title: Continuous administration of a selective alpha7 nicotinic partial agonist, DMXBA, improves sensory inhibition without causing tachyphylaxis or receptor upregulation in DBA/2 mice.
abstract: Stimulation of nicotinic receptors, specifically the alpha7 subtype, improves sensory inhibition and cognitive function in receptor deficient humans and rodents. However, stimulation with a full agonist, such as nicotine, produces rapid tachyphylaxis of the P20N40-measured sensory inhibition process. 3-(2,4-dimethoxybenzylidine) anabaseine (DMXBA, also GTS-21) selectively activates the alpha7 nicotinic receptor, and in acute administration studies, has been shown to improve deficient sensory inhibition in both humans and rodents with repeated dosing. Unlike nicotine, this partial agonist acted without inducing tachyphylaxis. Here, we assessed the ability of DMXBA to improve sensory inhibition in DBA/2 mice after 7 days of continuous administration via a subcutaneously implanted osmotic minipump. When assessed on day 8, mice receiving saline showed the characteristic deficient sensory inhibition seen with untreated DBA/2 mice. The 25- and 50-mg/ml infusion concentrations of DMXBA, but not the 100-mg/ml, produced significantly improved sensory inhibition in the mice, exclusively through a decrease in test amplitude. No concentration significantly upregulated hippocampal alpha7 receptor levels. DMXBA levels in the brain were higher than plasma at 2 of the 3 concentrations infused. These data suggest that continuous exposure to DMXBA does not significantly affect the underlying responsiveness of the sensory inhibition pathway to this partial agonist, nor cause receptor upregulation, at these relatively low brain concentrations. The ability of DMXBA to maintain its effectiveness during constant administration conditions may be due to an ability to activate alpha7 receptors at low concentrations, and consequently low fractional occupancy of the five possible binding sites on this homomeric receptor.
authors.affiliation: Medical Research Service, Veterans Affairs Medical Center, Denver, CO, USA. Karen.Stevens@ucdenver.ed
authors.forename: Karen E
authors.initials: KE
authors.lastname: Stevens
authors.forename: Brandon
authors.initials: B
authors.lastname: Cornejo
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Adams
authors.forename: Lijun
authors.initials: L
authors.lastname: Zheng
authors.forename: Joan
authors.initials: J
authors.lastname: Yonchek
authors.forename: Keith L
authors.initials: KL
authors.lastname: Hoffman
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.forename: William R
authors.initials: WR
authors.lastname: Kem
mesh_terms: D000818:Animals; D001597:Benzylidene Compounds / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018678:Cholinergic Agents / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008811:Mice, Inbred DBA; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012677:Sensation / Q000187:drug effects / Q000502:physiology*; D013618:Tachyphylaxis / Q000502:physiology*; D015854:Up-Regulation; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001597:Benzylidene Compounds; D018678:Cholinergic Agents; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C088936:3-(2,4-dimethoxybenzylidene)anabaseine