Lower Central Nervous System Serotonergic Function and Risk of Cardiovascular Disease

Abstract

See related article, pages 2228–2233. In 1994 I hypothesized that “deficient central nervous system serotonergic function” is a neurobiological substrate that could account for the clustering of psychosocial, biological and behavioral characteristics that increase risk of developing cardiovascular disease.1 It is gratifying, therefore, to see in this issue of Stroke the report by Muldoon et al2 that an established index of reduced central nervous system (CNS) serotonergic function—a smaller prolactin response to intravenous administration of the selective serotonin reuptake inhibitor (SSRI) citalopram—is associated with more severe preclinical atherosclerosis as indexed by carotid artery intima-medial thickness. This finding provides encouraging evidence that dysregulated CNS serotonergic function plays a role in the pathogenesis of cardiovascular disease (CVD). There are 2 questions that must be addressed, however, before this role can be considered as established, the precise mechanisms understood, and the knowledge used to guide the development of improved approaches to the prevention, treatment and rehabilitation of CVD. First, what determines the individual differences in prolactin response to 5HT reuptake inhibition? One important source of this variability across individuals is variation in genes that regulate 5HT synthesis (tryptophan hydroxylase), release and reuptake (5HT transporter) and metabolism (monoamine oxidase-A), and encode for 5HT receptors that mediate effects of synaptic 5HT on CVD endophenotypes. In their prior work this same group has demonstrated the importance of variation in some of these genes by showing that functional polymorphisms in the 5HT transporter ( 5HTTLPR ) and monoamine oxidase-A ( MAOA-uVNTR ) genes moderate the prolactin response to agents that increase synaptic 5HT in the CNS.3,4 5HTTLPR genotype also influences …