Brain injury following cardiorespiratory arrest in cats. Effects of alphaxalone-alphadolone

The effects of alphaxalone-alphadolone acetate (27.07 microM/kg-7.68 microM/kg) on neurologic injury following acute cerebral ischemia induced by an 8 min cardiorespiratory arrest (CRA) were investigated in cats through the analysis of neurological deficit scores and brain electrical activity; i.e., electroencephalogram (EEG) from parieto-occipital cortices and EEG and multiunit activity (MUA) from mesencephalic reticular formation (MRF). The CRA resulted from electrically induced cardiac arrest and stopping of mechanical ventilation in paralyzed cats which were successfully resuscitated within the immediate 4 min after the end of CRA. Two groups of cats were studied: I. Untreated, which received saline iv; II. Treated, which received alphaxalone-alphadolone acetate iv, 7-9 min after the end of CRA. Neuromuscular blockade and mechanical ventilation were maintained until 8 h following the CRA; then the cats were allowed to recover spontaneous respiratory activity. EEG phenomena were different in untreated and treated cats during this immediate post-arrest period. The former showed rhythmic bursts of fast (12-20 Hz) EEG activity at 1-2 sec intervals from 15-20 min until 3-4 h after the CRA, abundant spikes and delta-like waves. By contrast, administration of alphaxalone-alphadolone acetate resulted in burst suppression EEG pattern during 1 h. Progressive recovery of background EEG activity occurred afterwards. MUA from MRF disappeared during the CRA, however 6 h later the mean MUA frequency in untreated cats ranged between 32-46% and in treated cats 18-27% of their control mean frequencies during paradoxical sleep (100%). Daily electrographic records were performed in all the cats during quiet attentive behavior at each of the five days following the CRA. Significant differences were found in the frequency distributions of MUA from MRF (1st day, p less than 0.01; 5th day, p less than 0.01) as well as in the cortical EEG waves (1st day, p less than 0.01; 5th day, p less than 0.05) before and after the CRA in the untreated group. A wide dispersion of MUA values, and increased proportions of delta and theta-like waves and spindle bursts, besides a significantly high (p less than 0.001) number of spikes occurred in these EEG records the days following the CRA. The frequency distributions of MUA and EEG did not significantly differ before and after the CRA in the treated group; however, a significantly high (p less than 0.05) number of spikes was found in treated cats following the CRA.(ABSTRACT TRUNCATED AT 400 WORDS)     

Modifications of acoustic habituation by interruption of visual input in quipazine treated cats

The influence of interruption of the visual input on acoustic habituation was studied in cats before and following the administration of quipazine, 3 mg/kg iv. The characteristics of acoustic habituation were analyzed through the magnitude and temporal course of multiunit activity (MUA) responses elicited in the mesencephalic reticular formation (MRF) by repetitive acoustic stimuli (70 db, 50 Hz trains of 2 sec duration) in 6 freely moving cats with cortical electrodes over the parietal cortex and bipolar electrodes chronically implanted in MRF and basolateral amygdala (AMN). The cats were submitted to repetitive acoustic stimulation during one 30 min period before, and three 30 min periods after drug administration in the following conditions: a) with unmasked eyes; b) with masked eyes by means of dark contact lenses. Persistent attentive behavior, catatonic attitudes, hypersynchronous (6 Hz, 100-150 microV) EEG activity and significant increase of spontaneous MUA in FRM and AMN were induced by quipazine both in the cats tested with unmasked and with masked eyes. This increase of MUA was higher immediately following drug administration and progressively decreased, although MUA values remained significantly higher than controls 110 min after quipazine administration. Acoustic habituation, evidenced through the progressive decrease of MUA responses of MRF to acoustic stimuli, was observed before quipazine administration when the cats were tested with unmasked and with masked eyes; as well as in cats tested with unmasked eyes following drug administration. However, the MUA responses to acoustic stimuli did not decrease in cats with masked eyes during acoustic stimulation periods 0-30 min and 40-70 min after quipazine administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuronal septal activity during hippocampal seizure discharges generation in acute model of epilepsy

The activity of the neurones of the medial septal region (MS) and the hippocampal EEG in control and during the appearance of seizure discharges provoked by electrical stimulation of the perforant path were investigated in the awake rabbit. During afterdischarge generation in the hippocampus the dense neuronal bursts separated by periods of inhibition were recorded in the MS. In one group of neurons the bursts of spikes coincided with the discharges in the hippocampus, in other group-occured during inhibitory periods. When the afterdischarge stopped, in the septal neurons with theta activity the disruption of theta pattern was recorded, which have been correlated with the occurrence of low amplitude high frequency (20-25 Hz) waves in the hippocampal EEG. As a rule, the neuronal activivity of the MS recovered much quickly than EEG of the hippocampus; in some cases the increasing of the theta regularity was observed. The definite accordance of the electrical activity of the hippocampus and MS during seizure discharges suggests that the septohippocampal system operate as integral nervous circuit in these conditions. Diverse in the temporal interrelations between the discharges of MS neurones and ictal discharges in the hippocampus in the different cells possible indicate that various groups of the septal nervous elements have different participation in the seizure development. Appearance of the high frequency bursts in the MS is a possible "precursor" of the seizure onsets.     

Increase in receptor binding affinity for nimodipine in the rat brain with permanent occlusion of bilateral carotid arteries

The permanent occlusion of bilateral common carotid arteries (2VO) in rats has been shown to cause progressive and long-lasting cognitive deficits which may be due to impairment of memory retention and/or memory recall process. To clarify the function of voltage dependent calcium channels and the receptor binding of nimodipine by chronic cerebral ischemia, we examined specific (+)-[3H]PN 200-110 binding and the effect of oral administration of nimodipine in brain regions and hearts of rats, at 2 weeks to 4 months after permanent 2VO. There was no significant difference in either dissociation constant (Kd) or maximal number of binding sites (Bmax) for (+)-[3H]PN 200-110 in the cerebral cortex, hippocampus, corpus striatum and thalamus between 2VO and sham rats. In addition, in vitro inhibitory effect of nimodipine on cerebral cortical (+)-[3H]PN 200-110 binding in 2VO rats was similar to that in sham rats. Compared to control rats, oral administration of nimodipine to both 2VO and sham rats at 2 months after permanent 2VO brought about a significant increase in Kd values of specific (+)-[3H]PN 200-110 binding in the cerebral cortex, hippocampus, thalamus and myocardium, and the increase in Kd values was much larger in brain regions of 2VO rats than sham rats. However, the increase in Kd values in the myocardium did not differ between 2VO and sham rats. This observation suggests an increased in vivo binding affinity for nimodipine in chronic ischemic brain. In conclusion, the present study has shown that oral administration of nimodipine may cause a greater occupation in vivo of 1,4-dihydropyridine (DHP) calcium channel antagonist receptors in brains of permanent 2VO rats than in sham rats. Thus, nimodipine may be pharmacologically effective in preventing brain dysfunction due to cerebral ischemia in vivo.     

Nimodipine inhibits calcium-independent nitric oxide synthase activity in transient focal cerebral ischemia rats and cultured mouse astroglial cells

The effect of nimodipine on nitric oxide synthase (NOS) activities in brains in transient focal cerebral ischemia rats, in cultured mouse neurons and astroglial cells and bovine brain capillary endothelial cells (BCECs) was investigated. The administration of nimodipine (3 mg.kg(-1), p.o., twice a day, for 3 days) before middle cerebral artery (MCA) occlusion significantly reduced infarct size, decreased nitrite/nitrate (NOx) content and inhibited Ca2+-independent NOS activity in the infarct area. Nimodipine inhibited the Ca2+-independent NOS activity induced by lipopolysaccharide (LPS) + tumor necrosis factor alpha (TNF alpha) in mouse astroglial cells with an IC50 value of 0.036+/-0.003 mM and Ca2+-dependent NOS activity in mouse neurons with an IC50 value of 0.047+/-0.003 mM, but did not affect Ca2+-dependent NOS activity in BCECs. The inhibition of Ca2+-independent NOS activity by nimodipine in astroglial cells was competitive with respect to L-arginine. Nimodipine also inhibited the induction of Ca2+-independent NOS activity in vitro. These results suggest that nimodipine in addition to its cerebral vasodilating effect may protect brain from ischemic neuronal damage through modifying NOS activity.     

Effect of naloxone on acute ethylic intoxication. An EEG study

EEG recording has been used to evaluate in cats the effect of naloxone on acute ethylic intoxication (AEI). Naloxone was administered both before and during the course of AEI. Results of the experiment showed that administration of naloxone before the AEI potentiates the toxic effect of alcohol. However, the administration of naloxone in a continuous way along the course of AEI significantly diminished the toxic effect of alcohol.     

Effect of PGF2 alpha and 15(S)-15-methyl PGE2 methyl ester on feline generalized penicillin epilepsy.

The effect of PGF2alpha and 15(S)-15-methyl PGE2 methyl ester on transient generalized epilepsy in the cat induced by penicillin was examined. Epileptic activity before and after administration of the prostaglandins by several routes was determined from continuous EEG recordings and expressed in epileptic bursts per min. The PGE2 analogue given in single non-toxic doses (1.6-3 mug/kg) by intramuscular or intravenous routes at the peak of epileptic activity significantly reduced epileptic activity for up to four hours. Subcutaneous administration was less effective. PG2alpha given by the intramuscular route (0.3 mg/kg) also markedly reduced the number of epileptic bursts. Increasing the dosage 4-fold almost completely suppressed epileptic activity. Intracarotid infusion of PGF2alpha for one hour (10 mug/min) almost abolished all epileptic activity. Neither prostaglandin given in non-toxic doses induced EEG abnormalities in non-epileptic cats. Toxic doses of the E2 analogue (greater than 16 mug/kg) caused bilaterally synchronous high voltage slow wave activity. It is concluded that these prostaglandins reduce penicillin epilepsy in the cat. The findings are consistent with either a direct excitatory action on neurones of the medial reticular formation or anatagonism of the depressant action of norepinephrine on Purkinje cells.     

Delta9-tetrahydrocannabinol: subcortical spike bursts and motor manifestations in a Fischer rat treated orally for 109 days

A total of 12 Fischer rats was prepared surgically for chronic EEG recording from cortical and subcortical sites. Most rats, within 2 to 9 weeks after electrode implantation, developed polyspike activity in cortical and subcortical recordings that were without motor manifestations. Six of these rats, chronically treated po with Δ⁹-tetrahydrocannabinol (Δ⁹-THC) 10 mg/kg exhibited acute EEG changes with more frequent occurrence of EEG desynchronization and polyspike activity. On day 109 one of 6 rats displayed consulsive activity, with jerky movements of the head and paws, characteristics of Δ⁹-THC neurotoxicity. EEG alterations concomitant with motor signs included bursts of spikes of approximately 0.2 sec that occurred in subcortical, but not in cortical, recordings. It is concluded that in the Fischer rat acute and chronic treatment with Δ⁹-THC facilitated the occurrence of surgically-induced “polyspike” activity while chronic treatment caused occasional transient subcortical spike bursts with concomitant motor manifestations.     

Changes in the phasic activity of neuron microsystems of the somatosensory cortex of the cat during extinction of activation reactions to unreinforced stimuli

In chronic experiments on cats, three-phasic responses of neuronal microsystems in the cortical somatic area I were studied during habituation of the EEG activation reactions. Repeated stimuli of different modalities were used: electrical pulses to the forepaw, sounds, direct stimulation of the mesencephalic RF. Simultaneously with the extinction of EEG activation reactions, the three-phasic responses of the multiunit activity (MUA) also became progressively extinct: the 1st phase of primary excitation--only a little, the 2nd phase (inhibitory)--greatly, as well as the 3rd phase--the phase of secondary excitation (if it existed at the beginning). The MUA responses to all stimuli show that these neuronal microsystems are polysensory. Relatively to the nonspecific activating RF macrosystem, the investigated neuronal microsystems are autonomous because their two functionally opposed response phases--the 1st excitatory and the 2nd inhibitory--occur against the monotonous excitatory background of the EEG activation. But in some way the neuronal microsystems are connected with the RF-system because of the parallel development of the extinction process.     

大鼠脑血管痉挛时NO和ET—1变化及尼莫地平的影响

目的探讨蛛网膜下腔出血(SAH)后脑血管痉挛(CVS)时脑组织一氧化氮(NO)和内皮素-1(ET-1)含量变化及尼莫地平(ND)对其影响。方法将135只Wistar大鼠随机均分为SAH组、ND处理组和假手术组,观察手术前后基底动脉管径,及24h内局部脑血流量(rCBF)、脑组织NO和ET-1含量动态改变,并行海马病理检查。结果SAH后rCBF明显而持续降低,基底动脉管径显著缩小;海马CAl区锥体细胞严重受损;脑组织NO和ET-1含量均在SAH后1～24h显著增加(P＜0．05～0．01)。ND处理后使上述异常变化均减轻。结论SAH后脑组织NO、ET-1增多可能参与了CVS所致脑损害过程,ND通过减轻CVS和拮抗脑组织NO及ET-1的病理性改变而发挥脑保护作用。     

Effect of serotonin and acetylcholine on the electrical activity of isolated cortex in the rabbit

Neuronal isolation of the rabbit's cerebral hemisphere shifts the EEG spectrum in direction of slower processes. Application of acetylcholine on the cortex elicits EEG activation and appearance of the theta-rhythm. Initially serotonin application is accompanied by the appearance of the theta-rhythm periods; in the process of subsequent administration of the drug these periods are gradually substituted by slow delta-waves. Combined application of serotonin and acetylcholine on isolated cortex elicits bursts of high-amplitude activity, abruptly substituted by "silence" phases. In contrast to the intact cortex where serotonin elicited prolonged and rhythmic alternation on EEG of phases of high-amplitude activity and of "silence" periods, in the isolated cortex the bursts of activity of about 1 min duration appeared only after application of the acetylcholine to serotonin-saturated cortex. Repeated phases of activation were either absent or were of short duration and extinguished rapidly.     

Pharmacological basis for the use of nimodipine in central nervous system disorders

Nimodipine, a Ca2+ antagonist with cerebrovasodilatory and anti-ischemic effects, binds to rat, guinea pig, and human brain membranes with high affinity (less than 1 nM). Only at higher concentrations has nimodipine been reported to block the release of some neurotransmitters and hormones from neuronal tissue. Nimodipine has no consistent effect on brain oxygen consumption or cortical ATP or phosphocreatine levels, although the ischemia-induced fall of brain ATP levels in gerbils or the lowering of intracellular brain pH in rabbits with focal cerebral ischemia were antagonized by the drug. In rats and baboons with middle cerebral artery occlusion, nimodipine was found to reduce neurological deficits without an increase in intracranial pressure or brain edema. Electrophysiological studies with nimodipine suggested a direct neuronal action. In rabbit dorsal root ganglion cells, concentrations as low as 20 nM were reported to block inward Ca2+ currents. Recent studies have suggested that nimodipine may also improve memory in brain-damaged or old rats, restore sensorimotor function and abnormal walking patterns of old rats, and accelerate acquisition of associative learning in aging rabbits. Blockade of age-related changes in Ca2+ fluxes in rat hippocampal neurones by nimodipine in vitro pointed to neuronal plasma membrane as the site of nimodipine action. The therapeutic usefulness of nimodipine appears not to be limited to cerebral ischemia, but may include dementia, age-related degenerative diseases, epilepsy, and ethanol intoxication.     

Pattern and correlation of fast and slow spontaneous unit activity in the visual cortex

Spontaneous unit activity in the visual cortex and its changes during stimulation by continuous light or flashes were investigated in waking rabbits. The study of distributions of adjacent intervals showed that the neurons differ in the ratio of burst (fast, with intervals of up to 15–40 msec) and nonburst (slow) activity and in the character of changes from one type of activity to the other. Of the total number of spikes 63% were outside bursts; the ratio of their number to the number of spikes within bursts consisting of two or of three or more spikes was 27:3:1. The relative stability of the burst structure of spontaneous activity and the limited number of spikes in them (on average 2.4) were demonstrated. Bursts of three or more spikes (mean 3.6) were irregular, and in 79% of them a longer interval (18.6±2.4 msec) was observed before the shortest interval (7.9±0.9 msec). Bursts of spikes of most neurons during photic stimulation contain more spikes with shorter intervals; they also began more frequently with the shortest interval, possibly signifying an increase in the steepness and amplitude of the EPSPs lying at their basis. However, in 20% of neurons spontaneous bursts included more spikes and with shorter intervals than bursts evoked by flash stimulation.Research Institute of Psychiatry, Ministry of Health of the RSFSR, Moscow. Translated from Neirofiziologiya, Vol. 11, No. 4, pp. 311–320, July–August, 1979.     

Effect of Nimodipine on the Regional Cerebral Acidosis Accompanying Thiamine Deficiency in the Rat

The effect of the calcium channel blocker nimodipine on the previously described regional cerebral acidosis accompanying thiamine deficiency was investigated. Local cerebral pH (LCpH) and blood flow (LCBF) were separately determined autoradiographically in normal and 16-day thiamine-deficient rats administered the calcium antagonist drug and compared to appropriate controls. Nimodipine did not modify LCpH in normal brain. In thiamine deficiency, nimodipine significantly raised LCpH in 5 of 17 structures evaluated, two of which, the medial dorsal nucleus of the thalamus and the mammillary body, are vulnerable to the development of histological lesions in this condition. Although the calcium blocker augmented LCBF in normal brain, it had no effect on the hyperperfusion already present by day 16 of thiamine deprivation. Thus, the pH changes we are reporting are probably not related to an effect on cerebral perfusion, but could have resulted from an improved ability of the brain to reduce its proton load in the presence of nimodipine. These results may have wider therapeutic implications than in thiamine deficiency alone.     

Long-range temporal correlations in the EEG bursts of human preterm babies

The electrical activity in the very early human preterm brain, as recorded by scalp EEG, is mostly discontinuous and has bursts of high-frequency oscillatory activity nested within slow-wave depolarisations of high amplitude. The temporal organisation of the occurrence of these EEG bursts has not been previously investigated. We analysed the distribution of the EEG bursts in 11 very preterm (23-30 weeks gestational age) human babies through two estimates of the Hurst exponent. We found long-range temporal correlations (LRTCs) in the occurrence of these EEG bursts demonstrating that even in the very immature human brain, when the cerebral cortical structure is far from fully developed, there is non-trivial temporal structuring of electrical activity.     

Neural responses to antigenic challenges and immunomodulatory factors

In studies designed to examine the effects of the immune system, recordings of multi-unit electrical activity (MUA) in the central nervous system were made in the preoptic area/anterior hypothalamus (POA/AH) and paraventricular nucleus (PVN) of rats, following sheep red blood cell (SRBC) immunization. Peak increases in POA/AH MUA were observed on the fifth day following SRBC sensitization, the day on which serum antibodies were first detected. A significant increase in paraventricular nucleus (PVN) MUA was also observed on the sixth day. These changes in POA/AH and PVN MUA were found to be associated with increased plasma corticosterone levels on day 8. Induction of a second immune response to SRBC evoked a POA/AH MUA increase of extended duration but reduced amplitude, while administration of the immunosuppressive drug, cyclophosphamide, prevented both antibody generation and any increases in POA/AH MUA. These data suggest that activation of the immune system may provide signals, in the form of chemical messengers, which are able to alter neural activity in some regions of the brain that are important in neuroendocrine regulatory mechanisms. Accordingly, intracerebroventricular injections of thymic humoral factor or alpha-interferon decreased POA/AH MUA, increased EEG synchronization, and decreased plasma levels of corticosterone. Histamine and interleukin 1 did not alter POA/AH MUA but decreased EEG synchronization and increased plasma levels of corticosterone.     

Evidence for biorhythmicity from the preoptic nucleus of the rainbow trout Salmo gairdnerii under freely swimming conditions--an electrophysiological study

This study describes a technique which allows continuous recording of MUA (Multiple Unit Activity), from the NPO (Preoptic Nucleus), DAP (Dorsal Aortic blood Pressure) and ECG (Electrocardiogram) in freely swimming rainbow trout. From the 21 trout tested, six trout (29%) clearly showed rhythmic patterns of MUA during the five post-operative days (D2-D6). The mean length of rhythmic MUA was about 18 hr (range 6-33 hr) among the six trout during the recording days. Periodic MUA occurred approximately eight times/hr and lasted about 2 min. The maximal frequency of discharges was 20-30 spikes per sec. No change occurred in the mean level of blood pressure from the first operative day to the following post-operative days, where rhythmic MUA appeared or reappeared. These results demonstrate the existence of biorhythmicity within the NPO of freely swimming trout and suggest parallel oscillations in neurohormones secretion.     

Demonstration of spontaneous and stretch induced urinary bladder EMG in the living rabbit

Spontaneous bladder EMG was recorded in the living rabbit from an isovolumetric bladder without chemical or electrical stimulation. Mechanical intervention, either by lifting the bladder out of the abdomen or by rapid filling, resulted in stretch induced bladder EMG. A self made epoxy resin electrode device that embedded 32 EMG recording electrodes in a matrix like pattern, each electrode Ag/AgCl, d = 0.6 mm with an interdistance of 2.3 mm, was used for registration. The recorder used a common average reference technique and a sample frequency of 400 Hz. A signal bandwidth of 0.05 to 108 Hz was available for analysis. Spontaneous EMG consisted of single spikes and bursts (2-20 spikes), but not of continuous activity. The shape of spikes was triphasic. Single spikes appeared with and without burst activity. Small (2-5 spikes) and large bursts (6-20 spikes) were discerned; small bursts not necessarily propagated across electrodes, large bursts did and were able to organize, suggesting that they were under short neuron system control. Spontaneous EMG was probably related to both contraction and relaxation. Stretch induced EMG was characterised by continuous activity on all electrodes, spikes that followed each other immediately, slowly fading away. The spikes had an elongated third phase when compared to the shape of spontaneous activity. Highest activity and amplitudes were found after lifting the bladder out of the abdomen and placing it on the electrode device. A concept is put forward in which the continuous activity is not unequivocally related to muscle shortening, but where the current stress and strain situation of the bladder tissue can cause a muscle fibre elongation upon the appearance of electrical activity. The EMG activity found was in many aspects similar to results of a previous study using mortalized rabbits. Artifact sources like the heart, respiration, or local movement between electrode and bladder could easily be identified due to the new experimental methodology used.     

Effect of PGF2α and 15(S)-15-methyl PGE2 methyl ester on feline generalized penicillin epilepsy

The effect of PGF_2α and 15(S)-15-methyl PGE₂ methyl ester on transient generalized epilepsy in the cat induced by penicillin was examined. Epileptic activity before and after administration of the prostaglandins by several routes was determined from continuous EEG recordings and expressed in epileptic bursts per min. The PGE₂ analogue given in single non-toxic doses (1.6–3 μg/kg) by intramuscular or intravenous routes at the peak of epileptic activity significantly reduced epileptic activity for up to four hours. Subcutaneous administration was less effective. PGF_2α given by the intramuscular route (0.3 mg/kg) also markedly reduced the number of epileptic bursts. Increasing the dosage 4-fold almost completely suppressed epileptic activity. Intracarotid infusion of PGF_2α for one hour (10 μg/min) almost abolished all epileptic activity. Neither prostaglandin given in non-toxic doses induced EEG abnormalities in non-epileptic cats. Toxic doses of the E₂ analogue (>16 μg/kg) caused bilaterally synchronous high voltage slow wave activity. It is concluded that these prostaglandins reduce penicillin epilepsy in the cat. The findings are consistent with either a direct excitatory action on neurones of the medial reticular formation or antagonism of the depressant action of norepinephrine on Purkinje cells.     

Effect of PGF2α and 15(S)-15-methyl PGE2 methyl ester on feline generalized penicillin epilepsy

The effect of PGF_2α and 15(S)-15-methyl PGE₂ methyl ester on transient generalized epilepsy in the cat induced by penicillin was examined. Epileptic activity before and after administration of the prostaglandins by several routes was determined from continuous EEG recordings and expressed in epileptic bursts per min. The PGE₂ analogue given in single non-toxic doses (1.6–3 μg/kg) by intramuscular or intravenous routes at the peak of epileptic activity significantly reduced epileptic activity for up to four hours. Subcutaneous administration was less effective. PGF_2α given by the intramuscular route (0.3 mg/kg) also markedly reduced the number of epileptic bursts. Increasing the dosage 4-fold almost completely suppressed epileptic activity. Intracarotid infusion of PGF_2α for one hour (10 μg/min) almost abolished all epileptic activity. Neither prostaglandin given in non-toxic doses induced EEG abnormalities in non-epileptic cats. Toxic doses of the E₂ analogue (>16 μg/kg) caused bilaterally synchronous high voltage slow wave activity. It is concluded that these prostaglandins reduce penicillin epilepsy in the cat. The findings are consistent with either a direct excitatory action on neurones of the medial reticular formation or antagonism of the depressant action of norepinephrine on Purkinje cells.