There is an old joke that applies to the past–and only the past–of psychopharmacology: One dark night, a police officer notices a man furiously searching for something beneath a street lamp. “What are you looking for?“ he asks. The man replies, “My car keys. If I don't find them, I'll never get home.” “Well,” asks the police officer, “did you lose them here?” “No,” the man replies. “But this is the only place on the block that has any light.”

For example, once it was discovered that tricyclic antide pressants antagonize the presynaptic neuronal reuptake of norepinephrine (NE), the idea was put forth that the problem in depression is some abnormality in noradrenergic function. Some of the tricyclics, like desipramine and nortriptyline, are actually selective NE reuptake inhibitors. However, once it became apparent that selective serotonin (5-HT) reuptake inhibitors (SSRIs) are also effective in treating depression, consideration of the noradrenergic system suddenly disappeared from the literature, replaced by a new hypothesis that depression is caused by deficient serotonergic neurotransmission.

Over 20 years ago, Monte Buchsbaum first presented metabolic brain images belonging to a patient with schizophrenia at the American Psychiatric Association's annual meeting. This was a truly remarkable achievement brought about by the combined skills of the deoxyglucose technique developed by Lou Sokoloff and colleagues, and the advancement of statistical algorithms for the analysis of computerized images. Positron emission tomography (PET) had arrived, but more importantly, the imaging era of neuropsychiatry was dawning. Since then, we have been treated to a glorious array of technical developments which has seen not only coregistration of functional images (ie, PET) with corresponding structure (magnetic resonance imaging [MRI]), but a proliferation of MRI techniques that allow not only temporal and spatial resolutions undreamed of two decades ago, but permit safe, repeated testing of patients, allowing for experiments of considerable sophistication to be designed.

Now, at any neuroscience meeting, many presentations are accompanied by brain images, often PETs. However, more and more often now we are seeing one form or another of MRI. Such images are displayed from various angles, adorned with multiple colors, and garnished with institutional logos, confirming (and less regularly refuting) the presenter's hypothesis about how the brain is supposed to work in relation to various cerebral functions.

Norepinephrine and epinephrine are involved in the control of several important functions of the central nervous system (CNS), including sleep, arousal, mood, appetite, and autonomic outflow. Catecholamines control these functions through activation of a family of adrenergic receptors (ARs). The ARs are divided into three subfamilies (α1, α2, and β) based on their pharmacologic properties, signaling mechanisms, and structure. ARs in the CNS are targets for several therapeutic agents used in the treatment of depression, obesity, hypertension, and other diseases. Not much is known, however, about the role of specific AR sub-types in the actions of these drugs. In this paper, we provide an overview of adrenergic pharmacology in the CNS, focusing on the pharmacologic properties of subtype-selective AR agonists and antagonists, the accessibility of these drugs to the CNS, and the distribution of ARs in different areas of the brain.

The concatenation of convergent lines of evidence from basic to clinical research continues to reveal that norepinephrine (NE) is a crucial regulator of a myriad of behaviors ranging from stress response to memory formation. Furthermore, many neuropsychiatric disorders involve neurocircuitry that is directly modulated by NE. This report summarizes the physiological roles of NE, as well as the main findings implicating a role for NE system dysfunction in mood and anxiety disorders, posttraumatic stress disorder, attention-deficit/hyperactivity disorder, and Alzheimer's disease. In each of these disorders, there appears to be a complex dysregulation of NE function, with changes in locus ceruleus firing, NE availability, and both pre- and postsynaptic receptor regulation. Many symptoms of these disorders are attributable to abnormalities within distributed neural circuits regulated by NE. Appreciation of NE's role in modulating the neural circuitry mediating cognition and affect should help elucidate the pathophysiology of a variety of neuropsychiatric disorders and the development of novel treatments.

Presynaptic norepinephrine transporters (NETs) mediate the rapid clearance of norepinephrine from synaptic spaces. NET is a member of the Na+ and Cl− -coupled neurotransmitter transporter gene family, which also includes the serotonin and dopamine transporters. Recent studies reveal that these transporter molecules might be a dynamic component of synaptic plasticity, rather than a constitutive determinant of neurotransmitter levels in synaptic spaces. Recognition that cellular signaling molecules and transporter ligands, including cocaine, amphetamines, and antidepressants, can modify transporter intrinsic activity, trafficking, phosphorylation, and protein levels suggests opportunities for revealing unknown mechanisms of drug action. Control of these properties of transporter function may allow for the development of new strategies to modulate monoaminergic neurotransmission and identify regulatory pathways that may be compromised in psychiatric, neurologic, and neurodegenerative disorders.

Environmental stimuli and drugs affect the norepinephrine (NE) system and may be linked to the manifestation and treatment of anxiety and affective disorders. The activity of locus ceruleus NE neurons in the brainstem can alter the function offorebrain structures associated with several psychiatric disorders. In particular, NE neurons send and receive projections from sensory afferents, limbic areas, and cortical areas implicated in higher-order brain malfunctions and the symptomatology of anxiety and affective disorders. In turn, anxiolytic and antidepressant drugs are able to offset perturbations of NE activity and forebrain structures with a time course congruent with their therapeutic action. All antide-pressants, even the agents selective for other biogenic amines or peptides, act on the NE system. In the present review, the effects of antidepressants on NE neurons are summarized and applied to the treatment of neuropsychiatric disorders, with emphasis placed on mechanisms of action.

Antiepileptic drugs (AEDs) have a broad range of activity in the central nervous system and can thus be expected to have multiple clinical effects. Older AEDs have been used in psychiatry for some time. Introduction of the new AEDs within the last decade has been followed by reports of their efficacy in patients who had failed the more established treatment regimens. It has become evident that drugs such as gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, zonisamide, and tiagabine have beneficial safety and cognitive profiles and appear to be well tolerated by patients. While there are an increasing amount of data available indicating that these drugs may be effective in treating certain aspects of anxiety disorders, depression, and bipolar disorder, still not enough is known about all of their potential uses. It is difficult for clinicians to evaluate and use these drugs in the absence of clinical trials. Until more studies are done to increase the evidence base for the effectiveness of these agents, we have to rely on observations from community practice and personal experiences in making treatment choices.

In this paper, we review research utilizing postmortem brain tissue in order to investigate the potential neuropathology of the noradrenergic system in psychiatri disorders. The postmortem tissue approach to the study of the noradrenergic system has been used primarily in investigations of the biology of suicide and depression. Findings from postmortem studies provide data generally consisten with the hypothesis that a norepinephrine deficiency exist depression, and possibly in the victims of suicide. However postmortem studies do not presently provide irrefutable evidence of noradrenergic neuropathology. Technical shortcomings, issues of reproducibility, and the strengths postmortem research are reviewed. More rigorously performed postmortem research is needed to aid researchers in pinpointing specific neuropathologies associated with psychiatric disease.

In the central nervous system, the neurotransmitter norepinephrine is involved in normal physiology, neuropsychiatric disorders, and the effects of numerous drugs. Although alterations of the central noradrenergic system are involved in the pathophysiology and pharmacotherapy of mood disorders, the basis and nature of these changes remain unresolved. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging agents will be valuable for further elucidating the roles of norepinephrine in health and disease. This review discusses PET and SPECT radioligands that have been developed for the enzymes, receptors, and transporters involved in noradrenergic neurotransmission. Currently, imaging agents that exhibit specific in vivo uptake in the brain have been described for monoamine oxidase A and β-adrenergic receptors, but have not undergone detailed evaluation or experimental application. Based on the successful development and utilization of in vivo imaging agents for elements of the central dopaminergic and serotoninergic systems, PET and SPECT radioligands are expected to serve as new tools for studying the physiology, pathophysiology, and pharmacology of the central noradrenergic system.

In recent years, a number of antidepressants with varying degrees of selectivity for the noradrenergic neurotransmitter system have become available. However, these agents represent a pharmacologically heterogeneous group and differ in terms of their precise side-effect profile and, possibly, their clinical efficacy. Bupropion, which is thought to act on both the dopamine and norepinephrine (NE) systems, has not been widely used as an antidepressant and has more recently been licensed as adjunctive therapy for smoking cessation. The serotonin-NE reuptake inhibitors venlafaxine and nefazodone, the noradrenergic and specific serotonergic antide-pressant mirtazapine, and the selective NE reuptake inhibitor reboxetine (the only truly NE-selective agent available) have all demonstrated efficacy in the treatment of depressive disorders. Evidence is now emerging for their use in the treatment of anxiety and panic disorders. There is some suggestion of a role for noradrenergic agents in other disorders, including attention-deficit/hyper-activity disorder and social phobia. The full range of disorders for which noradrenergic agents can be used remains to be seen and further research in this area is necessary.