Relationship of Psychopathology to the Human Serotonin1B Genotype and Receptor Binding Kinetics in Postmortem Brain Tissue

Abstract

Knockout of the 5-HT 1B gene in mice results in increased aggression, as well as alcohol and cocaine consumption. Given the clinical association of aggression, suicide, alcoholism, and substance abuse, we studied relationship of psychopathology to the human 5-HT 1B receptor gene (N ϭ 178) and postmortem human 5-HT 1B receptor binding (N ϭ96Several neuropsychiatric disorders such as mood disorders, substance abuse, or alcoholism have been associated with dysfunctions of the central serotonergic system (Coppen 1972;Goodwin and Post 1983;Ballenger et al. 1979;Virkkunen et al. 1994). The risk for suicidal behavior and aggressive acts has been suggested to be related to a common underlying predisposition to impulsive behavior that is modulated by serotonergic activity (Mann 1998). In rodents and primates, aggressiveness is increased after inhibition of serotonin synthesis or in association with lower serotonergic activity (Vergnes et al. 1986;Molina et al. 1987;Higley et al. 1992). Both suicidal acts and aggression have a genetic contribution in terms of cause or diathesis that is independent of the heritability of major psychiatric disorders (Brent et al. Received October 15, 1998; revised February 15, 1999; accepted February 25, 1999. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 2 Psychopathology and Human 5-HT 1B Binding and Genotype 239 1996;Roy 1986;Roy et al. 1991;Schulsinger et al. 1979). The mechanism whereby genetics can affect aggressive and suicidal behavior is not known. The serotonergic system is one possibility because serotonergic activity is under substantial genetic control (Ishikawa et al. 1989;Higley et al. 1992;van Harten 1993). Patients at risk for suicidal acts not only have an increased level of lifetime aggression (Mann and Arango 1998), but also an increased rate of alcoholism and substance abuse. Alcoholism and substance abuse may facilitate suicidal acts, or may share a common predisposing factor with suicide and aggression, such as lower serotonergic activity. Genetic factors play a role in alcoholism (Schuckit et al. 1985) and major depression (Gershon et al. 1989) but their precise nature is unknown. Again, the serotonergic system may play a role.Recently, aggressive behavior as well as increased alcohol and cocaine intake have been reported in 5-HT 1B receptor gene knockout mice (Saudou et al. 1994;Ramboz et al. 1996;Crabbe et al. 1996;Rocha et al. 1998). This set of observations raises the possibility that abnormalities in the 5-HT 1B receptor gene may contribute to human psychopathologies such as suicide, aggression, major depression, alcoholism, or substance abuse.Molecular cloning techniques have revealed the existence of two humans 5-HT 1D receptor subtypes: 5-HT 1D ␣ and 5-HT 1D ␤ (Hamblin and Metcalf 1991;Demchyshyn et al. 1992;Weinshank et al. 1992;Levy et al. 1992). The mouse 5-HT 1B receptor is the homologue of the human 5-HT 1D ␤ . We have adopted the recommendation that the human 5-HT 1D ␤ receptor be renamed human 5-HT 1B (h5-HT 1B ) receptor (for a review see H...

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The 5HT1Dβ Receptor Gene in Bipolar Disorder A Family-based Association Study

“…A recent post-mortem study has suggested differences in the number and in the pharmacological properties of the 5HT1D␤ sites between subjects heterozygous and homozygous for the G variant (Huang et al 1999). However, further investigations are needed to better clarify this issue.…”

Consensus paper of the WFSBP Task Force on Biological Markers: Biological Markers in Depression

“…G861C, or most likely a variant in linkage disequilibrium with G861C, exhibits functional effects. Investigating variants of the 5-HT1B receptor in major depression, most of the studies do not find an association between the 5-HT1B receptor and major depression (Huang et al 1999;Fehr et al 2000;Tsai et al 2004). A single postmortem study investigating prefrontal cortical 5-HT1B receptor binding did not find differences between major depression and controls (Huang et al 1999).…”

“…Investigating variants of the 5-HT1B receptor in major depression, most of the studies do not find an association between the 5-HT1B receptor and major depression (Huang et al 1999;Fehr et al 2000;Tsai et al 2004). A single postmortem study investigating prefrontal cortical 5-HT1B receptor binding did not find differences between major depression and controls (Huang et al 1999). A cofactor of the 5-HT1B receptor, S100A10 (also termed p11) has been suggested to play a role in depression (Svenningsson et al 2006); however, its effect may also relate to anxiety.…”