Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity

Abstract

Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g., obsessive-compulsive disorder; OCD) and impulse-control (e.g., impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2−/−), the initial and rate-limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain 5HT) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2−/− mice show normal acquisition and reversal learning on a spatial learning task. Restoration of 5HT levels by treatment of Tph2−/− mice with its immediate precursor 5-hydroxytryptophan attenuated compulsive and impulsive-aggressive behaviors. Surprisingly, in Tph2−/− mice, the lack of 5HT was not associated with anxiety-like behaviors. The results indicate that 5HT mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis.

Marble Burying and Nestlet Shredding as Tests of Repetitive, Compulsive-like Behaviors in Mice

“…As a result of the null mutation in the gene for TPH2, these mice have no measureable brain 5HT 15,16,18 . These mice show a very interesting behavioral phenotype characterized primarily by repetitive, compulsive-like digging and burying 15,16 . Figure 1B shows a representative cage from WT mice and Figure 1C is a cage from a TPH2 knockout (KO) mouse after burying.…”

“…In general, these established models can be classified as genetic, pharmacological, neurodevelopmental and behavioral and most show good face, construct and predictive validity 6,7 . We have used two behavioral models-marble burying and nestlet shredding-to assess repetitive behaviors in mice genetically depleted of serotonin 15,16 . These methods have numerous advantages not the least of which are their ease of use, the accuracy with which the behaviors can be scored, the spontaneous exhibition of these behaviors in rodents, and their use in high-throughput screening of genetically modified mice for abnormal behavioral phenotypes.…”

The role of serotonin in adult hippocampal neurogenesis

“…Serotonin depletion in transgenic mouse models also results in altered behavior such as exaggerated aggressiveness that goes along with reduced anxiety (Mosienko et al, 2012) and increased impulsivity (Angoa-Perez et al, 2012 Gaspar, 2012, Mosienko et al, 2014); that may reflect unchanged baseline neurogenesis, but also indicates an uncoupling of the behavioral mechanisms governing depression and serotonin levels in a unique homeostasis created over time. Compensatory mechanisms seem to occur in life-long serotonin depletion and the replacement of this neurotransmitter by expression or activity of other neurotransmitter systems has been debated (Beckman and Santos, 2013).…”

Impact of Serotonin (5-HT)2C Receptors On Executive Control Processes

“…First, an important consideration in the interpretation of behavioral phenotypes in mice bearing constitutive null mutations is the possibility that they can reflect the effects of the mutation on brain development. In accord with this possibility, a large body of evidence indicates that genetic perturbations of components of the serotonin system are associated with impaired executive function (Chamberlain et al, 2006;Cools et al, 2008;Enge et al, 2011;Angoa-Perez et al, 2012). Second, in the pharmacological studies, drugs are typically administered after task acquisition had been performed in untreated animals.…”

“…Clinical and preclinical data suggest that serotonin (5-hydroxytryptamine, 5-HT) system activity impacts executive control processes (Chamberlain et al, 2006;Cools et al, 2008;Fineberg et al, 2010). A number of preclinical reports indicate that reducing the availability of brain serotonin produces behavioral inflexibility and impulsivity, whereas the effects on attentional functioning are less clear (Harrison et al, 1997;Clarke et al, 2004;Winstanley et al, 2004;Floresco and Jentsch, 2010;Angoa-Perez et al, 2012).…”