RT Journal Article SR Electronic T1 Chronic Elevation of Brain-Derived Neurotrophic Factor by Ampakines JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 297 OP 305 DO 10.1124/jpet.103.053694 VO 307 IS 1 A1 Julie C. Lauterborn A1 Giang S. Truong A1 Michel Baudry A1 Xiaoning Bi A1 Gary Lynch A1 Christine M. Gall YR 2003 UL http://jpet.aspetjournals.org/content/307/1/297.abstract AB The ampakine CX614 positively modulates α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptor-gated currents and increases brain-derived neurotrophic factor (BDNF) expression. In rat hippocampal slice cultures, CX614 rapidly increases BDNF gene expression but with time, mRNA levels fall despite the continued presence of active drug. The present study examined this apparent refractory period and the possibility that spaced ampakine treatments could sustain elevated BDNF protein levels. In cultured hippocampal slices, CX614, a second ampakine CX546, and the cholinergic agonist carbachol each increased BDNF mRNA levels with acute (3-h) treatment. After 4-day pretreatment with CX614, fresh ampakine (CX614 or CX546) did not induce BDNF mRNA, whereas carbachol did. Western blots confirmed that after an extended period of ampakine treatment, AMPA receptor protein levels are indeed reduced, suggesting that with longer treatments receptor down-regulation mediates ampakine insensitivity. Finally, using a “24-h on/24-h off” CX614 treatment protocol, the ampakine refractory state was circumvented, BDNF mRNA was induced with each ampakine application, and elevated BDNF protein levels were maintained through 5 days in vitro. These results suggest that spaced ampakine treatments can be used to sustain elevated neurotrophin levels and to test the utility of this manipulation for neuroprotection by endogenous neurotrophins. The American Society for Pharmacology and Experimental Therapeutics