An animal model for coexisting tardive dyskinesia and tardive parkinsonism: a glutamate hypothesis for tardive dyskinesia.
There is now ample evidence for long-term malfunctioning within five different brain GABAergic pathways in a monkey model for tardive dyskinesia (TD). Three of these GABA connections (GPe-STN, CP-SNr, and CP-GPi) are chronically downregulated during neuroleptic treatment and after some years they do not seem to regain their normal activity, even when the neuroleptics are discontinued. The persistent downregulation of these three GABA connections, evidenced by depressions of terminal GAD activity and GABA levels, appears to be a conceivable mechanism behind tardive parkinsonism (TP), often reported to coexist with TD in the clinic. The TD patients' well-known lack of awareness of their symptoms may be due to their parkinsonian "sensory neglect." Another two GABA malfunctioning connections were found in our monkey model: SNr-VA/VL and GPi-VA/VL. These pathways are upregulated during chronic neuroleptic treatment, partly due to an elevated glutamate release within subthalamofugal pathways. This chronic glutamatergic hyperactivity may have acted via an excitotoxic mechanism and consequently both GPi and VA/VL had a low synaptic activity in our dyskinetic monkeys, as measured by 2-deoxyglucose uptake, even 4 months after the last neuroleptic dose. It is hypothesized that TD may be due to an excitotoxic lesion of the inhibitory GABAergic VA/VL afferents, while TP has to do with persistent malfunctioning of downregulated SNr and GPi afferents.
Gunne
L M
LM
Department of Psychiatry, Ulleråker, Uppsala University, Sweden.
Andrén
P E
PE
D000818:Animals; D001923:Brain Chemistry; D002428:Cebus; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000150:complications* / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000032:analysis; D005971:Glutamates / Q000502:physiology*; D018698:Glutamic Acid; D010300:Parkinson Disease / Q000150:complications* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D005971:Glutamates; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase