Selective ablation of dopamine β-hydroxylase neurons in the brain by immunotoxin-mediated neuronal targeting: new insights into brain catecholaminergic circuitry and catecholamine-related diseases.

Abstract

The locus coeruleus (LC) has been implicated in a variety of physiological functions including sleep/wakefulness, cognition/memory, stress/emotion, and pain. Marked loss of LC-noradrenergic (NAergic) neurons is observed in autopsy specimens of patients with Alzheimer's disease and Parkinson's disease (PD), and part of the clinical symptoms of these diseases may be related to dysfunction of the LC. Neurotoxins have been utilized to ablate LC-NAergic neurons in experimental animals for elucidating the pathophysiological implication of the loss of LC, but there are methodological drawbacks in previously utilized methods. We employed immunotoxin-mediated neuronal targeting to overcome these problems. Following complete disruption of the LC-NAergic neurons by immunotoxin, mice showed behavioral changes, which resembled the nonmotor symptoms of PD. The LC-NAergic neurons did not regenerate following ablation, so the immunotoxin-mediated neuronal targeting may be useful especially for studying the long-term effects of the loss of LC-NAergic neurons on brain functions.