The possible mechanism of respiratory depression caused by the selective glycine transporter-1 inhibitor NFPS
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1
EGIS Pharmaceuticals Plc., Hungary
Glycine is an inhibitory neurotransmitter at the strychnine-sensitive glycineA receptors, and a stimulating co-agonist of glutamate at glycineB sites of NMDA receptors. Occupancy of glycineB sites fully depends on the concentration of glycine in the synaptic cleft, which is regulated by glycine transporters 1 and 2 (GlyT1 and GlyT2). Decreased NMDA activity is heavily implicated in the etiology of schizophrenia. Selective inhibition of GlyT1 could promote NMDA activity making this approach feasible for the treatment of schizophrenia. In our previous studies NFPS inhibited the PCP-induced hypermotility in mice, and reversed the PCP-induced changes in EEG power spectrum in conscious rats, suggesting an antipsychotic effect. However, NFPS caused respiratory depression at high dose both in rats and mice. In the current study we used whole-body plethysmography (Buxco) for continuous recording of respiratory parameters for 1 day in NMRI mice treated with NFPS (3 and 10 mg/kg per os; N=6/group). NFPS significantly decreased respiratory frequency at 3 mg/kg but enhanced tidal volume (TV), so minute volume (MV) remained stable. Respiratory changes and brain concentrations of NFPS changed in parallel. Treatment with NFPS at 10 mg/kg caused serious respiratory depression including decreased MV and markedly increased pause interval suggesting the development of airway obstruction. The effects of NFPS at the larger dose started 60 min after treatment, and lasted for more than 24 hours with peak effects observed 6-8 hours after treatment. Administration of strychnine nitrate (0.1 mg/kg sc.) 22 hours after treatment with NFPS normalized respiration for about 1 hour, which duration corresponds to the short plasma kinetics of strychnine. These results support the notion that inhibition of GlyT1 can depress respiration but glycine abundance at glycineA sites seems to be primarily responsible for the respiratory side effect after inducing large increases in brain glycine levels.
Conference:
41st European Brain and Behaviour Society Meeting, Rhodes Island, Greece, 13 Sep - 18 Sep, 2009.
Presentation Type:
Poster Presentation
Topic:
Poster presentations
Citation:
Ágoston
M,
Rónai
É,
Szabó
É,
Kiricsi
P,
Hársing
LG and
Szénási
G
(2009). The possible mechanism of respiratory depression caused by the selective glycine transporter-1 inhibitor NFPS.
Conference Abstract:
41st European Brain and Behaviour Society Meeting.
doi: 10.3389/conf.neuro.08.2009.09.068
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Received:
05 Jun 2009;
Published Online:
05 Jun 2009.
*
Correspondence:
Márta Ágoston, EGIS Pharmaceuticals Plc., Budapest, Hungary, agoston.marta@egis.hu