Locus coeruleus

Two AT-II receptors, AT and AT2 are known and show wide distribution (27). The AT receptor has been cloned and predominates ia regions iavolved ia the regulation of blood pressure and water and sodium retention, eg, the aorta, Hver, adrenal cortex, and ia the CNS ia the paraventricular nucleus, area postrema, and nucleus of the soHtary tract. AT2 receptors are found primarily ia the adrenal medulla, utems, and ia the brain ia the locus coeruleus and the medial geniculate nucleus. AT receptors are GCPRs inhibiting adenylate cyclase activity and stimulating phosphoHpases C, A2, and D. AT2 receptors use phosphotyrosiae phosphatase as a transduction system. 

NET (SLC6A2) Noradre-naline, dopamine 1 CNS noradrenergic neurons (emanate from locus coeruleus and lateral tegmental area), sympathetic nervous system Clearance of interstitial neuro-transmitter, reuptake into neurons... 

Ethanol also reduces the activity of the noradrenergic system in the locus coeruleus, and alterations in norepinephrine activity may account for some aspects of intoxication and the abstinence syndrome. The 0.2 antagonist clon-idine and the P-receptor antagonist propranolol reduce some symptoms of alcohol withdrawal (Bailly et al. 1992 Carlsson and Fasth 1976 Dobrydnjov et al. 2004 Kahkonen 2003 Petty et al. 1997 Wong et al. 2003). 

Cionidine. Clonidine dampens sympathetic activity originating at the locus coeruleus by stimulation of presynaptic a2-adrenergic receptors in the sympathetic chain (Covey and Classman 1991 Hughes 1994). It appears to have some efficacy for alcohol and opioid withdrawal and thus was evaluated for treatment of nicotine withdrawal as well (Covey and Classman 1991 Hughes 1994). Several clinical trials used oral or transdermal clonidine in doses of 0.1—0.4 mg/day for 2—6 weeks with or without behavior therapy. Three meta-analytic reviews reported that clonidine improved quit rates (Covey and Classman 1991 Courlay and Benowitz 1995 Law and Tang 1995). 

Pali), P and Stamford, JA (1994) Real-time monitoring of endogenous noradrenaline release in rat brain slices using fast cyclic voltammetry. 3. Selective detection of noradrenaline efflux in the locus coeruleus. Brain Res. 634 275-282. 

Certainly the activity of tyrosine hydroxylase is greater in the DA neurons of the substantia nigra (17.5 nmol dopa synthesised/mg protein/h) than in the NA neurons of the locus coeruleus (4-5), as is the turnover of the amine itself (1.7 pg/h) compared with that of NA (1.0) (see Bacopoulus and Bhatnager 1977). In the caudate nucleus and nucleus accumbens the turnover of DA is even higher at 7.4 and 2-6 pg/g/h respectively. 

Figure 8.2 The distribution of noradrenergic neurons in the brain. The cell bodies are clustered in nuclei (A1 A7) in the pons/medulla regions of the brainstem and their axons project both rostrally and caudally to most regions of the neuraxis. The major nucleus is the locus coeruleus...

Many brain areas are innervated by neurons projecting from both the locus coeruleus and the lateral tegmental system but there are exceptions (Fig. 8.3). The frontal cortex, hippocampus and olfactory bulb seem to be innervated entirely by neurons with cell bodies in the locus coeruleus whereas most hypothalamic nuclei are innervated almost exclusively by neurons projecting from the lateral tegmental system. The paraventricular nucleus (and possibly the suprachiasmatic nucleus, also) is an exception and receives an innervation from both systems. 

It is the a2A/D-adrenoceptor that predominates in the locus coeruleus and this subtype seems to be responsible for reducing neuronal excitability and transmitter release. Strangely, immunocytochemical studies suggest that most a2c-receptors are intracellular. The explanation for this finding and its functional implications are as yet unknown but it could reflect differences in intracellular trafficking of different receptor subtypes. 

Many electrophysiological studies have shown that single-unit activity of noradrenergic neurons in the locus coeruleus is increased by sensory stimuli. Effective stimuli range from those causing physical discomfort (e.g. footshock) and interoceptive... 

Several findings support this model. For instance, an early report suggested that there is a positive correlation between the density of (postsynaptic) jS-adrenoceptors in rat cortex and behavioural resistance to a mild environmental stress (novelty and frustration) but a negative correlation between these parameters when the stress is intensified (Stanford and Salmon 1992). More recently, it has been proposed that the phasic response of neurons in the locus coeruleus (which governs attentiveness ) depends on their tonic activity (which determines arousal). Evidence suggests that the relationship between these two parameters is described by a bell-shaped curve and so an optimal phasic response is manifest only at intermediate levels of tonic activity (Rajkowski et al. 1998). 

Aston-Jones, G, Shipley, MT, Chouvet, G et al. (1991) Afferent regulation of locus coeruleus neurons anatomy, physiology and pharmacology. Prog. Brain Res. 88 47-73. 

Aston-Jones, G, Rajkowski, J, Kubiak, P and Alexinsky, T (1994) Locus coeruleus neurons in monkey are selectively activated by attended cues in a vigilance task. J. Neurosci. 14 4467 480. 

Cederbaum, JM and Aghajanian, GK (1976) Noradrenergic neurons of the locus coeruleus inhibition by epinephrine and activation by the alpha-antagonist piperoxane. Brain Res. 112 413-419. 

Rajkowski, J, Kubiak, P, Ivanova, S and Aston-Jones, G (1998) State-related activity, reactivity of locus coeruleus neurons in behaving monkeys. Adv. Pharmacol. 42 740-744. 

The enzyme /i-phenylethanolamine-A-methyl transferase, which is required to convert noradrenaline (NA) to adrenaline (Ad), is present in the CNS and there is histofluoro-metric evidence (positive staining with antibodies to that enzyme and to tyrosine hydroxylase and dopamine /i-hydroxylase as well) for adrenergic cell bodies in two groups (nuclei) alongside NA neurons of the locus coeruleus (EC) but ventral and lateral (Ci) and dorsal and medial (C2) to it. Projections go to the hypothalamus and in... 

Of course, cholinergic neurons are not the only ones with axon terminals in the cortex and if their degeneration does originate in the cortex then other afferants and their neurons could also be affected. This contention is supported by reported reductions in the number of NA neurons in the locus coeruleus, and 5-HT neurons in dorsal raphe but these are less marked (approximately 50%) than the loss of cholinergic neurons. Accompanying reductions in cortical NA and 5-HT are also seen but are again lower than those for ChAT but 5-HT2 receptors are reduced (43%). 

The first suggestion that abnormal noradrenergic transmission was linked with anxiety came from Redmond s laboratory in the 1970s when he drew attention to the similarities in the symptoms and signs of anxiety with those of the acute stress response (Redmond and Huang 1979). He went on to stimulate the locus coeruleus of (chair-restrained) monkeys and showed that this caused behavioural changes, some of which resembled a cluster of behaviours displayed by the animals when under threat. This work led to the proposal that anxiety was due to (or exacerbated by) excessive... 

Kask, A, Rago, L and Harro, J (1998) Anxiolytic-like effect of neuropeptide Y (NPY) and NPY13-36 microinjected into vicinity of locus coeruleus in rats. Brain Res. 788 345-348. 

Libet, B and Gleason, CA (1994) The human locus coeruleus and anxiogenesis. Brain Res. 634 178-180. 

Rasmussen, K and Jacobs, BE (1986) Single unit activity of locus coeruleus neurons in the freely moving cat IE Conditioning and pharmacological studies. Brain Res. 371 335-344. 

Redmond, DE and Huang, YH (1979) New evidence for a locus coeruleus-norepinephrine connection with anxiety. Life Sci. 25 2149-2162. 

Curtis, A and Valentino, RJ (1994) Corticotropin-releasing factor neurotransmission in locus coeruleus a possible site of antidepressant action. Brain Res. Bull. 35 581-587. 

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