Phenytoin and cerebellar lesions. Similar effects on cerebral catecholamine metabolism.

Phenytoin has been shown to inhibit catecholamine (CA) metabolism in vitro. The present investigation examined its longer-term in vivo effects in rats. Phenytoin 100 mg/kg/day for two weeks, caused an increase in hindbrain norepinephrine (NE) concentration, a slight decrease in forebrain NE concentration, and little change in dopamine (DA) levels. The turnover rates of forebrain DA and NE estimated by synthesis inhibition, were increased by 70% and 100%, respectively. Surgical lesions of the anterior cerebellar vermis produced similar (but not additive) increases in turnover. It is concluded that long-term phenytoin use stimulates CA metabolism in the forebrain and that this effect may be mediated indirectly by the cerebellar vermis.

Kainic acid: enduring alterations in cerebellar morphology and in cerebral catecholamine and GABA concentrations after cerebellar injection in the rat.

Kainic acid injected locally in the vermian cortex produces a focal lesion with severe cellular loss. Microscopic changes in 3-week-old preparations are given for both central and peripheral segments. Biochemical studies indicate that norepinephrine, dopamine and gamma-aminobutyric acid (gaba) concentrations in the forebrain are consistently higher on the side of the lesion and remain elevated for at least 3 weeks. It is postulated that disinhibition of cerebellar activity traversing the uncrossed pathway from cerebellar nuclei to catecholamine cell bodies was a major mechanism causing increased catecholamine metabolism in the ipsilateral forebrain.

Focal cerebellar hyperthermia: effects on cerebral paroxysmal afterdischarges.

Small area hyperthermia is used to selectively increase cerebellar activity, and, as shown by electroencephalographic tracings of sensorimotor area, focal cerebellar hyperthermia with temperatures limited between 39.5 degrees and 41 degrees C effectively reduces the duration of electrically induced afterdischarges. Additional observations on paroxysms induced in the caudate nucleus which involve the sensorimotor area indicate that these also show shortened durations during focal cerebellar hyperthermia. A comparison of effects on these two forebrain structures is given and some similarities are noted between these results and those reported from previous studies in which electrical stimuli were applied directly to the cerebellar cortex.

Cerebellar control of basal forebrain seizures: amygdala and hippocampus.

Electroamygdalagrams and electrohippocampalgrams of the cat and monkey were studied before, during, and after electrically induced afterdischarges. Cerebellar stimulation, particularly of midline cortex, shortened or terminated afterdischarges. Prestimulation of the vermis suppressed afterdischarges for as long as 5 min. Excitation of nucleus fastigii prolonged afterdischarges, and legions of n. fastigii abolished the effects of stimulation of the vermis. Cooling of the vermis prolonged afterdischarges, an effect reversed by warming. Pretreatment with 6-OH dopamine to induce chemical lesions in the catecholamine system reduced the effectiveness of cerebellar stimulation. The findings indicate that the cerebellar cortex can exert a tonic suppressor (inhibitory?) INFLUENCE ON THE AMYgdala and hippocampus by way of n. fastigii. Evoked responses demonstrated cerebellar projection to the amygdala and the hippocampus. The evoked potentials were small with a short latency (4 to 10 msec to peak) and larger with a long latency (20 to 30 msec to peak) wave. Return projection to the cerebellum was shown, the small evoked potential having a latency of 6 to 12 msec and the larger one of 20 to 30 msec.

Alterations in forebrain catecholamine metabolism produced by cerebellar lesions in the rat.

Projections from the midline cerebellar nuclei to norepinephrine (NE) and dopamine (DA) cell groups in the brain stem have been demonstrated histologically. To determine if these connections are significant biochemically, unilateral electrolytic lesions were placed in either vermis or paravermis and levels of DA, NE and gamma-aminobutyric acid (GABA) were measured in each half of the forebrain at 1 1/2, 3 or 6 weeks. In the cerebral hemisphere ipsilateral to a vermis lesion, there was a decrease in NE levels at 3 and 6 weeks. Relative to the opposite side DA was also reduced at 3 and 6 weeks. Paravermal lesions caused a contralateral reduction in DA at 3 weeks but no change in NE. GABA was only slightly altered. These results suggest that the cerebellum can modify levels and turnover of catecholamines in the brain, possibly via direct anatomic connections as well as by functional interaction with catecholaminergic pathways.

Cerebellar contributions to the Papez circuit.

Cerebellar influences on the various substructures in the Papez Circuit are indicated by the following. 1. Anatomical studies indicate that the major midbrain areas to which this circuit projects are : 1) ventral tegmental area; 2) interpeduncular area; and 3) periaqueductal gray areas; and these same areas project back to the limbic system. There are projections to these regions from the cerebellar nuclei, as indicated by terminal degeneration studies which show that cerebellar nuclei connect, mostly by fine fibers, with a continuum of cells located on either side of the midline in the ventral tegmentum of the midbrain. Observations that the cerebellum also projects to the locus ceruleus (NA system) and VTA (DA system) indicate that cerebellar influences can also reach the limbic areas via the catecholamine fiber bundles. 2. Electrophysiological studies indicate that vermiam and fastigial stimulation induce evoked responses in the basolateral amygdala, the hippocampus, and the septum, with latencies to the peak of first wave ranging from 4 to 8 msec and to the second wave of 16-29 msec. Citations from the physiological literature indicate that electrical stimulation of the cerebellum, especially the vermis, can modify a wide range of responses which involve functional activities of either the sympathetic or parasympathetic nervous systems. 3. Studies on electrically induced afterdischarges in the septum, hippocampus, and amygdala indicate that cerebellar stimulation can shorten the duration of or terminate the afterdischarges, and the site of lowest threshold is the midline cortex. Focal cooling of the vermis promotes prolongation of the afterdischarges as does pretreatment of animals with 6-OH dopamine. Chemical lesions in the catecholamine system induced by 6-OH dopamine reduce the effectiveness of the cerebellar stimulation, as do lesions of nucleus fastigii. These data are interpreted to indicate that the cerebellum can exert a tonic suppressor (inhibitory?) influence on substructures within the Papez Circuit. 4. Citations from animal behavioral studies indicate that electrical stimulation of the anterior cerebellum can induce responses such as arousal, predatory attack, and feeding which mimic those obtained by amygdaloid stimulation. Fastigial stimulation can produce drowsiness and EEG changes which resemble the sleep patterns resulting from stimulation of the ventral amygdala.

Effects of hippocampal afterdischarges on Purkinje cell activity.

Hippocampal afterdischarges can induce increased Purkinje cell activity that characteristically shows a pronounced acceleration during the period of the afterdischarges. Increased Purkinje cell activity may continue for many seconds after termination of the hippocampal activity. Typical frequency histograms are presented. A short period of hippocampal afterdischarges (under 25 sec) may occur with few if any alterations in cerebral activity and vice versa. However, such afterdischarges can produce changes in cerebellar activity as shown by enhanced Purkinje cell activity. These data support the view that the nucleus tegmenti pontis may be prominently involved in relaying hippocampal afterdischarges to the cerebellum whereas much of the neocortical seizure activity is relayed trough the pons, inferior olive, and lateral reticular nucleus, rather than through nucleus tegmenti pontis. EEG tracings taken from these areas illustrate the findings.

Focal brain hyperthermia. I. The cerebellar cortex.

Focal brain hyperthermic methodology has been described and data presented on the cerebellum which show that enhancement of electrical activity of cerebellar cortex occurs when this method is used with careful monitoring of temperature. The duration of electrically induced cerebral after-discharges is shortened when cerebellar warming reaches 39.5--42.0 degrees C,. Since these effects are repeatable over many hours, there appears to be little, if any, resultant damage. Such induced changes in the cerebrum resemble those previously reported in which electrical stimuli were applied to the cerebellar cortex.