phosphatidic acid (PA) and phosphatidylinositol (PI) in calcium tolerant myocytes prepared from heart tissue. The density of muscarinic receptors, determined by [^3H]-QNB binding, is greater in the atria than in the ventricles. 250 uM carbachol decreased specific [^3H]-QNB binding to muscarinic receptors on myocyte membranes by fifty percent. Trifluoperazine, also a phospholipase C inhibitor, inhibited the carbachol stimulated increase in ^32Pi incorporation into PA and PI and did not interfere with muscarinic receptor binding. Therefore, isolated canine myocytes provide a suitable model system to further study the muscarinic receptor stimulated phospholipid effect, and its role in mediating biochemical processes and physiological function in the heart.