Introduction

Norepinephrine-containing neurons clustered within the locus coeruleus (LC) provide most of the norepinephrine present within the central nervous system. These cells have tonic pacemaker activity and this activity is regulated by a variety of neurotransmitter inputs. The focus of this review is primarily on classical, non-neuropeptide, neurotransmitter input to the LC and the reciprocal projections of noradrenergic neurons to those classical neurotransmitter systems. Input to the LC from serotonin-, dopamine-, γ-aminobutyric acid (GABA)-, glutamate-, and acetylcholine-containing neurons are described. In addition, input from the neuropeptide, substance P, receives attention because of the interest in this neuropeptide in psychiatric disease. Special attention is given to reciprocal projections from the LC to the monoamine neurotransmitters dopamine and serotonin. See Chapter 1 for a detailed description of the anatomy of the LC.

Noradrenergic circuitry: input to the LC

Early tract-tracing studies suggested that the LC received widespread input from many sites in the brain. A combination of techniques, however, including discrete injections of a more sensitive tract-tracing compound, anterograde labeling studies, and single-pulse stimulation studies forced a reconsideration of brain areas with direct input to the LC. The major afferents to the LC are rostral medullary in origin, with cell bodies located in the nucleus paragigantocellularis (PGi, using excitatory amino acid neurotransmitters) and nucleus prepositus hypoglossi (PrH, using GABA). However, dense projections from many brain regions terminate in the pericoerulear area, an area heavily invested with dendrites from LC neurons, and in the PGi and PrH.

The discovery of norepinephrine dates back to the late 1940s when the Swedish scientist, Ulf Svante von Euler first demonstrated that neurons of the sympathetic nervous system use norepinephrine, rather than epinephrine, as a neurotransmitter. Shortly thereafter in 1947, Peter Wilhelm Joseph Holtz demonstrated that norepinephrine occurred in the brain. Today, we know it is one of three major cate-cholamine (dopamine, norepinephrine, epinephrine) neurotransmitters found in the central nervous system (CNS). Over 50 years of subsequent research has led to an enormous accumulation of information regarding norepinephrine and its role in physiological and behavioral processes. In addition, drugs that directly manipulate brain norepinephrine have been used therapeutically for over 50 years, and even today, drugs are being developed that target noradrenergic neurons to deliver therapeutic effects. In fact, new disease indications continue to be identified for existing and newer noradrenergic drugs.

Given the revered tenure of this relatively old neurotransmitter and the recent advances and subsequent theories about its contribution to health and disease in the CNS, the authors of this book decided the time was right to bring together historical and recent information about norepinephrine in one book. The intention of this volume is to provide the reader with a thorough understanding of the anatomy, physiology, molecular biology, pharmacology, and therapeutics of norepinephrine in the CNS, including an extensive review of the role of norepinephrine in diseases of the CNS.

The postmortem human brain as a tool to study central nervous system disease

Abnormalities in noradrenergic transmission are likely to play a role in behavioral expressions of a number of psychiatric and neurological disorders. The extent to which these abnormalities are pathognomonic, or even principal pathological features contributing to the illness, remains debatable. Interest in the potential for pathological abnormalities in central norepinephrine in central nervous system (CNS) disorders derives from the three general observations: (1) disruption of behaviors known to be heavily influenced by noradrenergic transmission that are associated with the illness; (2) demonstration that pharmacological manipulation of noradrenergic transmission can precipitate, modify, or alleviate symptoms of these disorders; and (3) certain CNS disorders are characterized pathologically by a loss of noradrenergic neurons in the brain. Research on the pathology of central noradrenergic systems in CNS diseases and their relationship to behavioral alterations utilizes a variety of techniques, most of which are technically indirect, given that we currently are unable to directly measure noradrenergic neuron activity, noradrenergic receptor signaling, or norepinephrine release in vivo in living humans. In vivo imaging methods now permit investigators to measure occupancy of certain receptors, but application of these methods specifically to noradrenergic proteins, such as receptors, enzymes or transporters, has been limited.

One method to study the role of norepinephrine in the CNS disorders is to utilize postmortem brain tissue from subjects with a given psychiatric or neurological condition.