SUMMARY1. The effects of carbachol on hippocampal pyramidal neurones were studied in tissue slices in vitro with intracellular microelectrodes, employing current clamp and voltage clamp methods.2. The calcium-dependent potassium current, IAHP' and the voltage-dependent potassium current, IM' were both reversibly blocked by the application of carbachol (5-10 /IM).3. Carbachol (1-10 /SM) induced a steady inward current under circumstances in which both IAHP and IM were inactive. This inward current was sometimes difficult to reverse upon carbachol wash-out, an effect possibly related to receptor desensitization.4. The depolarizing effect of carbachol was reversed by 0-1 /iM-atropine, and exhibited an apparent dissociation coefficient of 1P2 ,UM for carbachol and 18 nm for pirenzepine, indicating that it is mediated by activation of an M1 muscarinic receptor.5. The depolarizing effect or inward current induced by carbachol was completely blocked by the potassium channel blockers caesium, tetraethylammonium and barium.6. The slope of the current-voltage (I-V) plots in carbachol was reduced in the majority of cells, and crossed the control I-V plots at a negative membrane potential. The reversal potentials in carbachol shifted in a positive direction when bathing potassium concentration was increased.7. In a number of cells, the I-V curves in carbachol were parallel to or converged positively with the control I-V curves.8. The effects of carbachol were compared to those of serotonin, which increases a 'pure' potassium conductance. Serotonin (10 /SM) produced an increase in the slope of the I-V curve, with a reversal potential sensitive to changes in bathing potassium concentration. The carbachol reversal potential values were negative to those of serotonin at 5 and 10 mM-potassium. The equilibrium potentials for carbachol and serotonin were equal at 25 mM-potassium. t To whom correspondence should be addressed.$ Laboratory in which work was carried out. D. M. BENSON AND OTHERS9. The negative values of the reversal potential at 5 and 10 mM-potassium and the occurrence of non-crossing I-V characteristics in carbachol could be explained by postulating a second effect of carbachol: namely, a non-specific conductance increase in the dendrites.10. It is concluded that carbachol depolarizes pyramidal cells in the hippocampus by blocking a voltage-insensitive potassium leak channel and does so by activating M1 muscarinic receptors. In addition, carbachol may also activate a second conductance in the dendrites, which could account for the anomalous I-V characteristics sometimes seen in response to carbachol in these cells.

No abstract

The ProModel Optimization Suite is a powerful yet easyto-use simulation tool for modeling all types of manufacturing systems ranging from small job shops and machining cells to large mass production, flexible manufacturing systems, and supply chain systems. ProModel is a Windows based system with an intuitive graphical interface and object-oriented modeling constructs that eliminate the need for programming. It combines the flexibility of a general purpose simulation language with the convenience of a data-driven simulator. In addition, ProModel utilizes an optimization tool called SimRunner that performs sophisticated "what-if' analysis by running automatic factorial design of experiments on the model, providing the best answer possible. This tutorial provides an overview of the ProModel Optimization Suite and presents its modeling, analysis, and optimization capabilities.

Three groups of rats received either kainic acid or vehicle in the ventral pallidum or no operation, and were then tested in photocell activity cages following recovery from surgery. Locomotor activity was measured following injections of saline, nicotine (0.1, 0.2, 0.4 mg/kg) or d-amphetamine (0.5, 1.0 mg/kg). The lesioned rats showed an enhanced locomotor response after injections of nicotine compared with sham operated or unoperated controls. In contrast, both lesioned and control rats showed increased activity after amphetamine; this effect was not influenced by the lesion. Since these lesions are known to produce neurochemical and cellular changes resembling those seen in human Alzheimer's disease, this increased response to nicotine might also be found in Alzheimer's patients and serve as the basis for a diagnostic test.

The ProModelOptimization Suite is a powerful yet