Introduction

Traditionally, cognitive disorders have been associated with alterations in acetylcholine (e.g. Alzheimer's disease) or dopamine (e.g. attention-deficit/hyperactivity disorder). However, there is a long and consistent body of literature establishing that norepinephrine (NE) has profound effects on the cortical and subcortical cognitive functions that are disturbed in these syndromes. These findings from basic research, in concert with efficacy of clinical NE treatment modalities, indicate that NE plays a major role in many cognitive disorders.

The definition of “cognitive disorder” has expanded in recent years as neuroscience has identified impaired prefrontal cortical (PFC) cognitive function at the core of many neuropsychiatric illnesses. This chapter will review NE mechanisms influencing PFC, posterior cortical and subcortical functions, and review the evidence that NE is altered significantly in a range of disorders involved in higher cortical dysfunction.

NE innervation of cerebral cortex

The noradrenergic input to the cortex arises from the cells of the locus coeruleus (LC) at the pontine-midbrain junction in the brain stem. The noradrenergic fibers target layer I in the rodent cortex, but have an expanded, bilaminar distribution in the monkey cortex in both deep and superficial cortical layers. In primates, the densest NE innervation targets the somatosensory cortex in the parietal lobe, while the most sparse innervation is of the primary visual cortex. Higher cortical areas such as the PFC have a moderate NE input.