The following is an extended excerpt from Floyd Bloom’s Feb 2010 review “The catecholamine neuron: Historical and future perspectives” from Progress in Neurobiology. It provides the best summary I’ve read on the physiology of the noradrenergic modulatory neurotransmitter system. Note that deficits in this neurotransmitter system are hypothesized to underlie attention deficit hyperactivity disorder (ADHD), and the mechanism of action of Ritalin (methylphenidate) and Adderol (amphetamine/dextroamphetamine) is to increase norepinephrine release from noradrenergic neurons. At a visiting-professor lunch, Dr. Aston-Jones told me that, non-intuitively, treatments for ADHD probably work by decreasing stimulus-induced norepinephrine release. A tonic increase of synaptic norepinephrine produced by the drug binds presynaptic alpha-2 autoreceptors and downregulates neurotransmitter release in response to unexpected stimuli. The consequence is a decreased likelihood of breaking one’s attention in response to unimportant environmental stimuli, and an improved ability to focus on the task at hand.
When do LC–NE neurons fire?
Although it was known that the locus ceruleus (LC) was the source of NE axonal projections across most of the neuraxis except the hypothalamus, direct electrophysiological observation of the firing patterns of these neurons was delayed until the mid-1970s, first in anesthetized rodents (Korf et al., 1974) and then in unanesthetized, freely behaving rats ([Aston-Jones and Bloom, 1981a] and [Aston-Jones and Bloom, 1981b]) and monkeys (Foote et al., 1980). The observations in the freely behaving animals greatly refined the anticipated functional repertoire of the LC neurons. In the anesthetized animal recordings, an early common feature was responsiveness to nociceptive stimuli, such as pressure on a paw or the tail; in fact, this nociceptive response was employed as one of the identifying electrophysiological parameters of LC neurons. From this response pattern, investigators predicted that LC discharge, and release of norepinephrine would generate anxiety as a functional consequence. However, when the discharge patterns of LC neurons were repeated in freely behaving rats and monkeys, these response patterns could be re-interpreted: instead of responding only to painful stimuli, LC neurons exhibited a more general and subtle pattern of activity: a slow, tonic, basal discharge rate, but with brief phasic responses to novel sensory stimuli of all kinds—visual, auditory, somato-sensory and gustatory. Furthermore, these neurons showed an interesting correlation between neuronal firing rate and wakefulness, with progressive diminution of already slow basal activity as the animals engagement with its environment decreased, and complete silencing of activity as the animal entered rapid eye movement sleep.
Just as the functional significances of the firing patterns of the DA neurons was refined from a simple ‘firing with reward’ concept to a more refined and biologically more profound functional consequence of error prediction, so has the insight into the behavioral consequences of the LC firing patterns been refined: from an initial, nociceptive-anxiety prediction, to more a general sensory events-alerting, with an attentional prediction.
(Aston-Jones and Cohen, 2005a) and (Aston-Jones and Cohen, 2005b) have taken these observations to a further refined interpretation with an integrative theory of locus coeruleus-norepinephrine function, that they term ‘adaptive gain and optimal performance’ invoking a more complex and specific role in the control of behavior than was previously thought. In their view, phasic LC activation is driven by the outcome of task-related decision processes and is proposed to facilitate ensuing behaviors and to help optimize task performance (exploitation). When the subject’s engagement in the task wanes, LC neurons revert to a slow tonic firing. They further note that in the non-human primate (and presumably also in man) the LC receives substantive inputs from the anterior cingulate cortex and the orbitofrontal cortices. As mentioned earlier, in the now-classic immunohistochemical mapping studies of Lewis and Morrison (see [Lewis et al., 1986] and [Lewis and Morrison, 1989]), these are precisely the forebrain regions with the most dense innervation by LC fibers, and are forebrain regions later shown by (Aston-Jones and Cohen, 2005a) and (Aston-Jones and Cohen, 2005b) and their co-workers that also send direct afferent connections to the LC neurons.
Aston-Jones and Cohen further propose that it is the output of these cortical afferent systems, known to monitor task-related utility that confers on the LC’s broad output the capacity to optimize utility on both short and long timescales. Cohen and his co-workers have expanded our views of these LC discharge patterns together with the post-excitatory refractory period attributed to noradrenergic collateral signals within the locus coeruleus to attribute to these neurons a role in attentional blink, a temporary deficit in processing of a target stimulus following successful processing of a previous target (Nieuwenhuis et al., 2005). Those observations, together with analyses of human visual and auditory discrimination tasks have created a very plausible case for attributing the p300 event related potential recorded with scalp electrodes in man to the novelty detection and attention focusing consequences of LC activation. Furthermore, when one considers the relatively short latency with which the LC neurons react to a salient and unexpected sensory stimulus (around 100 ms), the firing of LC axons to the cortex would allow for the synchronous activity at the tempero-parietal junction that is presently thought to be the origins of the P300 (see Aston-Jones and Cohen, 2005a G. Aston-Jones and J.D. Cohen, Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance, J. Comp. Neurol. 493 (2005), pp. 99–110. View Record in Scopus | Cited By in Scopus (53)[Aston-Jones and Cohen, 2005a], [Aston-Jones and Cohen, 2005b] and [Corbetta et al., 2008]).
What does NE do to target neurons?
As has been noted in many prior reviews, the initially reported effects of iontophoretically administered norepinephrine was to suppress the spontaneous activity of cerebellar Purkinje cells, dentate granule and hippocampal pyramidal neurons, and cerebro-cortical pyramidal neurons ([Aston-Jones et al., 1998], [Berridge and Waterhouse, 2003] and [Foote et al., 1983]). More in depth analysis, however, revealed that while basal activity was suppressed, the responses to spontaneous or evoked afferents was enhanced, both for excitatory and for inhibitory inputs; these sorts of modulatory effects help establish in my mind, if not for others, the dynamic synaptic vocabulary for monoamine neurons that I have long envisioned (Bloom, 1973). While we have long attributed most of this ‘enabling’ action to the transductive consequences of the beta-receptor and intracellular generation of cyclic adenosine monophosphate (Bloom et al., 1975), there are also reports that the actions of locally applied NE in cerebellum and hippocampal formation can be better antagonized by systemic alpha blockers than by beta blockers (Staunton et al., 1988). This is clearly an inconsistency that deserves further attention. One possibility for this discrepancy is that alpha-1 adrenergic receptors, like D1 dopaminergic receptors have a higher affinity for the natural ligand and their antagonists than the beta-adrenergic receptor and the D2 receptors (see [Arnsten and Goldman-Rakic, 1987] and Arnsten et al., 1999 A.F. Arnsten, R. Mathew, R. Ubriani, J.R. Taylor and B.M. Li, Alpha-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function, Biol. Psychiatry 45 (1999), pp. 26–31. Article |
PDF (98 K) | View Record in Scopus | Cited By in Scopus (98)[Arnsten et al., 1999]).