Positive allosteric modulators of the α7 nicotinic acetylcholine receptor potentiate glutamate release in the prefrontal cortex of freely-moving rats

Bortz, David M.; Upton, Brian A.; Mikkelsen, Jens D.; Bruno, John P.

doi:10.1016/j.neuropharm.2016.08.033

Cited by 9 publications

(15 citation statements)

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“…the MEA; Bortz et al, 2014; Bortz et al, 2016). The glutamate signal measured by this method has been referred to as phasic based on its high temporal resolution and faster kinetics (Burmeister & Gerhardt, 2001; Bortz et al, 2014; Parikh et al, 2008; Pocivavsek et al, SFN abstract 2014).…”

Section: 0 Discussionmentioning

confidence: 99%

“…The extended latency (40-120 sec) between the NAcSh stimulation by NMDA and the increase in the glutamate signal in the PFC was unexpected, as trans-synaptic activation of the presumed neural circuit (NAcSh to basal forebrain to PFC), which is believed to mediate this effect (Zaborszky and Cullinan, 1992; Zmarowski et al, 2007; St Peters et al, 2011; Bortz et al, 2016), would take only msec to occur. The delayed release of prefrontal glutamate following intra-NAcSh NMDA therefore suggests a more complex mechanism.…”

Section: 0 Discussionmentioning

confidence: 99%

“…Measured by either MEA or microdialysis, this effect is secondary to an initial activation of local α7nAChRs (Bortz et al, 2016; Valentini et al, SFN abstract 2016), which are located on both neurons (Wang et al, 2006; Livingstone et al, 2010) and astrocytes (Duffy et al, 2011). Both cell types participate in the regulation of glutamatergic neurotransmission in the PFC (Wang et al, 2006; Vollbrecht et al, 2014), however, the relative roles of neuronal and astrocytic mechanisms remain to be determined.…”

Section: 0 Discussionmentioning

confidence: 99%

Section: 0 Introductionmentioning

confidence: 99%

“…To this end, we utilized an experimental paradigm in which the release of glutamate was evoked by an infusion of NMDA into the shell region of the nucleus accumbens (NAcSh; Bortz et al, 2014; Bortz et al, 2016). This procedure results in an increase in cortical acetylcholine (ACh) release from basal forebrain and, subsequently, a local α7nAChR-dependent increase in prefrontal glutamate levels (Bortz et al, 2016). Notably, stimulation of the NAcSh in this manner facilitates the filtering of distractors during a sustained attention task in rodents, indicating that prefrontal glutamate, evoked under these conditions, has a positive impact on cognitive performance (St Peters et al, 2011).…”

Section: 0 Introductionmentioning

confidence: 99%

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Oral administration of a specific kynurenic acid synthesis (KAT II) inhibitor attenuates evoked glutamate release in rat prefrontal cortex

Bortz

Schwarcz

et al. 2017

Neuropharmacology

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Cognitive deficits represent core symptoms in schizophrenia (SZ) and predict patient outcome; however, they remain poorly treated by current antipsychotic drugs. Elevated levels of the endogenous alpha7 nicotinic receptor negative allosteric modulator and NMDA receptor antagonist, kynurenic acid (KYNA), are commonly seen in post-mortem tissue and cerebrospinal fluid of patients with SZ. When acutely or chronically elevated in rodents, KYNA produces cognitive deficits similar to those seen in the disease, making down-regulation of KYNA, via inhibition of kynurenine aminotransferase II (KAT II), a potential treatment strategy. We determined, in adult Wistar rats, if the orally available KAT II inhibitor BFF816 a) prevents KYNA elevations in prefrontal cortex (PFC) after a systemic kynurenine injection and b) reverses the kynurenine-induced attenuation of evoked prefrontal glutamate release caused by stimulation of the nucleus accumbens shell (NAcSh). Systemic injection of kynurenine (25 or 100 mg/kg, i.p.) increased KYNA levels in PFC (532% and 1104% of baseline, respectively). NMDA infusions (0.15 μg/0.5 μL) into NAcSh raised prefrontal glutamate levels more than 30-fold above baseline. The two doses of kynurenine reduced evoked glutamate release in PFC (by 43% and 94%, respectively, compared to NMDA alone). Co-administration of BFF816 (30 or 100 mg/kg, p.o.) with kynurenine (25 mg/kg, i.p.) attenuated the neosynthesis of KYNA and dose-dependently restored NMDA-stimulated glutamate release in the PFC (16% and 69%, respectively). The ability to prevent KYNA neosynthesis and to normalize evoked glutamate release in PFC justifies further development of KAT II inhibitors for the treatment of cognitive deficits in SZ.

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