Ethanol-Induced Cerebellar Ataxia: Cellular and Molecular Mechanisms

被引:31
作者
Dar, M. Saeed [1 ]
机构
[1] E Carolina Univ, Brody Sch Med, Dept Pharmacol & Toxicol, Greenville, NC 27858 USA
关键词
Cerebellar cortex; Ethanol-induced cerebellar ataxia; Cerebellar microinfusion; Rotorod; Cerebellar nitric oxide; Adenosine uptake inhibition; INDUCED MOTOR INCOORDINATION; STRIATAL ADENOSINERGIC MODULATION; NICOTINIC ACETYLCHOLINE-RECEPTORS; EXCITATORY SYNAPTIC-TRANSMISSION; PARALLEL-FIBER; GRANULE CELLS; NITRIC-OXIDE; EXTRACELLULAR ADENOSINE; GABAERGIC TRANSMISSION; PRESYNAPTIC INHIBITION;
D O I
10.1007/s12311-014-0638-4
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The cerebellum is an important target of ethanol toxicity given that cerebellar ataxia is the most consistent physical manifestation of acute ethanol consumption. Despite the significance of the cerebellum in ethanol-induced cerebellar ataxia (EICA), the cellular and molecular mechanisms underlying EICA are incompletely understood. However, two important findings have shed greater light on this phenomenon. First, ethanol-induced blockade of cerebellar adenosine uptake in rodent models points to a role for adenosinergic A(1) modulation of EICA. Second, the consistent observation that intracerebellar administration of nicotine in mice leads to antagonism of EICA provides evidence for a critical role of cerebellar nitric oxide (NO) in EICA reversal. Based on these two important findings, this review discusses the potential molecular events at two key synaptic sites (mossy fiber-granule cell-Golgi cell (MGG synaptic site) and granule cell parallel fiber-Purkinje cell (GPP synaptic site) that lead to EICA. Specifically, ethanol-induced neuronal NOS inhibition at the MGG synaptic site acts as a critical trigger for Golgi cell activation which leads to granule cell deafferentation. Concurrently, ethanol-induced inhibition of adenosine uptake at the GPP synaptic site produces adenosine accumulation which decreases glutamate release and leads to the profound activation of Purkinje cells (PCs). These molecular events at the MGG and GPP synaptic sites are mutually reinforcing and lead to cerebellar dysfunction, decreased excitatory output of deep cerebellar nuclei, and EICA. The critical importance of PCs as the sole output of the cerebellar cortex suggests normalization of PC function could have important therapeutic implications.
引用
收藏
页码:447 / 465
页数:19
相关论文
共 159 条
[1]   Ethanol sensitivity: a central role for CREB transcription regulation in the cerebellum [J].
Acquaah-Mensah, George K. ;
Misra, Vikas ;
Biswal, Shyam .
BMC GENOMICS, 2006, 7 (1)
[2]   Antagonism of ethanol ataxia by intracerebellar nicotine: Possible modulation by mouse cerebellar nitric oxide and cGMP [J].
Al-Rejaie, S ;
Dar, MS .
BRAIN RESEARCH BULLETIN, 2006, 69 (02) :187-196
[3]   Possible role of mouse cerebellar nitric oxide in the behavioral interaction between chronic intracerebellar nicotine and acute ethanol administration: Observation of cross-tolerance [J].
Al-Rejaie, S ;
Dar, MS .
NEUROSCIENCE, 2006, 138 (02) :575-585
[4]   Behavioral interaction between nicotine and ethanol: Possible modulation by mouse cerebellar glutamate [J].
Al-Rejaie, Salim ;
Dar, M. Saeed .
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH, 2006, 30 (07) :1223-1233
[5]  
ALLAN AM, 1986, MOL PHARMACOL, V29, P497
[6]   GAMMA-AMINOBUTYRIC-ACID AND ALCOHOL ACTIONS - NEUROCHEMICAL STUDIES OF LONG SLEEP AND SHORT SLEEP MICE [J].
ALLAN, AM ;
HARRIS, RA .
LIFE SCIENCES, 1986, 39 (21) :2005-2015
[7]   Distribution of mRNA encoding a nitrobenzylthioinosine-insensitive nucleoside transporter (ENT2) in rat brain [J].
Anderson, CM ;
Baldwin, SA ;
Young, JD ;
Cass, CE ;
Parkinson, FE .
MOLECULAR BRAIN RESEARCH, 1999, 70 (02) :293-297
[8]   Distribution of equilibrative, nitrobenzylthioinosine-sensitive nucleoside transporters (ENT1) in brain [J].
Anderson, CM ;
Xiong, W ;
Geiger, JD ;
Young, JD ;
Cass, CE ;
Baldwin, SA ;
Parkinson, FE .
JOURNAL OF NEUROCHEMISTRY, 1999, 73 (02) :867-873
[9]   ADENOSINE INDUCES CL- EFFLUX IN ENDOTHELIAL-CELLS VIA A PERTUSSIS-TOXIN-SENSITIVE G-PROTEIN [J].
ARIMA, M ;
UEDA, S ;
MATSUSHITA, S ;
OZAWA, T ;
YAMAGUCHI, H .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1994, 204 (03) :1143-1149
[10]   Nucleoside transporters: molecular biology and implications for therapeutic development [J].
Baldwin, SA ;
Mackay, JR ;
Cass, CE ;
Young, JD .
MOLECULAR MEDICINE TODAY, 1999, 5 (05) :216-224