4.7.9 The Clinical–Molecular Interface: Huntington’s Disease
as a GABAergic DisorderHuntington’s disease or Huntington’s chorea, a neurodegenerative disorder, has its
symptomatic basis in defective central GABA metabolism. Huntington’s is a hereditary
disease that manifests itself in disabling involuntary movements. These movements are
called chorea (from the Greek for dance). Choreiform movements are frequent, brief,
sudden, random twitches that can affect any part of the body. Other movement symp-
toms such as athetosis (slower, writhing movements) and dystonia (abnormal posturing
of body parts) may be superimposed upon the choreiform movements. As the disease
progresses, muscle rigidity appears and eventually a progressive dementia.
This progressive autosomal dominant disorder tends to become clinically apparent in
early adulthood. The gene abnormality is on the short arm of chromosome 4. This gene
abnormality, called a trinucleotide repeat disorder, results in too many glutamine amino
acids being incorporated into a particular protein. The gene product (“huntingtin”) is
cytotoxic to neurons producing neurotransmitter abnormalities that culminate in the
disease manifestations. Although many neurotransmitter abnormalities are implicated,
GABA is a central player.
Both GABA and glutamic acid decarboxylase (GAD), the enzyme central to GABA’s
biosynthesis, are markedly reduced in the brains of people with Huntington’s chorea.
Furthermore, the GABAergic neurons projecting from the caudate nucleus to the sub-
stantia nigra within the brain show lesions in patients with Huntington’s. The caudate
nucleus is a brain region implicated in the coordination of movement. Concomitant
with the reduction in GABAergic inhibition are imbalances in dopamine and acetyl-
choline. The clinical manifestations of the disease therefore seem to evolve from func-
tional underactivity of GABAergic pathways coupled to functional overactivity of
dopaminergic pathways, leading to a symptom complex characterized by concomitant
movement and mentation disorders.
Attempts to treat Huntington’s disease (or at least to alleviate the symptoms) by
enhancing central GABAergic processes have been disappointing at best. Since direct
replacement of the lost inhibitory functions is not possible, the usual treatment of
Huntington’s disease consists of inhibiting excessive dopaminergic activity by the
DA-antagonist neuroleptics haloperidol or chlorpromazine, thus restoring the balance
of GABAergic and dopaminergic functions. Extended use of the DA antagonists is
associated with iatrogenic (i.e., physician-induced) parkinsonism. Moreover, these
pharmacological manipulations are symptomatic at best, sometimes yielding inconsis-
tent, minimally beneficial responses.
4.8 INHIBITORY AMINO ACID NEUROTRANSMITTERS: GLYCINE
Glycine (4.203) is the simplest amino acid and was first identified as a neurotransmit-
ter in 1965. It is found predominantly in the brainstem and spinal cord, but also dif-
fusely throughout the CNS. Like GABA, it is a predominantly inhibitory transmitter,
but acts thus through a vastly different pharmacology. The biosynthetic precursor of
glycine is serine, which is metabolically converted to glycine through a process
catalyzed by the enzyme serine hydroxymethyltransferase. The action of glycine is
NEUROTRANSMITTERS AND THEIR RECEPTORS 281