The goal is to characterize actions of serotonin (5-HT) in the CNS and determine the role of 5-HT in the etiology and treatment of pathological states such as depression. The award of the RSDA would allow the Principal Investigator (P.I.) to learn new electrophysiological and neurochemical techniques and to continue collaborations that extend the scope of the research project beyond electrophysiology.
Specific Aim 1 is to identify the 5-HT receptors and cellular mechanisms underlying the fast transient increase in cell excitability elicited by 5-HT. Both extracellular and intracellular recordings will be used to determine if the excitation is due to: a) presynaptic modulation of neurotransmitter release; b) disinhibition; c) potentiation of glutamate responses or; d) amplification of a voltage dependent cation conductance.
Specific Aim 2 is to determine the G-protein or G-protein submits that link the 5-HT(1A) receptor to potassium channels. To accomplish this, the P.I. will learn whole cell voltage clamp procedures in dissociated cells in the laboratory of Dr. Traverse Slater. Dr. Ravi Iyengar will provide the purified G-proteins and G-protein subunits.
Specific Aim 3 is to determine if activation of 5-HT receptors can augment beta-adrenergic and/or cholinergic receptor mediated responses recorded intracellularly, since receptors that elicit similar cellular responses often share signal transduction mechanisms. Dr. George Battaglia will conduct analogous biochemical experiments to determine if 5-HT augments beta-adrenergic stimulation of adenylyl cyclase activity. Also, the modulation of the beta-adrenergic receptors by 5-HT will be probed following lesions of the 5-HT input to the hippocampus. Dr. Stanley Lorens will teach the P.I. this technique and how to quantitate 5-HT levels by HPLC.
Specific Aim 4 is to determine if distinct classes of antidepressant drugs differentially alter 5-HT and beta-adrenergic receptor- mediated responses. An alteration in the actions of a neurotransmitter by antidepressants may also affect the actions of other neurotransmitters due to shared effector mechanisms. Learning the actions of the drugs on the 5-HT and beta-adrenergic receptors will help elucidate the role of 5-HT, norepinephrine and the hippocampus in depressive illnesses.
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