A biogenic amine that functions as a Neurotransmitter and a hormone

Noradrenaline (NA, alias norepinephrine, 2-amino-1-(3,4-dihydroxyphenyl)ethanol) belongs to a family of compounds called catecholamines (see also *dopamine). It is synthesized from dopamine in the brain, sympathetic nerve, adrenal medulla, and heart by the enzyme dopamine-P-hydroxylase (DBH; Cooper et al. 1996). Noradrenaline fulfils multiple roles in *development, physiology, and behaviour (Mason 1984; Thomas et al. 1995; Thomas and Palmiter 1997a). A related catecholamine, adrenaline (AD, alias epineph-rine) is synthesized from NA by the enzyme phenyl-ethanolamine N-methyltransferase. Adrenaline was the first substance to be proposed as a neurotransmitter (Elliott 1904). In the periphery both NA and AD act as transmitters and hormones. In the brain, NA is much more abundant than AD, and less is known about the function ofthe latter.

The noradrenergic innervation in the brain is diffused and reaches a large variety of targets. The majority of the noradrenergic innervation originates in the locus ceruleus, in the pontine central grey (Figure 50). This cluster contains about 3000 neurons in the rat and 25,000 in human. Several major nora-drenergic tracts travel from the locus ceruleus and innervate targets in most of the brain. Noradrenergic neurons also reside outside the locus ceruleus, in the lateroventral tegmentum. Much of their output intermingles with that of the locus ceruleus but the targets are not identical.

Fig. 50 A schematic diagram of the central noradrenergic projections from the locus ceruleus (LC) in the mammalian brain. Only selected targets are marked. CTX, cerebral cortex; HIP, hippocampus; OB, olfactory bulb; TEC, tectum; TH, thalamus. (Adapted from Cooper et al. 1996.)

NA released from nerve terminals interacts with adrenergic *receptors (adrenoreceptors). These exist in multiple types, which differ in their localization, ligand binding properties, and downstream *intracellular signal-transduction cascades. A major classification of noradrenergic receptors is on the basis of rank affinity for NA, AD, and the synthetic agonist isopernaline (ISO); a-adrenoreceptors are defined as NA>AD >> ISO, and P-adrenoreceptors as ISO > AD = NA. All the adrenoreceptors are targets for potent drugs (Milligan et al. 1994). As is the case with many other neurotrans-mitters and neuromodulators, additional NA bindingproteins exist in brain, including cross-membrane transporters, active in reuptake (Blakely and Bauman 2000). The transporters are also targets for efficient neuroactive drugs.

The fact that noradrenergic drugs affect performance on memory tasks, and that the turnover of NA in the nervous system correlates with certain behavioural states, has led already more than 30 years ago to the suggestion that NA plays a part in learning and memory (Kety 1970). It is now agreed that in a variety behavioural paradigms, memory is enhanced by treatments that induce NA release or activate NA receptors, and impaired by treatments that reduce NA release or block NA receptors (Mason 1984; McGaugh and Cahill 1997; Roullet and Sara 1998). There is especially strong evidence for the involvement ofadrenoreceptors in the *amygdala in the storage of information for inhibitory avoidance (McGaugh and Cahill 1997; Ferry et al. 1999). Adrenoreceptors are also obligatory in the *cortex for the formation ofmemory in another avoidance paradigm, *conditioned taste aversion (Berman et al. 2000). In some other learning situations NA ligands were reported to have no effect (Pontecorvo et al. 1988). Similarly, mice lacking NA because of a knockout (*neurogenetics) in the DBH gene, display only mild defects in some learning and memory tasks and perform normally in others (Thomas and Palmiter 1997fe,c). All in all, the pharmacological, neuroanatomi-cal and genetic interventions suggest that NA affects functions that are obligatory for memory formation only in certain situations.

What could these functions be? There is evidence that the noradrenergic system contributes to the encoding of selective *attention, vigilance and novelty detection, stress, emotion, and motivation (Steketee et al. 1989; Decker and McGaugh 1991; Aston-Jones et al. 1994; Smith and Nutt 1996). NA does this in concert with other neuromodulatory systems, such as *acetylcholine and dopamine (Hasselmo 1995; McGaugh and Cahill 1997). At the system level, the

Fig. 50 A schematic diagram of the central noradrenergic projections from the locus ceruleus (LC) in the mammalian brain. Only selected targets are marked. CTX, cerebral cortex; HIP, hippocampus; OB, olfactory bulb; TEC, tectum; TH, thalamus. (Adapted from Cooper et al. 1996.)

aforementioned functions could be achieved via noradrenergic activation of the amygdala (McGaugh and Cahill 1997), of the cortex, and of the reciprocal thalamocortical processing (McCormick 1989; the modulation of thalamocortical information could specifically subserve novelty detection, Ahissar et al. 1997; "surprise). At the cellular level, it is noteworthy that NA was found to modulate "glutamatergic N-methyl-o-aspartate receptors in "hippocampus, via the cyclic adenosine monophosphate cascade (Gereau and Conn 1994; Raman et al. 1996). This fits with the idea that NA contributes to the encoding of "context, which modulates glutamatergic input, affects cellular signal-to-noise ratio (Segal and Bloom 1976; Hasselmo 1995; Jiang et al. 1996), and contributes to the overall decision made by the neuron and the circuit, whether or not to retain the incoming information.

The possibility could be raised that the activity of the noradrenergic system, similarly to that of the choliner-gic and the dopaminergic systems, is not essential for the operation of the 'core' molecular machinery that embodies lasting "synaptic changes in some systems of the mammalian brain. The distinction between a 'core' and an 'accessory' synaptic storage system is not self-evident. Generally speaking, it implies that there are molecular cascades that are essential for synaptic storage and there are others that are indispensable for encoding distinct cellular and circuit states but dispensable for the storage process per se. For example, certain subtypes of the intracellular signalling cascades that lead to the modulation of gene expression and to "protein synthesis in "consolidation of long-term memory, could be regarded as components of the core machinery of synaptic storage. It is likely that in a variety of areas of the mammalian brain, glutamatergic transmission is essential for the in vivo triggering of this core machinery. In contrast, certain neuromodulatory systems may trigger state-dependent activation of the core machinery or set the threshold of its activation, but storage could take place in their absence, provided the core machinery was set into action by other means. The identity of the core machinery itself, however, may still depend on the task.

Selected associations: Context, Dopamine, Neurotransmitter, Receptor, Synapse

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