The goal of this project is to characterize the 5-hydroxytryptamine (5-HT, serotonin) receptors mediating changes in electrophysiological responses in the hippocampal slice preparation in vitro, and to learn the mechanism of action of some psychotropic drugs acting on these receptors. This research project extends our autoradiography and homogenate experiments that revealed differences in 5-HT binding site density in the subfields of the hippocampus, CA1, CA3 and the dentate gyrus. These electrophysiological experiments are designed to relate the information on 5-HT receptors to physiological mechanisms at a cellular level. The first objective is to complete the characterization of the 5-HT receptors mediating changes in extracellular field potential recordings from area CA1 with agents that have been shown to be 5-HT agonists and/or antagonists on receptors in other systems or that compete for 5-HT binding sites. For agonists, complete concentration-response curves will be generated from which EC50, Emax and slope values will be calculated. For antogonists, the dissociation constant will be calculated from Schild plots. These values provide the basis for the rank order of potencies which will be compared to those obtained, in this and other laboratories, from 5-HT binding studies and from studies of 5-HT receptors in other tissues. The second objective is to learn the actions of the novel anxiolytics (buspirone and TVX Q 7821) and the acute and chronic effects of selected antidepressants on these 5-HT receptors. Learning the actions of these drugs on the 5-HT receptors will provide a foundation for future research to elucidate the role of 5-HT and the hippocampus in anxiety states, depressive illnesses, the therapeutic action of the drugs or their side effects. The third and fourth objectives are to define regions that are sensitive to 5-HT, its agonists and antagonists, and the psychotropic drugs, i.e. CA1 vs CA3 vs dentate gyrus, dorsal vs ventral hippocampus, and dendrite vs cell body. This set of experiments will reveal the regional distribution of the 5-HT receptors in the hippocampus. The fourth objective is to measure the effects of the 5-HT agonist and antagonists and drugs on intracellulary recorded membrane characteristics. Intracellular analysis is necessary to determine if these agents elicit similar responses via the same or different cellular effectors, and to reveal if the 5-HT receptors are segregated either on different neurons or on different sites (e.g. soma vs dendrites).
| Beck, S G; Choi, K C; List, T J (1992) Comparison of 5-hydroxytryptamine1A-mediated hyperpolarization in CA1 and CA3 hippocampal pyramidal cells. J Pharmacol Exp Ther 263:350-9 |
| Beck, S G (1992) 5-Hydroxytryptamine increases excitability of CA1 hippocampal pyramidal cells. Synapse 10:334-40 |
| Beck, S G; Clarke, W P; Goldfarb, J (1989) Chronic estrogen effects on 5-hydroxytryptamine-mediated responses in hippocampal pyramidal cells of female rats. Neurosci Lett 106:181-7 |
| Beck, S G; Halloran, P M (1989) Imipramine alters beta-adrenergic, but not serotonergic, mediated responses in rat hippocampal pyramidal cells. Brain Res 504:72-81 |
| Zgombick, J M; Beck, S G; Mahle, C D et al. (1989) Pertussis toxin-sensitive guanine nucleotide-binding protein(S) couple adenosine A1 and 5-hydroxytryptamine1A receptors to the same effector systems in rat hippocampus: biochemical and electrophysiological studies. Mol Pharmacol 35:484-94 |
