Bilateral Locus Coeruleus Research Articles

Origin and organization of brainstem catecholamine innervation in the rat.

The catecholamine (CA) innervation of the rat brainstem was studied by biochemical analysis of discrete nuclei or areas and by glyoxylic acid-formaldehyde freeze dry fluorescence histochemistry. CA assays demonstrate that the highest norepinephrine (NE) content in brainstem is present in the trigeminal motor nucleus, nucleus tractus solitarius, dorsal motor nucleus of the vagus and nucleus raphe dorsalis. Bilateral locus coeruleus (LC) lesions do not significantly alter NE content in these nuclei but do decrease NE content in the superior and inferior colliculi, medial geniculate body, interpeduncular nucleus, pontine nuclei and the main sensory trigeminal nucleus (60-75%). Dopamine (DA) and epinephrine (E) are found in significant concentration in only a few of the nuclei examined. Fluorescence histochemical analysis indicates that two groups of NE axons innervate rat brainstem. LC neuron axons with a distinctive morphology principally innervate sensory and association nuclei of the brainstem. These disappear completely after bilateral LC lesions. The second group of axons originates from lateral and dorsal tegmental NE cell groups. Primary motor and visceral nuclei are densely innervated by fine and thick axons from these groups. Lesions of LC do not alter the NE innervation in any of the nuclei which contain axons of the second group. These results indicate that the brainstem NE innervation is divided into two major systems. The locus coeruleus complex innervates mainly primary sensory and association nuclei whereas the lateral tegmental NE neurons innervate primary motor and visceral nuclei. Although some overlap is present, the LC and lateral tegmental NE systems predominantly innervate separate and functionally distinct areas of the brainstem. DA and E neurons provide a very minor component of the brainstem CA innervation.

Significance of central noradrenergic system on harmaline induced tremor

Since there is degeneration of substantia nigra concomitant with that of locus coeruleus (LC) in patients with Parkinson's disease, the study was performed to determine the role of central norepinephrine (NE) on harmaline induced tremor. The duration of harmaline (10 mg/kg IP) induced tremor was significantly reduced by intraventricular administration of L-threo-3,4-dihydroxyphenylserine (200 μg/rat) and 1-NE (50 μg/rat) which increased NE levels in the cerebral cortex, striatum, diencephalon, cerebellum and brain stem. Electrical stimulation of bilateral LC suppressed harmaline-induced 10–12/sec EMG activities in the neck muscle. Bilateral LC lesion upon electrocoagulation and 6-hydroxydopamine treatment resulted in a significant prolongation of the duration of harmaline induced tremor, reducing NE levels in the brain. These data suggest that central NE originating in the LC neurons has an inhibitory effect on the development of the tremor induced by harmaline.

Experimental central hypertension produced by chemical degeneration of the locus coeruleus in the rat.

The role of noradrenergic neurons originating from the locus coeruleus (LC) in blood pressure regulation was studied by stereotaxic administration of 6-hydroxydopamine (6-OHDA) into the LC in Wistar-Kyoto rats. The administration of 6-OHDA (12 micrograms/6 microliters) into the bilateral LC resulted in hypertension and tachycardia, which lasted for 12 days and gradually returned to the levels observed before administration. The systolic blood pressure and heart rate were 172 mmHg and 460 beats/min on the mean respectively, one day after administration. The induced hypertension and tachycardia were closely correlated with the depletion of norepinephrine (NE) content in the cortex and the medulla-pons in rats in a hypertensive state. The correlation between the NE content of the cortex and blood pressure was particularly marked (r = -0.793, p less than 0.02). Furthermore, destructive change of the LC was observed histologically in the hypertensive rats. They hypertension was completely prevented by pretreatment with desipramine before 6-OHDA administration. These findings suggest that 6-OHDA induced degeneration, probably mainly in the dorsal bundle originating from the LC and in the LC itself. It is suggested, therefore, that localized chemical degeneration of the bilateral LC causes hypertension and tachycardia as a consequence of denervation of the dorsal bundle of noradrenergic neurons originating from the LC.

Innervation of forebrain regions by medullary noradrenaline neurons, a biochemical study in cats with central tegmental tract lesions

In order to determine quantitatively the relative contribution of medullary noradrenaline neurons to the noradrenaline terminal innervation of forebrain regions in the cat, bilateral lesions of the central tegmental tract were performed at the level of the caudal pons in adult cats. The results indicate that the medullary neurons provide approximately 75% of the total noradrenaline innervation to the hypothalamus, only 20–25% of that of the thalamus and midbrain and no measurable contribution to the noradrenaline innervation of the cerebral cortex or hippocampus. These results are comparable to previous ones of bilateral locus coeruleus lesions in the cat which showed that the locus coeruleus neurons provide approx. 15% of the total noradrenaline innervation to the hypothalamus, 60% of that to the thalamus and midbrain and the entire innervation to the cerebral cortex and hippocampus.

Locus coeruleus and labile memory

Memory lability is defined as the period of time recently-formed memory remains susceptible to experimental modification. Electrolytic lesions delivered through chronic indwelling electrodes to the locus coeruleus (LC) complex of mice, made shortly after learning, resulted in an extension of memory lability. Mice with unilateral, but not bilateral LC damage became amnesic following electroconvulsive shock (ECS) administered 7 days (168 hr) after memory formation. ECS had no effect on memory in LC-lesioned mice when administered 14 days following training. In a second experiment, the temporal relationship between time of memory formation and time of LC damage was found to be critical to the occurrence of this extended period of lability. In a third experiment, we tested the possibility that prolonged trace lability was the result of weaker memory formation as reflected by decreased persistence (i.e. faster forgetting) of the memory. The results indicated equal rates of forgetting for normal and LC-lesioned mice. Present results support the hypothesis that the locus coeruleus complex normally plays an important role in delimiting the time-course of initially labile stages of memory. By inference, these data suggest further that such a delimiting function of the locus coeruleus is mediated through its noradrenergic modulation of other brain regions.

Noradrenergic involvement in dopamine-dependent stereotyped and cataleptic responses in the rat.

Two animal models were used to investigate the effect of lowered central noradrenaline levels on two dopamine-dependent behavioural parameters in the rat. Newborn rats were injected with 6-hydroxydopamine or adult animals had bilateral electro-lesions placed in the region of the locus coeruleus in the brain stem. The effect of these two lesions on amphetamine- and apomorphine-induced stereotyped behaviour and on haloperidol-induced catalepsy was studied. 1. Both 6-hydroxydopamine treatment at birth and bilateral locus coeruleus lesions specifically harmed the ascending dorsal noradrenergic pathway, causing significant decreases in cortical and limbic forebrain noradrenaline concentrations. 2. Both types of lesion had no apparent effect on stereotyped behaviour induced by either amphetamine and apomorphine. 3. Both types of lesions significantly enhanced the cataleptic response induced by varying doses of the neuroleptic agent haloperidol. 4. The results indicate that noradrenergic function may partly influence some dopaminergic mechanisms, and its possible site of action in terms of neostriatal and limbic populations of dopamine receptors is discussed.

Brain stem self-stimulation attenuated by lesions of medial forebrain bundle but not by lesions of locus coeruleus or the caudal ventral norepinephrine bundle

Midbrain tegmental intracranial self-stimulation (ICSS) was not attenuated by ipsilateral or bilateral locus coeruleus lesions. Certain of these lesions were followed by histochemical confirmation that the majority of locus coeruleus neurons was destroyed, and biochemical evidence that over 80% of the cortical norepinephrine was depleted. To test the possibility that the surviving ICSS was due to stimulation of another norepinephrine system, histochemically verified ipsilateral or bilateral lesions of the ventral norepinephrine bundle were administered to a second group of midbrain tegmental ICSS animals. These lesions resulted in marked loss of body weight, but had no effect on ICSS. In a third experiment, lesions were made in the medial forebrain bundle (MFB) ipsilateral to midbrain tegmental ICSS electrodes. These lesions resulted in attenuation of ICSS which was directly proportional to the extent of MFB damage. On the basis of these data alone, however, it was not possible to identify the critical fibers supporting ICSS. It was concluded that the locus coeruleus does not play a necessary role in midbrain tegmental ICSS.

Impaired learning and decreased cortical norepinephrine after bilateral locus coeruleus lesions.

Bilateral lesions of the nucleus locus coeruleus in rats deplete the cerebral cortex of norepinephrine and significantly diminish the rate of increase of running for food reward in a simple L-shaped runway. As assessed in this situation, learning was absent in those rats with the most complete ablations of the locus coeruleus, although these rats showed normal weight gain and normal motor and exploratory activity.