Hypolocomotion in rats with chronic liver failure is due to increased glutamate and activation of metabotropic glutamate receptors in substantia nigra.
OBJECTIVE
Patients with hepatic encephalopathy show altered motor function, psychomotor slowing and hypokinesia. The underlying mechanisms remain unclear. This work's aims were: (1) to analyse in rats with chronic liver failure due to portacaval shunt (PCS) the neurochemical alterations in the basal ganglia-thalamus-cortex circuits; (2) to correlate these alterations with those in motor function and (3) to normalize motor activity of PCS rats by pharmacological means.


METHODS
Extracellular neurotransmitters levels were analysed by in vivo brain microdialysis. Motor activity was determined by counting crossings in open field.


RESULTS
Extracellular glutamate is increased in substantia nigra pars reticulata (SNr) of PCS rats. Blocking metabotropic receptor 1 (mGluR1) in SNr normalizes motor activity in PCS rats. In ventro-medial thalamus of PCS rats GABA is increased and it is normalized by blocking mGluR1 in SNr. Blocking mGluR1 in SNr increases and mGluR1 activation reduces glutamate in motor cortex and motor activity.


CONCLUSIONS
Increased extracellular glutamate and activation of mGluR1 in SNr are responsible for reduced motor activity in rats with chronic liver failure. Blocking mGluR1 in SNr normalizes motor activity in PCS rats, suggesting that, under appropriate conditions, similar treatments could be useful to treat the psychomotor slowing and hypokinesia in patients with hepatic encephalopathy.
Cauli
Omar
O
Laboratory of Neurobiology, Centro de Investigacion Principe Felipe, Valencia, Spain.
Llansola
Marta
M
Erceg
Slaven
S
Felipo
Vicente
V
D000818:Animals; D001479:Basal Ganglia / Q000503:physiopathology; D002867:Chromones / Q000494:pharmacology; D002908:Chronic Disease; D018756:GABA Antagonists; D018698:Glutamic Acid / Q000134:cerebrospinal fluid* / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000134:cerebrospinal fluid / Q000209:etiology*; D017093:Liver Failure / Q000150:complications* / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D009043:Motor Activity / Q000502:physiology*; D009044:Motor Cortex / Q000503:physiopathology; D011167:Portacaval Shunt, Surgical / Q000009:adverse effects; D011596:Psychomotor Disorders / Q000209:etiology* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology*; D013378:Substantia Nigra / Q000503:physiopathology*; D020531:Subthalamic Nucleus / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000134:cerebrospinal fluid / Q000378:metabolism
C117789:7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; D002867:Chromones; D018756:GABA Antagonists; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid