Nina K. Popova

Evidence for the involvement of central serotonin in mechanism of domestication of silver foxes

Silver foxes selected for more than 30 years for tame behavior and displaying no defensive reaction to human contact were shown to have a higher serotonin level in midbrain and hypothalamus, and a higher 5-hydroxyindole acetic acid (5-HIAA) content in midbrain, hypothalamus and hippocampus in comparison to nonselected wild silver foxes bred in captivity over the same time span. Tryptophan hydroxylase (TPH) activity in midbrain and hypothalamus in domesticated foxes was increased as compared with their aggressive/defensive counterparts. Monoamine oxidase type A (MAO A) activity was was decreased with an increased Km and unchanged Vmax in domesticated foxes. No changes in specific [3H]ketanserin or [3H]8-OH-DPAT binding in frontal cortex was revealed. A reduced density (Bmax) of 5HT1A receptors in hypothalamic membranes in domesticated foxes was shown. It is suggested that the brain serotonergic system is involved in the mechanism of domestication converting wild aggressive/defensive animals into tame ones.

Female-induced sexual arousal in male mice and rats: behavioral and testosterone response

Exposure of a male mouse to a female mouse separated from it by a holed partition induced specific behavior and an increase in blood testosterone in the male. The male made more approaches to the partition and spent more time at it. The time spent by the male mouse over the first 10 min at the partition, behind which an estrus female was placed, was increased sixfold compared to the time spent by a male mouse exposed to the vacant neighboring compartment; and 1.5-fold compared to that spent by a male mouse exposed to a nonreceptive female or a male. Increased blood testosterone level was detected at 20 min of exposure to a receptive female in winter and at 40 min in summer. No variation in blood testosterone levels in the male mouse exposed to a nonreceptive female or a male was observed. Similar response to a receptive female placed in the neighboring compartment was shown in a male rat. The time spent by the male rat at the partition was 12 times higher when there was an estrus female behind it than in control. Blood testosterone in the male rat increased in response to a female rat and did not change in response to a male rat indicating female-induced motivation. It was concluded that the partition time might serve as a quantitative measure of sexual motivation in the males and that the model of female-induced sexual arousal used was suitable for studying both motivational and hormonal components of sexual arousal in male mice and rats.

Association between Tph2 gene polymorphism, brain tryptophan hydroxylase activity and aggressiveness in mouse strains

The brain neurotransmitter serotonin is involved in the regulation of aggressive behavior. The main factor determining the brain serotonin level is the activity of the rate‐limiting enzyme in the biosynthesis of the neurotransmitter – tryptophan hydroxylase isoform (TPH) 2 encoded by the Tph2 gene. Recently the C1473G single‐nucleotide polymorphism in the Tph2 gene was reported. Here we study the C1473G polymorphism in 10 inbred mouse strains (C57BL/6J, AKR/J, DD/He, C3H/HeJ, YT/Y, BALB/cJLac, CC57BR/Mv and A/He) and demonstrate the association of the polymorphism with brain TPH activity and intermale aggressiveness. TPH activity in the midbrain of mice homozygous for the 1473C allele was higher than that in mice carrying 1473G alleles. A close association of the 1473C allele with increased number of attacks towards another male was found. The results support a link between the C1473G polymorphism in Tph2 gene, trypthophan hydroxylase activity and intensity of intermale aggression.

Role of genotype and dopamine receptors in behaviour of inbred mice in a forced swimming test

The role of genotype in the effects of selective D1 and D2 dopamine agonists and antagonists on behavioural despair (Porsolts test) was studied. Mice of nine inbred strains showed significant interstrain differences in duration of immobility. The influence of dopaminergic drugs was assessed in six strains characterized by different levels of swimming activity. SKF 38393 (10 mg/kg), an agonist at D1 dopamine receptors, increased swimming activity, while the D1 antagonist SCH 23390 (0.2 and 0.5 mg/kg) reduced it, the effects being genotype dependent. The involvement of D2 dopamine receptors in the regulation of mouse behaviour in the forced swimming test was not so evident; the D2 agonist bromocriptine (10 mg/kg) produced no significant effect. The D2 agonist quinpirole (2.5 mg/kg) increased immobility in the majority of the mouse strains studied, while in CBA mice it resulted in a marked reduction of immobility. The D2 antagonist sulpiride (20 mg/kg) decreased immobility and increased active swimming only in two strains. The present results suggest a different role for D1 and D2 dopamine receptors in the regulation of swimming in the mouse.

Reduction in 5-HT1A receptor density, 5-HT1A mRNA expression, and functional correlates for 5-HT1A receptors in genetically defined aggressive rats

The present experiments tested the hypothesis that one of the critical mechanisms underlying genetically defined aggressiveness involves brain serotonin 5‐HT1A receptors. 5‐HT1A receptor density, the receptor mRNA expression in brain structures, and functional correlates for 5‐HT1A receptors identified as 8‐OH‐DPAT‐induced hypothermia and lower lip retraction (LLR) were studied in Norway rats bred for 59 generations for the lack of aggressiveness and for high affective aggressiveness with respect to man. Considerable differences between the highly aggressive and the nonaggressive rats were shown in all three traits. A significant decrease in Bmax of specific receptor binding of [3H]8‐OH‐DPAT in the frontal cortex, hypothalamus, and amygdala and a reduction in 5‐HT1A receptor mRNA expression in the midbrain of aggressive rats were found. 5‐HT1A receptor agonist 8‐OH‐DPAT (0.5 mg/kg, i.p.) produced a distinct hypothermic reaction in nonaggressive rats and did not affect significantly the body temperature in aggressive rats. Similar differences were revealed in 8‐OH‐DPAT‐induced LLR: LLR was expressed much more in nonaggressive than in aggressive animals. Additionally, 8‐OH‐DPAT (0.5 mg/kg i.p.) treatment significantly attenuated the aggressive response to man. The results demonstrated an association of aggressiveness with reduced 5‐HT1A receptor expression and function, thereby providing support for the view favoring the idea that brain HT1A receptor contributes to the genetically defined individual differences in aggressiveness.

Quantitative RT-PCR assay of 5-HT1A and 5-HT2A serotonin receptor mRNAs using genomic DNA as an external standard.

Brain serotonin 5-HT(1A) and 5-HT(2A) receptors have been implicated in both normal and pathological behavior, and in the action of anxiolytic and antidepressant drugs. In this study, detailed description and verification of a new RT-PCR technique to quantify the number of copies of 5-HT(1A) and 5-HT(2A) receptor mRNAs in the brain is presented. The number of copies of beta-actin and 5-HT(1A) or 5-HT(2A) receptor mRNAs in rat brain samples was evaluated with respect to the genomic DNA solution as the external exogenous standard. The expression of 5-HT receptors was calculated as the number of receptor mRNA copies per 100 copies of corresponding beta-actin mRNA. This presented technique is reliable, simple and can be easily set up in any neurobiological laboratory.

C1473G polymorphism in mouse tph2 gene is linked to tryptophan hydroxylase-2 activity in the brain, intermale aggression, and depressive-like behavior in the forced swim test

Tryptophan hydroxylase‐2 (TPH2) is the rate‐limiting enzyme of brain serotonin synthesis. The C1473G polymorphism in the mouse tryptophan hydroxylase‐2 gene affects the enzymes activity. In the present study, we investigated the linkage between the C1473G polymorphism, enzyme activity in the brain, and behavior in the forced swim, intermale aggression, and open field tests using mice of the C57BL/6 (C/C) and CC57BR/Mv (G/G) strains and the B6‐1473C (C/C) and B6‐1473G (G/G) lines created by three successive backcrossings on C57BL/6. Mice of the CC57BR/Mv strain had decreased brain enzyme activity, aggression intensity, and immobility in the forced swim test, but increased locomotor activity and time spent in the central part of the open field arena compared with animals of the C57BL/6 strain. Mice of the B6‐1473G line homozygous for the 1473G allele had lower TPH2 activity in the brain, aggression intensity, and immobility time in the forced swim test compared with animals of the B6‐1473C line homozygous for the 1473C allele. No differences were found between the B6‐1473G and B6‐1473C mice in locomotor activity and time spent in the central part of the arena in the open field test. Thus, the C1473G polymorphism is involved in the determination of TPH2 activity and is linked to aggression intensity and forced‐swim immobility in mice. At the same time, the polymorphism does not affect locomotion and anxiety‐related behavior in the open field test. The B6‐1473C and B6‐1473G mice represent a valuable experimental model for investigating molecular mechanisms of serotonin‐related behavior.

Inheritance of predisposition to catalepsy in mice

Abstract“Pinch-induced” catalepsy (excessive freezing) was studied in mice of nine inbred strains. The CBA/Icg strain had the highest predisposition to catalepsy, with 56% males and 73% females exhibiting 120-s immobility after four tests. A Mendelian analysis of predisposition to catalepsy was performed on CBA/Icg and AKR/J mice contrasting in this trait. Reciprocal F1 hybrids did not display freezing after 10 tests. The number of cataleptic and noncataleptic animals among the F2s and in the families of the CBA×F2 backcrosses agreed with the hypothesis that the pronounced predisposition to catalepsy in the CBA/Icg mice was determined by a single autosomal locus in homozygous recessive condition.

5-HT1A receptor as a key player in the brain 5-HT system.

Abstract Among an impressive variety of identified serotonin receptors, 5-HT1A attracts particular attention due to its central role in the regulation of 5-HT-ergic neurotransmission and the data on its involvement in the mechanisms of stress response, aggressive behavior, anxiety, and depression. This review concentrates on the cross-regulation between 5-HT receptors and the implication of the 5-HT1A receptor in the genetic control of 5-HT-related behavior. Specifically, it describes the (1) functional interactions between 5-HT1A, 5-HT2A, 5-HT3, and 5-HT7 receptors; (2) cross-talk between 5-HT1A receptor and genes encoding key members of the brain 5-HT system; (3) implication of the 5-HT1A receptor in natural hibernation and genetic predisposition to different kinds of defensive behavior; and (4) role of 5-HT1A autoreceptors and heteroreceptors in anxiety, depression, and suicide, and in the antidepressant effect of serotonin reuptake inhibitors. This review provides converging lines of evidence that the 5-HT1A receptor contributes to the action of other 5-HT receptors, modulating their effect on behavior, and describes new data on the unique role of the 5-HT1A receptor in the indirect regulation of gene expression and in the autoregulation of the brain 5-HT system.

From gene to aggressive behavior: The role of brain serotonin

This article addresses a question at the juncture of neurophysiology and neurogenetics — the role of the brain neurotransmitter serotonin in the genetic control of behavior. Published data are presented, along with results obtained from studies performed at the Behavioral Neurogenomics Laboratory. The role of protein elements of the brain serotonin system (key enzymes in serotonin metabolism and serotonin 5-HT1A receptors), which are subject to the direct influence of genes, in the genetic predisposition to aggressive behavior is discussed. Experimental results obtained in Norwegian rats selected over more than 50 generations for the absence of aggressivity and for high aggressivity to humans are presented, along with data from experiments on mouse lines and mice with genetic knockout of MAO A. These data provide evidence that 1) brain serotonin makes a significant contribution to the mechanisms underlying genetically determined individual differences in aggressivity, and 2) the genes encoding the main enzymes of serotonin metabolism in the brain (tryptophan hydroxylase-1 and MAO A) and the 5-HT1A receptor are members of a set of genes modulating aggressive behavior.