Neuropharmacology: From Receptors to Neuronal Circuits. Research interest has been to understand cellular and molecular mechanisms underlying long-term potentiation (LTP), a form of synaptic plasticity that is considered to be a mechanism of memory encoding. AMPA-type glutamate receptors are increasingly recognized as playing a critical role in LTP in at least two regards. One is that they provide the excitatory drive needed to initiate potentiation; the second and more intriguing aspect is that a change in AMPA receptor kinetics may be the mechanism underlying potentiation itself. Much of my research has focused on studying the mode of operation of AMPA receptors and on elucidating the relationship between their kinetic properties and the time course of synaptic transmission, the rules underlying synaptic plasticity, and the signal processing across neuronal networks. Results from these studies also prompted the development of a novel class of drugs that positively modulate AMPA receptors; these so-called ‘ampakines’ have now been clinical trials for mild cognitive impairment, ADHD, depression and schizophrenia. A more recent research focus is on endogenous signaling mechanisms that modulate excitatory synaptic transmission. We study in particular the role of the novel neuropeptide kiddpeptin (metastin) and its receptor GPR54, as well as the role of related neuropeptides such as Prolactin-Releasing Peptide, in regulating synaptic, cellular and network physiology in the hippocampus, amygdala and thalamus.
Arai AC, Xia Y-F, Rogers G, Lynch G, Kessler M (2002) Benzamide-type AMPA receptor modulators form two subfamilies with distinct modes of action. J. Pharmacol. Exp. Ther. 303: 1075-1085.
Arai AC, Xia Y-F, Kessler M, Phillips D, Granger R, Chamberlin R, Lynch G (2002) Effects of 5'-alkyl-benzothiadiazides on AMPA receptor biophysics and synaptic responses. Mol. Pharmacol. 62: 566-577.
Lin SHS, Arai AC, Espana RA, Berridge CQ, Leslie F, Huguenard JR, Vergnes M, Civelli O. (2002) Prolactin Releasing Peptide (PrRP) promotes waking and suppresses absence seizures in rats. Neuroscience 114: 229-238.
Lin SHS, Arai AC, Wang Z, Nothacker HP, Civelli (2001) The carboxyl terminus of the prolactin releasing peptide (PrRP) receptor interacts with PDZ domain proteins involved in AMPA receptor clustering. Mol. Pharmacol., 60: 916-924.
Arai AC, Kessler M, Rogers G, Lynch G (2000) Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: interactions with cyclothiazide and GYKI 52466. Molecular Pharmacol. 58: 802-813.
Kessler M, Rogers G, Arai AC (2000) The norbornyl moiety of cyclothiazide determines the preference for flip-flop variants of AMPA receptor subunits. Neurosci. Lett. 287: 161-165.
Arai AC (2001) GYKI 52466 has positive modulatory effects on AMPA receptors. Brain Res, 892: 396-400.
Arai, A. and Lynch, G. (1998) AMPA receptor desensitization modulates synaptic responses induced by repetitive afferent stimulation in hippocampal slices.Brain Res. 799: 235-242.
Arai, A. and Lynch G. (1998) The waveform of synaptic transmission at hippocampal synapses is not determined by AMPA receptor desensitization.Brain Res. 799: 230-234.
Arai, A., Kessler, M., Rogers, G., and Lynch, G (1996) Effects of a memory enhancing drug on AMPA receptor currents and synaptic transmission in hippocampus. J. Pharmacol. Exp. Ther. 278: 527-638.
Arai, A., Kessler, M., Ambros-Ingerson, J., Quan, A., Yigiter, E., Rogers, G., and Lynch, G. (1996) Effects of a centrally active benzoylpyrrolidine drug on AMPA receptor kinetics. Neuroscience 75: 573-585.
Arai, A. and Lynch, G. (1992) Factors regulating the magnitude of long-term potentiation induced by theta pattern stimulation. Brain Res. 598: 173-184.