Hippocampal Norepinephrine Research Articles

Facilitated reversal learning of a spatial-memory task by medical septal injections of 6-hydroxydopamine

To assess the role of hippocampal norepinephrine in learning and memory, rats were treated with medial septal injections of 6-hydroxydopamine either prior to or after acquisition of a spatial-memory task. No effect on acquisition learning or retention was observed. However, reversal learning was significantly enhanced in all treated animals regardless of whether treatment was prior to or after acquisition. Our results do not support a role of hippocampal norepinephrine in selective attention, but rather indicate a direct involvement in memory processes.

The effects of low-level lead exposure in developing rats: changes in circadian locomotor activity and hippocampal noradrenaline turnover.

The circadian spontaneous locomotor activity of rats exposed to 0.1 mg lead/kg, po from 3 days until 4 and 6 weeks of age was similar to that of controls. However, hyperactivity during initial hours of recording was observed in rats that were treated with lead (Pb) until 8 weeks of age. When treatment was discontinued for 2 weeks, previously Pb-exposed rats had a tendency to be hypoactive. The elevated locomotor activity in 8-week-old lead-treated rats was not accompanied by any significant changes of noradrenaline levels in the cerebral cortex or hippocampus. Alterations in noradrenaline content of the hippocampus were, however, observed in rats that had been treated with Pb for 4 and 6 weeks. The turnover rate of noradrenaline in the hippocampus was also found to be significantly reduced following treatment for 6 weeks. Regional distribution of Pb in the brains of lead-exposed rats showed a large accumulation of the metal in the hippocampus. The alterations of the noradrenergic function in the hippocampus may be associated with the preferential storage of lead in this region.

Depletions of central norepinephrine by intraventricular xylamine in rats

A series of neurochemical studies evaluated the selectivity of the depletions of norepinephrine produced by intraventricular injections of xylamine. Brain monoamines were assayed by liquid chromatography with electrochemical detection. With ether anesthesia, bilateral injections of 50 or 100 μg xylamine reduced hippocampal levels of norepinephrine and serotonin without affecting striatal dopamine or serotonin. The depletion of hippocampal norepinephrine was significant as soon as 24 h. Animals treated with the combination of 20 mg/kg fluoxetine and 100 μg xylamine had selective depletions of central norepinephrine with no significant changes in serotonin.

Effect of DSP-4, pCPA, and haloperidol on hippocampal electrical activity and behavior in rabbits

An experimental model, including novel and fearful stimuli, has been used to study the effect of noradrenaline, serotonin, and dopamine depletion on hippocampal electrical activity and behavior in freely moving rabbits. DSP-4 (N-(2-chloroethyl)-N-ethyl-2- bromobenzylamine hydrochloride, 40 mg/kg ip), a selective hippocampal noradrenaline depletor, decreased the overall exploratory activity and significantly increased RSA (rhythmic slow activity) percentage. The high frequencies of the hippocampal RSA were significantly reduced. When this noradrenaline depletion was coupled with a serotonin depression by p-chlorophenylalanine (pCPA), the above described effect was potentiated. In particular, the frequency distribution of RSA was characterized by a further reduction of the high values with a concomitant increase of the low frequency band. Moreover, a more evident decrease of the exploratory activity and a similar increase of RSA percentage was observed. These results show that the hippocampal electrical activity is modulated by noradrenaline and serotonin by an inhibitory effect on RSA occurrence and a frequency selection. The block of dopamine receptors by chronic haloperidol administration (5 mg/kg ip/day) did not seem to exert any effect on RSA parameters. Results are discussed in the light of attentional and emotional theories.

Plasma catecholamine and corticosterone as well as brain catecholamine changes during coping in rats exposed to stressful footshock

Rats received 60 minutes of footshock that was escapable (coping group) or inescapable (noncoping group). Plasma taken by jugular catheter showed that noncoping rats, compared with coping rats, had significantly higher peak norepinephrine (NE) and epinephrine (E) concentrations and significantly longer elevation of these catecholamines after footshock. Similarly, plasma corticosterone levels remained elevated significantly longer after footshock in noncoping rats. In brain, hypothalamic NE concentrations were lower in noncoping rats compared with coping controls, and this difference remained for at least 30 minutes after shock. A fall in hippocampal NE concentration was seen only in coping rats once they learned to terminate shock. Our data indicate that neurochemical changes can be separated into changes due to the aversive nature of the stimulus and the ability to cope with a stressor. The inability to cope augments plasma catecholamine increases in response to a stressor and prolongs their return to baseline values. The latter is also true for corticosterone levels. The decrease in hippocampal NE in coping and the decrease in hypothalamic NE in noncoping rats is not due to footshock by itself but to the ability of the rat to terminate this stressor. No strong correlation between central and peripheral catecholamine changes became apparent except a possible negative correlation between hypothalamic NE and peripheral NE and E levels.

Septal modulation of the population spike in the fascia dentata produced by perforant path stimulation in the rat

Electrical stimulation of the perforant path, which originates in the entorhinal cortex, produces a characteristic excitatory postsynaptic field potential (extracellular EPSP) which can be recorded in the fascia dentata This evoked response may include a population spike, if stimulation is sufficient. In the anaesthetized rat, stimulation of the medial septum, when paired with stimulation, was found to augment the population spike component of the evoked field potential. Stimulation of the septum alone produced no apparent field potential. The augmentation effect was found to have a rapid onset (4 ms), which is sufficient for the participation of interneurons, and a relatively long time course (150 ms). Presynaptic mechanisms of facilitation were ruled out as there was no concurrent af the extracellular EPSP. A change in population spike threshold, compatible with a postsynaptic mechanism, was obserered and some possible models of action discussed. Augmentation survived depletion of hippocampal norepinephrine caused by injections of 6-hydroxydopamine into the dorsal noradrenergic bundle, indicating that the facilitation was not due to an activation of the ascending noradrenergic fibres of passage originating from the locus coeruleus. The cholinergic septo-hippocampal pathway was ruled out as a likely candidate for the modulation as the augmentation survived injections of the muscarinic antagonists atropine and scopolamine and the nicotinic antagonists tubocurarine and dihydro-ß-erythroidine. A relationship between the septal modulation and hippocampal theta was suggested.

Lesions of the dorsal noradrenergic bundle and rewarded running: The role of pretraining

Local injection of 6-hydroxydopamine was used to selectively destroy the dorsal ascending noradrenergic bundle (DB), producing 75% loss of hippocampal noradrenaline. Lesioned and control rats were trained to run in a straight alley for food reward with or without pretraining (handling and habituation to the apparatus). Lesioned rats ran more slowly than controls only if they had not been pretrained. This result may explain previous discrepancies in the literature; it is discussed in relation to existing hypotheses of DB function.

Epinephrine, norepinephrine, dopamine and serotonin: Differential effects of acute and chronic stress on regional brain amines

Following acute cold swim stress, hypothalamic epinephrine concentrations were markedly lowered and remained decreased for 24 h, while norepinephrine concentrations were decreased, but returned to baseline within 14 h. With oscillation stress repeated daily for 21 days, hypothalamic norepinephrine, hypothalamic epinephrine, and hippocampal norepinephrine turnover were decreased and absolute concentrations were increased. Repeated stress had little effect on serotonin, dopamine or their metabolites. These results suggest that hypothalamic epinephrine concentration and turnover are particularly responsive to acute and chronic stress. The decreased epinephrine and norepinephrine turnover under chronic stress may be responsible in part for the behavioral and endocrine changes observed in chronically stressed rats.

Social housing conditions influence escape deficits produced by uncontrollable stress: Assessment of the contribution of norepinephrine

A series of experiments assessed the effects of uncontrollable stress on escape behavior and on levels of brain dopamine (DA) and norepinephrine (NE) among mice housed in social isolation or in groups. Exposure to 60 inescapable foot-shocks markedly disrupted escape performance. The magnitude of the deficits was more pronounced among mice housed individually than in mice that had been group-housed. Moreover, the progressively greater escape deficits seen over the 168-hr period following the initial stress appeared to be due to the interaction between shock treatment and isolation. Exposure to 60 inescapable shocks resulted in hypothalamic and hippocampal NE depletion, regardless of housing condition. Exposure to 30 shocks resulted in NE depletion in isolated but not group-housed mice. Although the NE depletion produced by 60 shocks was transient, reexposure to 10 shocks 24 hr later reinduced the depletion. Such an effect was independent of housing condition but absolute levels of NE were lower in isolated than group-housed mice. The behavioral deficits induced by uncontrollable stress were discussed in terms of the contribution of catecholamine changes induced by stress.

Short and long term changes in tyrosine hydroxylase activity in rat brain after subtotal destruction of central noradrenergic neurons

The administration of 6-hydroxydopamine into the cerebroventricles of the rat produced a rapid and permanent decrease of norepinephrine in hippocampus due to an apparent degeneration of central catecholaminergic nerve terminals. The decrease in norepinephrine levels was accompanied by a decrease in the activity of the rate-limiting biosynthetic enzyme, tyrosine hydroxylase. However, the decrease in enzyme activity was less pronounced than the decrease in norepinephrine levels, resulting in an increase in the ratio of tyrosine hydroxylase activity to norepinephrine content. This relative increase in enzyme activity was shown to result from two processes. Within 36 hr after the lesion, the apparent Vmax had decreased in parallel to the norepinephrine loss. However, there was an apparent activation of the remaining enzyme molecules. This activation was only detectable in the presence of subsaturating cofactor concentrations and at a pH above the pH optimum. The activation resembled that produced in control samples by in vitro adenosine 3':5'-monophosphate-dependent protein-phosphorylating conditions, and incubation under these conditions had no further effect on enzyme activity. The activation was followed by a gradual increase in the apparent Vmax of tyrosine hydroxylase toward control values. This increase was preceded by a 2-fold rise in the amount of enzyme present in the region of the locus coeruleus, an area rich in noradrenergic cell bodies. The time course of the increased Vmax in terminal fields appeared to be related to their proximity to the locus coeruleus, since it was more rapid for cerebellum (peak activity, 7 days) than for hippocampus (21 days) and probably represented a 3- to 4-fold increase in the amount of tyrosine hydroxylase per residual terminal. The increase in the Vmax was accompanied by a return to a basal activation state of the enzyme molecules and a restoration of the ability of in vitro protein-phosphorylating conditions to increase enzyme activity. These short and long term alterations in tyrosine hydroxylase activity after 6-hydroxydopamine treatment may represent adaptive responses to the lesion.

Effects of 6-hydroxydopamine and 6-hydroxydopa on development of behavior

Rats treated at birth with 6-hydroxydopamine (6-OHDA) (60 μg/g, IP) or 6-hydroxydopa (6-OHDOPA X2) (60 μg/g, IP at birth and 48 hr later) exhibited increases in general activity throughout the initial 5 weeks after birth, with peak activity occurring around 20 days postnatally. Activity changes in the 6-OHDOPA×2 group appeared to be due to increased exploratory behavior (ambulation, climbing, rearing, sniffing), while the 6-OHDA changes appeared to be due to the increased self-directed behavior (eating, grooming, scratching). Despite these behavioral differences there was no obvious difference between treated groups in norepinephrine (NE) levels in the various brain regions, i.e., all treatments resulted in a reduction in neocortical and hippocampal NE and an elevation in cerebellar NE. These findings suggest that noradrenergic neurons may be altered to different degrees by each agent in more discrete brain regions than tested, or that other neurotransmitter systems may be more selectively altered by either of the drug treatments. Because striatal dopamine was unaltered in any of the groups, however, there is a reason to question a previously suggested link between minimal brain dysfunction (MBD) and dopamine depletion in the neonatal brain.

Initiation of maternal behavior in the rat: possible involvement of Limbic norepinephrine

The dorsal norepinephrine (NE) fiber system was manipulated in pregnant female rats. Brainstem lesions of the dorsal bundle, depleting NE in cortex and hippocampus, resulted in deficits in maternal-behavior onset in primiparous rats. Similarly, fornix-bundle transections, depleting only hippocampal NE, were associated with an absence of pup care. Hypothalamic NE levels, as well as dopamine and serotonin concentrations in cortex, hippocampus and hypothalamus, were not significantly affected by these manipulations. The data are discussed in terms of behavioral specificity, possible hormonal involvement and interactions with diencephalic mechanisms controlling the onset of maternal behavior in the female rat.

Ouabain induced stereotyped behavior in rats.

Stereotyped behavior was induced in rats with ouabain administered intraventricularly in doses of 2, 3 and 4 microgram in 50 microliter saline. Haloperiodol reduced the stereotyped behaviour. Monoamine turnover studies showed a reduction in concentration of norepinephrine in hippocampus and midbrain, an increase in norepinephrine turnover in the medulla oblongata and a reduction in dopamine turnover in the striatum. The interpretation of these finds is discussed. It is suggested that this model could be significant clinically as it demonstrates that impairment of Na+-K+-ATP'ase may result in behavioral abnormalities characterised by stereotypy.

An investigation of the role of cortical and cerebellar noradrenaline in associative motor learning in the rat

The role of the noradrenergic projections from the locus coeruleus to the cerebral and cerebellar cortices in the learning of a novel motor response was investigated using two techniques of administration of the relatively selective neurotoxin, 6-hydroxydopamine (6-OHDA). In one technique, 8 μg of 6-OHDA was stereotaxically injected bilaterally into the fibres of the dorsal noradrenergic bundle in the mesencephalon. This produced severe depletion of cortical and hippocampal noradrenaline (NA) but did not damage the cerebellar projection. The second 6-OHDA technique involved intraperitoneal injection of 100 mg/kg of 6-OHDA into neonatal rats on days 1, 3, 5, 7, 9, and 11 after birth. This produced depletions of cortical and hippocampal NA comparable to the dorsal bundle technique, but also gave a profound loss of cerebellar NA. Neither technique altered striatal dopamine (DA). These animals were tested on the acuisition of a complex motor learning task involving the pulling or pushing of a ball out of a tunnel in order to reach food. Neither preparation was impaired on acquisition of this novel motor response, nor in tests of behavioural flexibility requiring the transfer from pull to the push response and vice versa. Both NA depleted preparations, however, showed a marked difference from normals when tested in extinction. When food was no longer presented, the 6-OHDA treated animals continued emitting the response for longer and with greater rapidity than control animals. This resistance to extinction is a further demonstration of the role of the dorsal noradrenergic bundle in mechanisms involved in the extinction process. The findings are discussed in relation to noradrenergic theories of associative and motor learning and to previously demonstrated alterations in the extinction process in 6-OHDA treated animals.

Maintenance of intracranial self-stimulation in hippocampus and olfactory bulb following regional depletion of noradrenaline

As a test of the ‘noradrenergic’ theory of brain-stimulation reward rats were trained to respond for stimulation at sites in the hippocampus and olfactory bulb. Inasmuch as there is evidence that the noradrenergic innervation of these two areas arisesexclusively from the locus coeruleus, the effects of 6-hydroxydopamine-induced lesions of this protection on hippocampal and olfactory bulb self-stimulation were examined. Depletion of hippocampal noradrenaline levels to less than 5% and olfactory bulb levels to less than 9% of controls had no significant effect on self-stimulation at these loci. Therefore noradrenaline does not seem to be an essential substrate of brain-stimulation reward in these regions of the brain. The effect of this lesion on the rate-increasing properties of d-amphetamine sulphate (1.0 mg/kg) was also examined with hippocampal placements. A significant increase in self-stimulation rate was observed both before and after the lesion, thus questioning traditional explanations of the facilitatory effect of amphetamine on self-stimulation.

Effects of selective forebrain noradrenaline loss on behavioral inhibition in the rat.

Virtually total depletion of cortical and hippocampal noradrenaline by stereotaxic injection of 6-hydroxydopamine into the fibers of the dorsal noradrenergic bundle produced no impairment in acquisition learning of a runway response for food reward. Extinction of this response, once learned, was markedly slower in the treated group than in controls, the treated animals perseverating in rapid running to the goal box even with no food present there. Similarly, no impairment was found on acquisition of a continuously reinforced lever-pressing response for food. Extinction of this response, however, was again slower in the treated group. Subsequent acquisition of a successive light-dark discrimination task was also slower in the treated group, with these animals perseverating in responding to the negative stimulus. Although selective forebrain noradrenaline loss does not impair the acquisition of appetitive responses, the suppression of responses in the absence of reward is impeded. A parallel is drawn with those effects found classically after surgical lesion to the hippocampus.

Diurnal Rhythms in Pineal N-Acetyltransferase and Hippocampal Norepinephrine: Effects of Water Deprivation, Blinding and Hypothalamic Lesions

The pineal gland in the rat exhibits a diurnal rhythm in activity of the enzyme serotonin N-acetyltransferase (N-AT) with peak values during the dark period of a diurnal lighting schedule approximately 100-fold those during the light period. After blinding the rhythm becomes free-running. It is abolished by partial hypothalamic deafferentation with a knife cut made caudal to the optic chiasm. Water deprivation for 23 h daily has no effect on the pineal rhythm in either intact, blinded or deafferented animals. In contrast to this, there is a diurnal rhythm in hippocampal formation in norepinephrine content which can be entrained by a water deprivation schedule in both intact and blinded animals. These observations indicate that in the same animals 1 diurnal rhythm may remain entrained to the light-dark cycle while another rhythm is entrained to a secondary synchronizer, the water deprivation schedule.

Time-dependent aspects of CO 2 induced amnesia and hippocampal monoamine metabolism in rats

The time course of amnesia for a one-trial passive avoidance response after treatment with carbon dioxide (CO 2) was studied. Amnesia developed gradually over the first 4 hr following the amnesic treatment. Once established, amnesia remained during a 4 week test period. Previously, we reported that acquisition of the passive avoidance response was attended with a rise in the hippocampal concentration of serotonin 24 hr later and that this rise was not observed when acquisition was followed by amnesic treatment. In the present study, it was found that a rise in hippocampal serotonin parallelled the transient retention of the avoidance response 2 hr after amnesic treatment. However, 2 weeks after acquisition and amnesic treatment no changes in hippocampal monoamine metabolism could be detected. Hippocampal noradrenaline did not correlate with avoidance and amnesia.

Hippocampal monoamine metabolism and the CO 2 induced retrograde amnesia gradient in rats

It was found that in rats a gradient of retrograde amnesia for a passive avoidance response could be established when carbon dioxide (CO 2) was used as the amnesic agent. The extent of passive avoidance increased as the period between application of a mild foot shock and CO 2 treatment was increased. The amnesia gradient was found to cover a period of at least 60 min. Changes in hippocampal serotonin metabolism parallelled the amnesia gradient. Thus, the concentration of serotonin increased as the interval between the foot shock and the CO 2 treatment increased. The changes in hippocampal noradrenaline and dopamine did not correlate with the amnesia gradient.

Food and water restriction shifts corticosterone, temperature, activity and brain amine periodicity.

The circadian periodicity of plasma corticosteroid levels was determined in individual adult male and female rats, sampled every 4 hr over a 48-hr period. Access of these rats to food and water was then restricted to 9:30 AM–11:30 AM for a 15-day period, the animals being kept under normal laboratory lighting conditions (lights on 8:00 AM, off 8:00 PM). At the end of this period, such animals had a 12-hr shift in the time of the circadian peak of plasma corticosteroid levels. A similar alteration in the time of the peak of body temperature levels was also seen in these animals. Alteration of patterns of running activity, with a marked increase in daytime running activity was also present in such food and water restricted animals. There was also a reversal of AM/PM ratios of hippocampal norepinephrine and of serotonin levels in these animals. These findings demonstrate that presence of normal light-dark alteration is not sufficient for the maintenance of normal circadian periodicity of plasma corticos-tero...