THE EFFECTS OF THE TREMORGENIC MYCOTOXIN PENITREM-A ON THE RAT CEREBELLUM

Within 10 minutes of intraperitoneal injection of penitrem A (3 mg/kg) , rats develop severe generalized tremors and ataxia that persist for up to 48 hours. These are accompanied by a three-to fourfold increase in cerebellar cortical blood flow. Mitochondrial swelling occurs in ce rebellar stellate and basket cells within 30 minutes of dosing and per sists for more than 12 hours without leading to cell death. From 2 hou rs, Purkinje cell dendrites show early cytoplasmic condensation accomp anied by fine vacuolation of smooth endoplasmic reticulum and enlargem ent of perikaryal mitochondria. From 6 hours, many Purkinje cells deve lop intense cytoplasmic condensation with eosinophilia that resembles ''ischemic cell change,'' and from 12 hours, many other Purkinje cells show marked watery swelling. Astrocytes begin to swell from 0.5 hours after injection and show hypertrophy of organelles from 6 hours. Also from 6 hours onward, discrete foci of necrosis appear in the granule cell layer, while permeability of overlying meningeal vessels to horse radish peroxidase becomes evident at 8 hours. All changes are more sev ere in vermis and paravermis. Despite widespread loss of Purkinje cell s, the animals' behavior becomes almost normal within a week. While tr emor occurs with doses of 1.5 and 0.5 mg/kg, cellular damage is minima l. The tremor mechanism differs from that of harmaline since destructi on of inferior olivary nuclei abolishes neither the tremor response to penitrem A nor the cellular damage. No morphological changes are foun d in other brain regions. The affinities of penitrem A for high-conduc tance calcium-dependent potassium channels and for gamma-aminobutyric acid receptors with the probability of resultant excitotoxity are cons idered to be important underlying factors for these changes.