Intraventricular Injection Of 6-hydroxydopamine Research Articles

Modification of the drug-taking behavior in rats by interference in the metabolism of 5-hydroxytryptamine and catecholamines

Forty naive female rats had the choice between drinking either tap water or 0.3 mg/ml levorphanol in saccharose solution. Nine animals preferred the levorphanol/saccharose solution which, on average, comprised 83% of their total fluid intake, and became physically dependent. In order to assess the influence of the sweet taste on the drug-taking behavior of these rats, the saccharose concentration of the levorphanol solution was subsequently lowered in three steps from 17% to 0%. Down to 5% saccharose no significant difference in the daily levorphanol intake could be observed. On average 77% of the total fluid intake (~53.0 mg/kg) was due to the levor-phanol solution. Without saccharose the levorphanol consumption diminished to 10% (~3.9 mg/kg), i.e., the aversion to the bitter taste of the opioid obviously counteracted the possibly positive reinforcement effect of the drug. After subtotal destruction of noradrenaline and dopamine neurons by intraventricular injection of 6-hydroxydopamine the levorphanol consumption (8% saccharose) was reduced to 53% of the total fluid intake (~24.8 mg/ kg). The same effect occurred after interference with the 5-hydroxytryptamine metabolism by 320 mg/kg p-chlorophenylalanine (~25.8 mg/kg) indicating that voluntary drinking of levorphanol/saccharose solution in levorphanol-dependent rats is not only due to a preference for saccharose.

A new experimental model of stress ulcers employing aggressive behavior in 6-OHDA-treated rats

Rats receiving intraventricular injection of 6-hydroxydopamine (6-OHDA) were housed in isolation for one month and placed in the same cage as an untreated rat while being subjected to continuous tail pinching. 6-OHDA-treated rats violently attacked the untreated rat and stabilized fighting between the two animals persisted for over 1 hr. The 6-OHDA-treated rats consistently played the dominant role in the dominant-subordinate relationship established between the rats. By allowing this fighting to continue for 1 hr, gastric erosion associated with severe hemorrhage occurred with a high incidence in the untreated rats. These erosions were comparable in rats examined immediately after fighting and in those examined after 1 hr and 3 hr. Poststress rest was not required for erosion to occur. The presence of bite wounds incurred during fighting was unrelated to the incidence of gastric erosion. In addition, it was unnecessary to fast the untreated rats beforehand. Based on these findings, the present model apparently does not rely on physical stimulation. These factors and the ease of its execution make the present new experimental model of stress ulcers very useful.

Evidence for involvement of the frontal cortex in pain-related cerebral events in cats: increase in local cerebral blood flow by noxious stimuli

Noxious stimuli were shown to induce a remarkable increase in local cerebral blood flow restricted to the forepart of the cerebral hemispheres bilaterally anterior to the posterior sigmoid gyrus in cats. This increase in local cerebral blood flow was averted by lesions in the bilateral ventromedial thalamus and attenuated by pretreatment with an intraventricular injection of 6-hydroxydopamine.

Comparison of behavioral changes in cats treated with intracerebroventricular 6-hydroxydopamine and reserpine

In singly- and group-housed cats, an intraventricular injection of 6-hydroxydopamine (6-OHDA) in doses up to 1.0 mg, after a latent period of 1 to 3 days, evoked motor responses including tremor, ataxia, rigidity, weakness with adynamia and clonic-tonic convulsions. However, the intraventricular administration of 6-OHDA in a dose of 2.0 mg in group-housed cats, also after a latent period of 1 to 3 days, caused aggression, a restlessness, irritability, rage, fear, threat, attack, fighting and flight. These responses were accompanied by autonomic signs of mydriasis and dyspnoea and motor changes including tremor, ataxia, rigidity, weakness with adynamia and clinic-tonic convulsions. In the singly-housed cat only the latter motor phenomena were observed after the higher dose. Intraventricular injection of reserpine (0.5-1.0 mg) in both singly- and group-housed cats produced catalepsy, sedation, miosis, ptosis, defecation and micturition as well as motor responses of tremor, rigidity and akinesia. It is concluded that although 6-OHDA and reserpine evoke different behavioral effects, the motor changes are similar.

Dopamine depletion by 6-hydroxydopamine prevents conditioned taste aversion induced by methylamphetamine but not lithium chloride

Specific lesions of the central dopaminergic system produced by intraventricular injections of 6-hydroxydopamine with pargyline and desmethylimipramine pretreatment significantly attenuated conditioned taste aversions to a sweetened-condensed milk solution induced by methylamphetamine. Identically treated rats formed an aversion to the milk solution when lithium chloride was utilized. These results suggest that the methylamphetamine-induced aversion is dependent upon intact dopaminergic neurons.

Effects of intraventricular injection of 6-hydroxydopamine in the developing kitten. III. Histochemical fluorescence and radioautographic studies of the noradrenaline hyperinnervation in the pons

In the present study, using neonatal intraventricular injections of 6-hydroxydopamine (6-OHDA) and the fluorescence histochemical method for monoamines, it is observed that an extensive plexus of noradrenaline (NA) fibres develops in the pontine region of the cat brain subsequently to the neonatal destruction of the ascending NA bundles and of the NA innervation in the cerebral cortex by the neurotoxin. This plexus is only partly conserved 10 months after the 6-OHDA treatment. Generally, only a limited number of NA perikarya degenerate in the region of the locus coeruleus, the others (nucleus subcoeruleus senso lato) exhibiting the same strong fluorescence as the new NA fibres. Using the radioautographic method after intraventricular injections of [ 3H]NA, our work demonstrates also the transient disappearance (at least one month) of the uptake of [ 3H]NA in the pons, whose NA cell bodies and nerve terminals are no longer labeled in the same number as in control animals. The possibility of again labeling significantly NA perikarya and numerous nerve terminals occurred between 3 and 5 months of age, probably indicating both a re-establishment of normal uptake properties in the preserved NA perikarya and nerve terminals and some maturation of the uptake mechanisms in the abnormal NA fibres of the pons. This last observation is at variance with data from newborn animals showing that the uptake of NA develops in parallel with the accumulation of endogenous NA in catecholamine nerve terminals. The present results, however, do corroborate and complement previous biochemical data obtained in the cat after neonatal injection of 6-OHDA.

Intraventricular 6-hydroxydopamine in the newborn rat and locomotor responses to drugs in infancy: no support for the dopamine depletion model of minimal brain dysfunction.

Bilateral intraventricular injections of 6-hydroxydopamine (6-OHDA) after desmethylimipramine (DMI) in rats 1 and 2 days of age, severely depleted brain dopamine (DA) particularly in the neostriatum, where levels in adulthood were about 7% of control. Compared to vehicle-injected controls these rats were hyperactive only at 15 and 20 days of age, and in adulthood were impaired in a two-way avoidance. Rats with similar 6-OHDA treatment but without DMI pretreatment showed severe depletion of brain norepinephrine (NE) as well as DA, and were behaviorally similar to the DA-depleted only rats. This behavioral syndrome is similar to that reported after intracisternal injection of 6-OHDA in 5-day-old rats, which has been argued as a model for minimal brain dysfunction (MBD). Contrary to expectation from this model, however, challenge doses of either d-amphetamine or methylphenidate did not reduce, but instead increased activity of these rats. The 6-OHDA treatments also did not alter the enhancement of locomotor activity by scopolamine, which was present at 30 days but not at 15 days.

Changes in local cerebral blood flow and neuronal activity during sensory stimulation in normal and sympathectomized cats

Activities of neurons of the thalamic relay nucleus and cortical somatosensory area which are capable of producing excitatory potentials in response to stimulation of the sciatic nerve were recorded, and local cerebral blood flow was measured simultaneously using a double microelectrode under local anesthesia in both non-pretreated cats and cats undergoing chemical denervation of the vasoadrenergic nerves by intraventricular injection of 6-hydroxydopamine (6-OHDA), in order to unmask the neural control on the cerebral vessels during increase of local metabolic rate. The results obtained may be summarized as follows. (1) A positive correlation was found between an increase in firing rate of a single neuron in the thalamic relay nucleus and somatosensory area and an increase in local cerebral blood flow following stimulation of the sciatic nerve. A distinct spatial and quantitative correlation was thus observed between neural activity and cerebral blood flow. (2) In 6-OHDA-pretreated cats, an increase in neuronal firing rate was observed following stimulation of the sciatic nerve, as it was nn non-pretreated cats, but the concurrent response of local cerebral blood flow was seriously impaired. All these findings indicate that the increase in local cerebral blood flow occuring in association with increased neural activity does not result solely from increased local metabolism and a consequent increase in CO 2 production, but requires for its occurence that certain basic conditions be satisfied and maintained by the vasoadrenergic innervation.

Neurotransmitter receptor localizations: Brain lesion induced alterations in benzodiazepine, GABA, β-adrenergic and histamine H 1-receptor binding

Selective neuronal lesions have been utilized in efforts to localize binding sites in rat brain for β-adrenergic, γ-aminobutyric acid (GABA), histamine H 1 and benzodiazepine receptors. The various receptors respond differentially to lesions both in extent of change and in time course. After kainate lesions in the corpus striatum, benzodiazepine receptors are depleted up to 45% at 45–78 days but are unaffected after 7 days. By contrast striatal GABA receptors are increased at 7 days but depleted at later times. Thus both striatal benzodiazepine and GABA receptors appear to be associated at least in part with intrinsic neurons. In the cerebellum both benzodiazepine and GABA receptors are reduced in kainate treated rats and in Nervous mice, mutants which lack Purkinje cells. The most pronounced dissimilarity between benzodiazepine and GABA receptors occurs in Weaver mice, which selectively lack granule cells and display a 60% reduction in GABA receptors but a 40% augmentation in benzodiazepine receptors. A major portion of cerebellar GABA receptors, therefore, appear to be localized to granule cells. Striatal β-adrenergic receptors are reduced following intrastriatal kainate injections but are unaffected by cerebral cortex ablation, suggesting an association with intrinsic neurons but not with axon terminals of the corticostriate pathway. While intraventricular injections of 6-hydroxydopamine enhance [ 3H]dihydroalprenolol binding to β-adrenergic receptors in the cerebral cortex and hippocampus, such binding is not augmented in the corpus striatum, brain stem, midbrain or thalamus-hypothalamus by this treatment. Moreover, medial forebrain bundle lesions, which destroy ascending adrenergic neurons, fail to alter cerebral cortical or striatal β-adrenergic receptors. Thus denervation-elicited increase in β-adrenergic receptors vary with brain region and the type of denervating lesion. Histamine H 1-receptors are the most resistant of all to neuronal lesions. In the corpus striatum [ 3H]mepyramine binding is unaffected by cerebral cortex ablation, nigral injections of 6-hydroxydopamine or brain stem hemisection. In the hippocampus, medial forebrain bundle lesions, intrahippocampal kainate injection, and fimbria and fornix transection largely fail to alter [ 3H]mepyramine binding. Accordingly, a major portion of these receptors may be associated with nonneuronal elements such as glia or blood vessels.

Effect of noradrenaline and 5-hydroxytryptamine depletion on locomotion in the cat

It has recently been hypothesized that stimulation of the mesencephalic locomotor region (MLR) can give rise to locomotion in mesencephalic cats due to activation of descending monoaminergic pathways to the spinal cord. This notion is based on the findings that monoamine agonists and precursors can induce hindlimb stepping in acute low spinal animals, and on the similarities between the effects of the noradrenaline (NA) precursor, l-DOPA, and stimulation of the MLR. The hypothesis that the descending monoamine systems comprose the only pathways which control the initiation of locomotion has been tested in the present study. NA was depleted from the CNS using intraspinal and intraventricular injections of 6-hydroxydopamine and i.v. injections of the NA synthesis inhibitor, α-methyltyrosine. Depletion of 5-hydroxytryptamine (5-HT) was achieved using intraventricular injections of 5,6-dihydroxytryptamine and i.p. p-chlorophenylalanine. These treatments did not abolish evoked locomotion in spite of substantial depletion of NA and 5-HT in the spinal cord and brain stem (maximal depletions of NA up to 14% of control in lumbar cord and 16% of control in pons; maximal depletions of 5-HT up to 19% of control in sacral cord and 25% of control in medulla). Combined depletion of NA and 5-HT did not abolish evoked locomotion in mesencephalic cats, although the treated animals displayed pronoounced ataxia prior to decerebration. Depletion of NA or 5-HT alone did not alter locomotion in otherwise intact animals. A previous report that phenoxybenzamine antagonizes the effects of MLR stimulation was not confirmed. The results therefore do not support the hypothesis that descending pathways containing monoamines are essential for locomotion evoked by brain stem stimulation.

Effects of neonatal and adult 6-hydroxydopamine treatment on random-interval behavior

Rats were given intraventricular injections of 6-hydroxydopamine (6-HDA) or saline-ascorbate vehicle as neonates (3-days old) and as adults (49 and 51 days old). At 73 days of age, they were trained on a random interval 90-sec schedule of water reinforcement. The rats treated with 6-HDA as adults stabilized at response rates approximately twice those of vehicle-treated rats, while rats treated with 6-HDA as neonates showed response rates which were not significantly different from vehicle-treated rats. Both L-Dopa and apomorphine decreased response rates at all doses tested. There were no differences among the groups with respect to the effect of these drugs. Adult-treated rats showed greater response rate decreases following peripheral decarboxylase inhibition with Ro 4-4602. Catecholamine analyses revealed the rats treated with 6-HDA as neonates had greater depletions in the striatum and the remainder of telencephalon than adult-treated rats but an increase in brainstem norepinephrine. These findings suggest that age of treatment is an important determinant of the biochemical and behavioral effects of treatment with 6-HDA.

Compensatory increase in tyrosine hydroxylase activity in rat brain after intraventricular injections of 6-hydroxydopamine.

The neurotoxin 6-hydroxydopamine produced a permanent loss of endogenous norepinephrine and of 3H-labeled norepinephrine uptake sites in the hippocampus within 5 days. These losses were initially accompanied by parallel decreases in tyrosine hydroxylase activity and synaptosomal norepinephrine synthesis. Within 21 days, however, hippocampal tyrosine hydroxylase activity and norepinephrine synthesis rate increased three- to fivefold. These data suggest a novel form of plasticity in brain-damaged animals characterized by an increase in the capacity for transmitter biosynthesis in residual neurons.

DRL performance in 6-hydroxydopamine-treated rats

Adult rats were given intraventricular injections of 6-hydroxydopamine (6-HDA) or saline-ascorbate vehicle prior to exposure to a differential-reinforcement-of-low-rate (DRL) 18-sec schedule of water reinforcement. The 6-HDA treatment did not alter the acquisition or maintenance of DRL performance despite large depletions of dopamine and norepinephrine in brain. The 6-HDA treatment completely blocked the response rate-increasing effects of amphetamine but did not alter the rate-decreasing effects of amphetamine on DRL performance. These findings suggest that 6-HDA-treated rats are able to respond to the contingencies necessary to maintain reinforcement on a DRL schedule.

Dopa accumulation is a measure of dopamine synthesis in the median eminence and posterior pituitary.

A radioenzymatic assay was employed to measure the accumulation of DOPA in a variety of rat brain tissues 30 min after the administration of a decarboxylase inhibitor in order to estimate the activity of dopamine (DA) nerves which terminate in these regions. In the median eminence and posterior pituitary the accumulation of DOPA appears to occur primarily in DA nerves since: (1) the rate of synthesis of norepinephrine (NE), as estimated from the alpha-methyltyrosine-induced decline of catecholamines, accounts for less than 10% of total catecholamine synthesis in these two brain regions; and (2) the accumulation of DOPA is not significantly altered when the NE concentrations in these regions are reduced to 40--50% of control by prior intraventricular injections of 6-hydroxydopamine. These results suggest that the accumulation of DOPA in the median eminence and the posterior pituitary can be used to estimate the activity of tubero-infundibular and tuberohypophyseal DA nerves, respectively.

Chlorophenylpiperazine: a central serotonin agonist causing powerful anorexia in rats.

Meta-chlorophenylpiperazine inhibited serotonin and noradrenaline uptake by synaptosomes to the same extent with IC50 of 1.3 x 10(-6) M and 5.8 x 10(-6) M respectively. Dopamine uptake was less affected by meta-chlorophenylpiperazine (IC50 of 2.2 x 10(-5) M). Unlike d-amphetamine and d-fenfluramine, the drug did not significantly increase monoamine release in synaptosomal preparations. On the other hand, metachlorophenylpiperazine showed an IC50 of 620 nM in displacing 3H-5HT binding to brain membranes. Meta-chlorophenylpiperazine produced a dose-dependent reduction of food intake and this effect was prevented by a pretreatment with methergoline, a serotonin antagonist. The effect of metachlorophenylpiperazine was not modified by an intraventricular injection of 6-hydroxydopamine, electrolytic lesions of nucleus medianus raphe or ventral noradrenergic bundle, nor by a pretreatment with penfluridol, propranolol or phentolamine. The data suggest that the decrease of food intake induced by metachlorophenylpiperazine depends on its ability to act as a serotonin agonist is the brain. The specificity of the effects on serotonin suggests that this compound could prove an important tool for studies aimed at elucidating the functional role of serotonin in the central nervous system.

Preservation of binocularity after monocular deprivation in the striate cortex of kittens treated with 6‐Hydroxydopamine

The results of single unit recordings from Area 17 of monocularly deprived kittens were compared with similar ones from littermates who had been monocularly lid-sutured for the same period of time, but who had in addition been given intraventricular injections of 6-hydroxydopamine (6-OHDA) to deplete brain catecholamines. This visual cortices of all catecholamine-depleted kittens showed high proportions of binocular neurons, in contrast to the control group, a majority of whose visual cortical neurons were driven exclusively by the non-deprived eye. Preservation of binocularity in 6-OHDA-treated kittens was dose-related. Even after a 1 to 2-week period of lidsuture which reduced binocularity to 20% in controls, normal proportions of binocular neurons (greater than 75%) were preserved if the cumulative dose had been 10 mg 6-OHDA or more. The density of single neurons sampled from electrode tracks through the cortex of drug-treated kittens was high and did not differ significantly from controls. Neurons were isolated every 100 micron on the average. There was some indication that the drug's effect in preventing an ocular dominance shift disappears by six weeks following cessation of 6-OHDA treatment. This reversal of the physiological effects in cortex is preceded by recovery from the behavioral manifestations of 6-OHDA treatments. Binocularity was only slightly increased in a kitten who received large doses of 6-OHDA after a period of monocular deprivation. This observation, together with control recordings from normal kittens and adults treated with 6-OHDA, indicates that the direct effects of 6-OHDA on cortical neurons' response properties play a minor role in comparison to its effects in reducing the sensitivity of the cortex to monocular deprivation. The overwhelming majority of cortical neurons in 6-OHDA-treated kittens remained normal in receptive field properties after a period of monocular deprivation. These data support the hypothesis that catecholamines are required for the maintenance of visual cortical plasticity during the critical period.

Evidence for presynaptic cholinergic receptors on dopaminergic terminals: Degeneration studies with 6-hydroxydopamine

Intraventricular injections of 6-hydroxydopamine (6-OHDA) caused a significant decrease in the tyrosine hydroxylase of striatal synaptosomes of rats, without influencing GABA levels. Significant decreases in the muscarinic and nicotinic receptors also occurred in this preparation after 3 days. The receptors were measured by specific binding studies with N-methylatropine and α-bungarotoxin respectively. These results indicate that muscarinic and nicotinic receptors are located on the dopaminergic nerve terminals of corpus striatum.

Effects of intraventricular injection of 6-hydroxydopamine in the developing kitten. II. On the central monoaminergic innervation

Summary The intraventricular administration of 6-hydroxydopamine (6-OHDA) to kittens between 5 days and 4 months of age induced marked changes in the endogenous levels of DA, NE and 5-HT in various brain areas. In contrast to the well-known selective effect of 6-OHDA against catecholaminergic neurones in the rat, serotoninergic neurones were also markedly affected by 6-OHDA treatment in kittens; particularly in the hippocampus and the colliculi, 5-HT levels were markedly and permanently decreased after the intraventricular administration of 6-OHDA. A significant but less pronounced reduction in 5-HT levels was also noted in other areas such as the piriform cortex, the cerebral neocortex, the cerebellum and the septum. Only very discrete changes were detected in the caudate nucleus, the olfactory tubercle and the raphe area. The administration of chlorimipramine (10 mg/kg, i.p.) 1 h before 6-OHDA treatment completely prevented the effects of the neurotoxic agent on serotoninergic innervation. Marked regional differences were also noted concerning the effects of 6-OHDA treatment on dopaminergic neurones. Whereas DA levels in the raphe area and the hypothalamus were almost unaffected, they were permanently reduced by about 50% in the caudate nucleus and the olfactory tubercle after the intraventricular administration of 6-OHDA. In the caudate nucleus, the reduction was even much more pronounced (−90%) when 6-OHDA was administered during the first 3 postnatal weeks. In most forebrain areas (hippocampus, piriform cortex and cerebral neocortex) and in the cerebellum, NE levels were permanently reduced to about 10% of those of control kittens as soon as the third day following the intraventricular injection of 6-OHDA. In contrast, after a transient drop, NE levels in the lateral brain stem (containing the locus coeruleus) of 6-OHDA-treated kittens returned and even surpassed (+100%) those found in age-paired controls. Analyses of the characteristics of l -[ 3 H]NE uptake in synaptosomes indicated that 6-OHDA treatment resulted in both a striking loss of specific uptake sites in forebrain areas and a significant increase in the V max of the NE uptake process in synaptosomes from the lateral brain stem. However, in contrast to the rapid increase in NE levels, this change in V max occurred much later, since it was first detected at more than one month after 6-OHDA treatment. This delay suggests that the doubling in NE levels occurring for the first month following the intraventricular administration of 6-OHDA simply resulted from an increased accumulation of the catecholamine in noradrenergic terminals in the lateral brain stem. Later on, the change in V max might indicate a sprouting of new noradrenergic terminals in the vicinity of the locus coeruleus area. The intraventricular administration of 6-OHDA resulted in a significant increase in the maximal stimulatory effect of l -isoproterenol on adenylate cyclase activity in homogenates of the cerebral cortex and the lateral brain stem. Therefore, not only the degeneration (in the cerebral cortex) but also the proliferation (in the lateral brain stem) of noradrenergic terminals were associated with an increase in the density of beta-adrenergic receptors. These results are discussed in relation to the possible function of the noradrenergic sprouts in the lateral brain stem.

Effects of intraventricular injection of 6-hydroxydopamine in the developing kitten. 1. On the sleepwaking cycles

Intraventricular 6-OHDA was injected in kittens at different stages of development, and the subsequent sleep polygram was analyzed, in order to determine the role of the catecholaminergic system in the ontogenesis of sleep regulations during the first and the second postnatal months. 6-OHDA, used with or without previous chlorimipramine treatment, led within a 10-day period to drastic reductions of the endogenous monoamines in the forebrain of all age groups. Although the neurotoxicity of 6-OHDA was almost constant among the different age groups, the effects on sleep depended on the age of the animals at the time of the injection. In the 5-week-old injected kittens, 6-OHDA affected PS according to an adult-like pattern. In the 3-week-old kittens, 6-OHDA alone (leading to both catecholamines and serotonin decreases) induced the same PS deficit as in the adult cat. In the 1- and 2-week-old kittens, neither 6-OHDA alone, nor 6-OHDA with previous chlorimipramine treatment, distrubed the sleep regulations. These data are compared to similar experiments performed in the adult cat. They are discussed in terms of sleep control ontogenesis. It is concluded that the catecholaminergic system plays no important role in the mechanisms of sleep regulation in the early postnatal period in the kitten, whereas its regulatory influence on PS is confirmed in the juvenile animal. The functional maturation of the catecholaminergic system in terms of sleep regulation is achieved between the third and the fifth week of postnatal life.

Electrical activity of the hippocampus and neocortex in rats depleted of brain dopamine and norepinephrine: Relations to behavior and effects of atropine

Spontaneous behavior and cerebral electroencephalographic (EEG) activity were studied in rats depleted of the brain catecholamines dopamine (DA) and norepinephrine (NE) by intraventricular injections of 6-hydroxydopamine. It was found that there was a direct relation between the amount of DA depleted and degree of adipsia-aphagia, akinesia (lack of spontaneous activity), and sensorimotor neglect. Results from a number of tests as well as 24-h videorecordings showed that the rats with little or no central dopamine did not eat or drink, walk spontaneously, or orient to tactile stimulation, but they did initiate grooming as often as control rats. Video-recordings also showed that the DA-depleted rats made continuous postural adjustments, a behavior which may be similar to the akathisia or motor impatience described as a human Parkinson's disease symptom. EEG recordings revealed that both atropine-resistant (movement-related), and atropine-sensitive (immobility-related) forms of neocortical low-voltage, fast activity (LVFA) and hippocampal rhythmic slow activity (RSA or theta) survive depletion of brain DA and NE. Furthermore, the amplitude and frequency of theta activity were not changed by DA depletion. It is suggested that neither DA nor NE are critically important for the production of LVFA or RSA although DA may be indirectly involved in regulating the probability of their occurrence by regulating the probability of the occurrence of movement.