Localized infusions of the partial alpha 7 nicotinic receptor agonist SSR180711 evoke rapid and transient increases in prefrontal glutamate release

Abstract

The ability of local infusions of the alpha 7 nicotinic acetycholine receptor (α7 nAChR) partial agonist SSR180711 to evoke glutamate release in prefrontal cortex was determined in awake rats using a microelectrode array. Infusions of SSR180711 produced dose-dependent increases in glutamate levels. The lower dose (1.0μg in 0.4μL) evoked a rapid rise (∼1.0s) in glutamate (1.41±0.30μM above baseline). The higher dose (5.0μg) produced a similarly rapid, yet larger increase (3.51±0.36μM above baseline). After each dose, the glutamate signal was cleared to basal levels within 7-18s. SSR180711-evoked glutamate was mediated by the α7 nAChR as co-infusion of the selective α7 nAChR antagonist α-bungarotoxin (10.0μM)+SSR1808711 (5.0μg) reduced the effect of 5.0μg alone by 87% (2.62 vs. 0.35μM). Finally, the clearance of the SSR180711 (5.0μg)-evoked glutamate was bidirectionally affected by drugs that inhibited (threo-beta-benzyl-oxy-aspartate (TβOA), 100.0μM) or facilitated (ceftriaxalone, 200mg/kg, i.p.) excitatory amino acid transporters. TβOA slowed both the clearance (s) and rate of clearance (μM/s) by 10-fold, particularly at the mid-late stages of the return to baseline. Ceftriaxone reduced the magnitude of the SSR180711-evoked increase by 65%. These results demonstrate that pharmacological stimulation of α7 nAChRs within the prefrontal cortex is sufficient to evoke rapid yet transient increases in glutamate levels. Such increases may underlie the cognition-enhancing effects of the drug in animals; further justifying studies on the use of α7 nAChR-positive modulators in treating cognition-impairing disorders in humans.

Keywords: (+)-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine maleate; AA; ACh; ANOVA; BSA; CEF; DA; EAAT; Gluox; MEA; MK-801; PFC; SZ; T(x); Tc(x); TβOA; acetylcholine; alpha 7; analysis of variance; bovine serum albumin; ceftriaxone; cognition; dopamine (3-hydroxytyramine); excitatory amino acid transporter; glutamate; glutamate oxidase; l-ascorbic acid; m-PD; m-Phenylenediamine dihydrochloride; microelectrode array; nAChR; nicotinic acetycholine receptor; prefrontal cortex; rat; schizophrenia; the clearance rate during x time period; the time to clear x% of the signal from the maximum amplitude; threo-beta-benzyl-oxy-aspartate; α-bungarotoxin; α7; αBGT.