Single low dose of MPTP decreases extracellular levels of noradrenaline and monoamine metabolites in the ventrobasal thalamus of the rats.

A single low dose of the neurotoxin: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results paradoxical sleep deprivation and reduction in food intake without any detectable motor deficiencies. In the present study we monitored the in vivo extracellular levels of monoamines and their metabolites following intraperitoneal (i.p.) administration of a single dose of MPTP (5 mg/kg). Microdialysates were collected from the ventrobasal thalamic nucleus (VB) of Halothane anesthetized rat. We found a significant decrease in noradrenaline (NA), 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) levels and a significant increase in 3,4-dihydroxyphenylalanine (DOPA) concentration whereas amino acid levels were unchanged throughout the 4-hour long perfusion. We found no significant difference in the post mortem release of NA and DOPA between the control and MPTP treated animals, suggesting that the intracellular NA pool were maintained. The above findings support the idea that the neurochemical mechanism of rapidly developing and transient behavioral changes induced by MPTP may be an immediate decrease in monoaminergic transmission and metabolism following MPTP injection.

Paradoxical sleep deprivatory effect of a single low dose of MPTP which did not produce dopaminergic cell loss.

In a previous study, we reported on a selective and long-lasting paradoxical sleep (PS) deprivation in cats following repeated administration of the Parkinson syndrome-inducing neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). While the characteristic motor deficits occurred only from the 2nd to 3rd day of a 5-day long administration of 5 mg/kg per day MPTP i.p., the PS deprivation started immediately after the first injection and lasted altogether for 11-13 days. The motor deficiencies induced by repeated administration of MPTP are mainly due to the selective depletion of dopaminergic neurons in the nigrostriatal system as the histological and biochemical data show. The immediate onset of PS deprivation and the PS recovery, despite the definite cell loss, suggests a mechanism independent of cell destruction. In our present study we investigated the occasional histological and the PS-deprivatory effect of a single low dose of MPTP in cats. A single injection of 2 mg/kg MPTP i.p. resulted in PS deprivation lasting for 2.5-3.5 h. The duration of other sleep stages showed no significant change and PS recovery was without rebound phenomenon, as in the case of repeated administration. Even a higher single dose of MPTP (5 mg/kg) resulted in no visibly detectable nigrostriatal cell loss. We suggest that the changes in monoamine release and/or turnover are involved in the PS deprivatory effect of MPTP.

A novel effect of MPTP: the selective suppression of paradoxical sleep in cats.

We studied the effect of MPTP on sleep-wakefulness cycle in cats. Five mg/kg n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was administered i.p. for 5 consecutive days. Electrocorticographic, electrooculographic and electromyographic recordings were performed before (5 days), during (5 days) and after (14 days) the treatment. Total selective paradoxical sleep deprivation was observed from the first injection. This effect lasted 6-9 days after the last dose, while the relative amount of slow wave sleep increased. The Berg-Fourier analysis showed no significant change in the EEG power spectra of slow-wave sleep during the paradoxical sleep deprivation compared to control period. Recurrence of paradoxical sleep was parallel to the disappearance of the motor symptoms. Histopathological investigation showed neuronal loss mainly in the substantia nigra. Our present study suggests a complex behavioral effect of MPTP.

Electrochemical calibration of in vivo brain dialysis samplers.

Measurement of state-related changes in the concentration of an endogenous substance using the in vivo dialysis technique requires a definition of the factors which relate the concentration detected in the outflowing perfusate to the concentration actually occurring in the extracellular space in which the sampler is located. In determine these factors, a rapid and highly accurate detector system is required which measures the concentration recovery in the perfusate and the dead space of the entire sampling system. To reduce the limitations of the microdialysis technique, two electrochemical microcells were developed for calibration of dialysis probes by computerized voltammetry. The electrochemically calibrated samplers were implanted into freely moving cats to measure concentration changes of monoamine metabolites in synchrony with sleep stages identified by polygraphy in order to demonstrate the applicability of electrochemical calibration in dialysis methods used in behavioral investigations.

Local perfusion of the thalamus with GABA increases sleep and induces long-lasting inhibition of somatosensory event-related potentials in cats.

The extracellular concentration of gamma-aminobutyric acid (GABA) was increased in the ventroposterolateral nucleus of the thalamus in cats using in vivo microdialysis probes. In freely moving cats, the permanent injection of 8 x 10(-9) M/mm2 x min GABA induced a significant increase in sleep proportion. The duration of paradoxical sleep was particularly increased resembling the effects of benzodiazepines. In chloralose anesthesia, a similar increase in GABA concentration in the thalamus induced a tonic decrease in the peak-to-peak amplitude of cortical event-related potentials evoked by stimulation of the radial nerve. Following 10-15 min of inhibition during which the responses were as small as 20% of the original ones, the potentials started to recover. Finally, the responses were stabilized at a reduced amplitude. The present data suggests the important role of the thalamic GABAergic neurons in the regulation of sleep.