0145-6008/96/2007-1141$03.00/0 zyxwvutsrqponm ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH Vol. 20, No. 7 October 1996 Differential Age-Related Loss of Pigmented Locus Coeruleus Neurons in Suicides, Alcoholics, and Alcoholic Suicides zy Victoria Arango, Mark D. Underwood, Donna K. Pauler, Robert E. Kass, and J. John Mann We previously reported fewer locus coeruleus zyxwvuts (LC) neurons in both suicide victims and alcoholics than among a group of nonpsychiatric controls. In the present paper we examine the rate of decline in the number of LC neuronswith age, looking for possibledifferential rates among suicide victims, alcoholics, and controls. We also compare these groups with a group of alcoholics who died by suicide, and consider the effects of sex, race, and postmortem interval. LC neu- ron counts were obtained from a total of zyxwvuts 32 subjects. In all groups, the number of neurons decreasedwith age, but by roughly age 40 the average LC count among the three suicide and/or alcoholic groups was lower than among controls. The rate of LC neuron loss was greater among suicides than among controls, but the rate of loss among alcoholics who were at least 30 years old was the same as that among the controls. Our group of alcoholic suicides had counts that were statistically indistinguishable from those of suicides. Dif- ferences among groups appear to be most pronouncedin the middle third of the LC. Further studies are neededto determine the mecha- nisms of noradrenergicneuron loss and whether it is associatedwith an underlying major depression in suicide victims, zyxwvutsr or acquiredafter a period of excessive alcohol consumption. Key Words: human, postmortem, norepinephrine, brainstem. RAIN ABNORMALITIES have been identified post- B mortem in tissue of suicide victims and alcoholics. Studies of the effect of alcohol and suicide on the brain are complicated by the degenerative process associated with aging. Although alcoholism or alcohol abuse has long been recognized as a significant risk factor for suicidal behavior, few studies have attempted to understand the compound effect of suicide tendencies, alcoholism, and age on the brain. A growing body of evidence suggests that suicide is as- sociated with not only reduced serotonergic neurotransmis- sion but also reduced noradrenergic function. Increased binding to P-adrenergic receptors in the cerebral cortex in From the Department zyxwvutsrqpo of Neuroscience and the zyxwvutsrqp NIMH Clinical Research Center for the Study of Suicidal Behavior, New York State Psychiatric Insti- tute, Department of Psychiaty, College of Physicians & Surgeons of Colum- bia University, New York, New York (VA., M.D.U., J.J.M.); and the Depart- ment of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania (D. K P., R. E. K ). Received for publication May 2, 1995; accepied March 10, 1996 This work was supported by AA09004, MH40210, MH44745, MH47097, CA54852, and the American Suicide Foundation. Reprint requests: Victoria Arango, Ph.D., Department zyxwvuts of Neuroscience, New York State Psychiatric Institute, 722 West 168th St., Box 28, New York, zyxwvut NY 10032. Copyright 0 1996 by The Research Society on Alcoholism. Alcohol Clin Erp Res, Vol20, No 7, 1996 pp 1141-1147 suicide victims has been reported by some inve~tigators~l-~ but not by other^.^-^ Some studies also report increased a,-adrenergic and/or a,-adrenergic receptor binding in sui- cide victims in the cerebral ~ o r t e x . ~ , ~ Too few studies of brainstem norepinephrine concentrations have been con- ducted to draw firm conclusions,9~10 but we recently found that the number of pigmented neurons in the locus coer- uleus (LC), which provide noradrenergic innervation to the cerebral cortex, was reduced in a group of suicide victims compared with control cases.” A minority12713 of stud- ies14-19 found reduced concentrations of the principal nor- epinephrine metabolite 3-methoxy7 4-hydroxyphenylglycol (MHPG) in the cerebral spinal fluid (CSF) of suicide at- tempters. Urinary excretion of MHPG appears to be re- duced in suicide at tempter^.'^.'^ Taken together, these studies suggest a relationship between reduced noradren- ergic neurotransmission and suicidal behavior. Similarly, the brain norepinephrine (NE) system is af- fected by exposure to alcoho120-22 but despite suggestive evidence in animals, studies of human tissue are scarce. We previously reported fewer pigmented LC neurons postmor- tem in alcoh~lics.~~ zyxw An age-related decline in the number of LC neurons has been reported by some,24-z7 although not investiga- tors. The reduction in LC neuron number appears to occur after the 7th decade, although there are relatively few cases in the literature at middle and younger ages. Consistent with the reports of declining numbers of LC neurons with age is the finding that the amount of norepinephrine trans- porter binding in the LC decreases with age.29 The rela- tionships among the LC, aging, and various disease states have been little explored. Noradrenergic innervation of the mammalian cerebral cortex is derived nearly exclusively from pigmented neu- rons of the LC.30-34 These neurons also provide wide- spread innervation throughout the neuraxis including the limbic system. Fewer LC neurons than normal has been reported in Alzheimer’s d i ~ e a s e , ~ ~ - ~ ~ Parkinson’s dis- depression726and alcoholism,z3741 suggesting that noradrenergic neurons may play a role in mood, mem- ory, and cognition. The studies of the LC in depression and alcoholism are of particular relevance given the high inci- dence of major depression and alcoholism in suicide vic- tim~.~~ 1141