Abstract
Tardive dyskinesia (TD) from long-term neuroleptic treatment may be irreversible; therefore prevention has become a major concern. A controversial issue with regard to the clinical use of neuroleptic drugs is the possible influence on the development of TD of drug holidays. The major characteristics of kindling, theories of TD and the role of multiplicity in the development of TD are described. Some clinical studies point to interruption of neuroleptic therapy being a risk factor for development of irreversible TD. Induction of dyskinesia in non-human primates has been demonstrated after repeated administration of haloperidol. Rodent studies have not been conclusive. Several experimental results link TD with kindling: both conditions involve repeated stimulations, both seem to involve increased receptor responsiveness and in both conditions does depression in GABA transmission in SNR (substantia nigra; pars reticulata) play an important role. It is concluded that the kindling hypothesis is relevant to the investigation of TD.
Highlights
Kindling refers to the progressive development of neuronal after-discharges following repeated electrical stimulation of a given brain site with an initially subthreshold current (Goddard et at., 1969)
Iadarola and Gale (1982) have reported that local injection of gammaaminobutyric acid (GABA) into SN provides protection against electrically and chemically induced seizures without a widespread augmentation of GABA-mediated activity throughout the brain. They conclude that synapses in SN represent an important control mechanism for inhibiting the propagation of generalized convulsions. In agreement with this interpretation is the finding that bilateral microinjection of the GABA agonist muscimol into the substantia nigra, pars reticulata (SNR) suppresses kindled motor seizures and limbic seizures (McNamara et at., 1983), and the observation that the activity of a marker of GABA neurons, glutamic acid decarboxylase (GAD), is significantly lower in SN of amygdala-kindled rats compared to non-kindled rats (Loscher and Schark, 1985)
One of the most controversial issues that currently exists with regard to the clinical use of neuroleptic drugs is the possible influence on the development of Tardive dyskinesia (TD) of drug holidays
Summary
According to the original description (Goddard et at., 1969; Post and Ballenger, 1981; Wada et at., 1974; Racine, 1972) the kindling procedure involves:. 5 Optimal stimulus interval 24 hours-7 days. A kindled animal will still seize after a I-year seizure free interval. (1) Sprouting neuronal collaterals (2) Increased synaptogenesis (3) Dendritic swelling (4) Presynaptic terminal enlargement. Kindling results in a long-term enhancement of evoked potentials in multiple brain regions in response to a constant test stimulus in the kindled amygdala (McNamara et at., 1980; Racine et at., 1972). Electrophysiological studies have shown long-term potentiations of synapses (Racine et at., 1972; Douglas and Goddard, 1975; Goddard and Douglas, 1975; Bliss, 1979), and an increased excitability of the postsynaptic neurons has been found (Goddard, 1983)
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