Drug-induced Movement Disorders
Pathophysiology
The pathophysiology of DIMD is not clearly elucidated, yet is complex and multifactorial, likely related to a combination of genetic predisposition, dopaminergic system hypersensitivity in the basal ganglia, decreased functional reserve, and over activation of the cholinergic system.
Postsynaptic Dopamine Receptor Hypersensitivity Theory
The chronic blocking of presynaptic dopamine receptors enhances excitatory glutamatergic neurotransmission. The neurotoxic stress in the striatum, which is caused by increasing glutamate release and extracellular glutamate levels at corticostriatal terminals, ultimately destroys the output neurons, leading to dopaminergic hypersensitivity. Although this theory has been the long-held hypothesis as the cause of DIMD, it cannot completely account for the clinical findings, primarily because it does explain the fact that DIMD are not a universal phenomenon among people exposed to DRBDs.
Neurotoxicity Theory
Because the use of DRBDs increases the turnover of neurotransmitters and because the basal ganglia are particularly vulnerable to the effects of membrane lipid peroxidation, this premise proposes that DIMD are caused by the neurotoxic effects of free radicals that are created as a byproduct of catecholamine metabolism. The support for this theory comes primarily from the treatment of oral buccal lingual dyskinesias with the use of branched-chain amino acids in studies in humans and antioxidants in animal studies.
Dopamine-GABA Hypothesis
In this theory, which does not disregard the fact that dopamine receptors become increasingly sensitive to the effects of DRBD, the interaction between the dopamine and γ-aminobutyric acid (GABA) neurons plays a greater role, likely accounting for the different, yet simultaneous, effects of the DRBD. Dopamine has both inhibitory and excitatory effects on GABA neurons, determined by the location of the dopamine receptors in the brain. Unfortunately, this theory has not been able to be converted into a treatment paradigm because of the toxicity of the agents.
