The antitussive cloperastine improves breathing abnormalities in a Rett Syndrome mouse model by blocking presynaptic GIRK channels and enhancing GABA release
NEUROPHARMACOLOGY
Authors: Johnson, Christopher M.; Cui, Ningren; Xing, Hao; Wu, Yang; Jiang, Chun
Abstract
Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder caused mainly by mutations in the MECP2 gene. One of the major RTT features is breathing dysfunction characterized by periodic hypo- and hyperventilation. The breathing disorders are associated with increased brainstem neuronal excitability, which can be alleviated with GABA agonists. Since neuronal hypoexcitability occurs in the forebrain of RTT models, it is necessary to find pharmacological agents with a relative preference to brainstem neurons. Here we show evidence for the improvement of breathing disorders of Mecp2-disrupted mice with the brainstem-acting drug cloperastine (CPS) and its likely neuronal targets. CPS is an over-the-counter cough medicine that has an inhibitory effect on brainstem neuronal networks. In Mecp2-disrupted mice, CPS (30 mg/kg, i.p.) decreased the occurrence of apneas/h and breath frequency variation. GIRK currents expressed in HEK cells were inhibited by CPS with IC50 1 mu M. Whole-cell patch clamp recordings in locus coeruleus (LC) and dorsal segmental nucleus (DTN) neurons revealed an overall inhibitory effect of CPS (10 mu M) on neuronal firing activity. Such an effect was reversed by the GABA(A) receptor antagonist bicuculline (20 mu M). Voltage clamp studies showed that CPS increased GABAergic sIPSCs in LC cells, which was blocked by the GABA(B) receptor antagonist phaclofen. Functional GABAergic connections of DTN neurons with LC cells were shown. These results suggest that CPS improves breathing dysfunction in Mecp2-null mice by blocking GIRK channels in synaptic terminals and enhancing GABA release.
The effects of music therapy on amino acid neurotransmitters: Insights from an animal study
PHYSIOLOGY & BEHAVIOR
Authors: Hao, Juanjuan; Jiang, Keyu; Wu, Min; Yu, Jianer; Zhang, Xin
Abstract
Background: This study aimed to explore the neurobiological effects of "Chinese Traditional Five-Elements Music Therapy" on rats and to determine its effects on amino acid neurotransmitter levels, the excitatory/inhibitory(E/I) balance and the Glu-Gln cycle. Methods: Male Wistar rats were assigned at random to the experimental groups (Gong/powerful; Shang/sad; Jue/gentle; Zhi/joyful; Yu/serene music group) and the control group(n=8/group).The experimental groups were exposed daily to music(2 hours per day; mild sound pressure levels, between 50 and 60 dB) for 28 consecutive days. Finally, we hypothesized concentrations of Glu and GABA to match the music types and measured additionally Asp, Gly, Gln, and Glu/GABA ratio in striatum by UPLC-3QMS. Result: Effects in the predicted direction were observed for Gong (Glu +, GABA -); Shang (Glu -; GABA +); Jue (Glu 0; GABA 0); and Zhi (Glu +; GABA -); but not Yu music (Glu + contrary to hypothesis; GABA + as hypothesized)." In addition, significant difference in Gln levels were also present in the zhi, Gong and Yu music groups compared to the controls. Conclusion: Our study showed that different melodic music produced different effects on amino acid neurotransmitter levels. "Chinese Traditional Five-Elements Music Therapy" affected the amino acid neurotransmitter levels, the E/I balance and the Glu-Gln cycle in the striatum of rats, which may reflect altered glutamatergic and GABAergic system.