Neurotransmitter receptor alterations in hepatic encephalopathy: A review

Hepatic encephalopathy (HE), a complex neuropsychiatric syndrome with symptoms ranging from subtle neuropsychiatric and motor disturbances to deep coma and death, is thought to be a clinical manifestation of a low-grade cerebral oedema associated with an altered neuron-astrocyte crosstalk and exacerbated by hyperammonemia and oxidative stress. These events are tightly coupled with alterations in neurotransmission, either in a causal or a causative manner, resulting in a net increase of inhibitory neurotransmission. Therefore, research focussed mainly on the potential role of γ-aminobutyric acid-(GABA) or glutamate-mediated neurotransmission in the pathophysiology of HE, though roles for other neurotransmitters (e.g. serotonin, dopamine, adenosine and histamine) or for neurosteroids or endogenous benzodiazepines have also been suggested. Therefore, we here review HE-related alterations in neurotransmission, focussing on changes in the levels of classical neurotransmitters and the neuromodulator adenosine, variations in the activity and/or concentrations of key enzymes involved in their metabolism, as well as in the densities of their receptors.

► Hepatic encephalopathy associated with a net increase in inhibitory neurotransmission.
► Glutamatergic system mediates ammonia-induced toxicity.
► Mechanisms involved in “increased GABAergic tone” not yet fully understood.
► Monoaminergic alterations underlie concomitant neurological and psychiatric symptoms.
► Adenosine receptors altered in early and late stages of hepatic encephalopathy.