Highlights • Actual spaceflight considerably decreased BCL-XL gene expression in the hypothalamus. • Long-term spaceflight significantly increased BCL-XL gene expression in the hippocampus. • Actual ...spaceflight considerably reduced BCL-XL gene expression in the striatum. • Shuttle cabin housing also considerably reduced BCL-XL gene expression in the striatum. • Long-term spaceflight failed to affect BAX, BDNF, TrkB and p75 gene expression.
Highlights ► Central BDNF administration produced ameliorative effect on depressive-like behavior. ► Long-term BDNF effect on “depressive” ASC mice involves profound genetic mechanisms. ► In ASC mice ...BDNF increased Tph2, Htr1A and Htr2A genes expression. ► In ASC mice BDNF produced sensitization of Htr2A receptor.
Mice were exposed to 1 month of spaceflight on Russian biosatellite BION-M1 to determine its effect on the expression of key genes in the brain dopamine (DA) and serotonin (5-HT) systems. Spaceflight ...decreased the expression of crucial genes involved in DA synthesis and degradation, as well as the D1 receptor. However, spaceflight failed to alter the expression of tryptophan hydroxylase-2, 5-HT transporter, 5-HT
1A
, and 5-HT
3
receptor genes, though it reduced 5-HT
2A
receptor gene expression in the hypothalamus. We revealed risk DA and 5-HT neurogenes for long-term spaceflight for the first time, as well as microgravity-responsive genes (tyrosine hydroxylase, catechol-O-methyltransferase, and D1 receptor in the nigrostriatal system; D1 and 5-HT
2A
receptors in the hypothalamus; and monoamine oxidase A (MAO A) in the frontal cortex). Decreased genetic control of the DA system may contribute to the spaceflight-induced locomotor impairment and dyskinesia described for both humans and rats.
In spite of numerous studies, pathogenesis of the sporadic (not inherited) form of Alzheimer’s disease (AD) still remains largely unclear; nevertheless, there is general consensus as regards the ...complex involvement of neurotrophic factors and neurotransmitters in the mechanisms of this disease. In light of recent data on the physical interaction between serotonin (5-HT) receptors and receptors of the brain-derived neurotrophic factor (BDNF), the reciprocal modulation between 5-HT and BDNF systems is of particular interest, inter alia, in the context of AD development. The OXYS lineage of prematurely aging rats is a unique model of sporadic AD. Previously, it has been reported on the changed neurotrophin balance in the brain of these animals; however, the changes in the expression of BDNF and its receptors in the dynamics of development of AD symptoms has been studied insufficiently. Even less is known about the patterns of expression of 5-HT receptors in OXYS rat brain. In the present work, we have compared the expression of BDNF and its receptors, TrkB and p75
NTR
, as well as serotonin 5-НТ
1А
, 5-НТ
2А
, 5-НТ
4
and 5-НТ
7
receptors in the brain of OXYS and Wistar rats aged 20 days, 3.5 and 18 months. The frontal cortex of 20-day-old OXYS rats demonstrated a significant increase in the mRNA level of the
Bdnf
,
Htr2a
and
Htr7
genes and, at the same time, a decrease in the ratio of phosphorylated and nonphosphorylated forms of the TrkB receptor. In the hippocampus of 20-day-old OXYS rats, the mRNA levels of the
Bdnf
,
Htr1a
,
Htr2a
and
Htr4
genes are also elevated. A substantially higher mRNA level of the above genes for 5-HT receptors was observed in the hippocampus of OXYS rats also at the age of 3.5 months, in the period of manifestation of the first AD symptoms. The nature of change in gene expression patterns indicates the potential involvement of 5-HT receptors in suppression of the TrkB receptor function in the early period of postnatal development of OXYS rats, which may be one of the mechanisms, through which 5-HT receptors are involved in the development of pathological process in the period of manifestation of AD symptoms in OXYS rats.
Background and Purpose
One important syndrome of psychiatric disorders in humans is catalepsy. Here, we created mice with different predispositions to catalepsy and analysed their pharmacological and ...behavioural properties.
Experimental Approach
Two mouse lines, B6‐M76C and B6‐M76B, were created by transfer of the main locus of catalepsy containing the 5‐HT1A receptor gene to the C57BL/6 genetic background. Behaviour, brain morphology, expression of key components of the serotoninergic system, and pharmacological responses to acute and chronic stimulation of the 5‐HT1A receptor were compared.
Key Results
B6‐M76B mice were not cataleptic, whereas 14% of B6‐M76C mice demonstrated catalepsy and decreased depressive‐like behaviour. Acute administration of the 5‐HT1A receptor agonist 8‐OH‐DPAT resulted in dose‐dependent hypothermia and in decreased locomotion in both lines. Chronic 8‐OH‐DPAT administration abolished the 5‐HT1A receptor‐mediated hypothermic response in B6‐M76C mice and increased locomotor activity in B6‐M76B mice. In addition, 5‐HT metabolism was significantly reduced in the hippocampus of B6‐M76C mice, and this effect was accompanied by an increased expression of the 5‐HT1A receptor.
Conclusions and Implications
Our findings indicate that transfer of the main locus of hereditary catalepsy containing the 5‐HT1A receptor from CBA mice to the C57BL/6 genetic background led to increased postsynaptic and decreased presynaptic functional responses of the 5‐HT1A receptor. This characteristic establishes the B6‐M76C line as an attractive model for the pharmacological screening of 5‐HT1A receptor‐related drugs specifically acting on either pre‐ or postsynaptic receptors.
Linked Articles
This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc
The effects of chronic 5-HT1A receptor activation on the behavior, functional activity of 5-HT1A receptors, and expression of key genes of the brain 5-HT system were studied in mice of the ...catalepsy-prone CBA strain and the catalepsy-resistant C57BL/6 strain. Chronic treatment with 8-Hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) (1.0 mg/kg i.p., 14 days) led to a significant decrease in the hypothermic response to acute administration of 8-OH-DPAT in CBA and C57BL/6 mice, which indicates the desensiti-zation of 5-HT1A receptors in both strains. Pretreatment with the 5-HT7 receptor agonist SB 269970 did not affect the hypothermic response to the acute administration of 8-OH-DPAT, which suggests an independent functional response of 5-HT1A receptors. The treatment did not induce any changes in the behavior in the open field paradigm in CBA mice, but significantly increased the total path, the time spent in the center, and the number of rearings in C57BL/6 mice, which indicates the enhancement of locomotor and exploratory activity in C57BL/6 mice. The chronic activation of 5-HT1A receptor downregulated 5-HT1A gene expression, as well as the expression of the gene that encodes tryptophan hydroxylase 2, a key enzyme of 5-HT biosynthesis, in the midbrain and the expression of the gene that encodes the 5-HT2A receptor in the frontal cortex of CBA, but not C57BL/6 mice. The obtained data provide a new evidence on the receptor-gene cross talk in the brain 5-HT system that may underlie the loss of pharmacological efficacy of 5-HT1A receptor agonists. In turn, the loss of the behavioral response and compensatory alterations in key genes of the brain 5-HT system in CBA mice suggests that catalepsy-prone and -resistant genotypes demonstrate different sensibility to the effects of drugs.
The effects of chronic 5-HT
1A
receptor activation on the behavior, functional activity of 5-HT
1A
receptors, and expression of key genes of the brain 5-HT system were studied in mice of the ...catalepsy-prone CBA strain and the catalepsy-resistant C57BL/6 strain. Chronic treatment with 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (1.0 mg/kg i.p., 14 days) led to a significant decrease in the hypothermic response to acute administration of 8-OH-DPAT in CBA and C57BL/6 mice, which indicates the desensitization of 5-HT
1A
receptors in both strains. Pretreatment with the 5-HT
7
receptor agonist SB 269970 did not affect the hypothermic response to the acute administration of 8-OH-DPAT, which suggests an independent functional response of 5-HT
1A
receptors. The treatment did not induce any changes in the behavior in the open field paradigm in CBA mice, but significantly increased the total path, the time spent in the center, and the number of rearings in C57BL/6 mice, which indicates the enhancement of locomotor and exploratory activity in C57BL/6 mice. The chronic activation of 5-HT
1A
receptor downregulated 5-HT
1A
gene expression, as well as the expression of the gene that encodes tryptophan hydroxylase 2, a key enzyme of 5-HT biosynthesis, in the midbrain and the expression of the gene that encodes the 5-HT
2A
receptor in the frontal cortex of CBA, but not C57BL/6 mice. The obtained data provide a new evidence on the receptor–gene cross talk in the brain 5-HT system that may underlie the loss of pharmacological efficacy of 5-HT
1A
receptor agonists. In turn, the loss of the behavioral response and compensatory alterations in key genes of the brain 5- HT system in CBA mice suggests that catalepsy-prone and -resistant genotypes demonstrate different sensibility to the effects of drugs.
The programmed cell death (or apoptosis) plays an important role both in developing and mature brains. Multiple data indicate the involvement of processes of apoptosis in mechanisms of different ...psychopathologies. At the same time, nothing is known about the role of apoptosis in the regulation of genetically defined aggression. In the present work, the expression of the genes that encode main pro- and antiapoptotic BAX and BCL-XL proteins, as well as caspase 3 (the main effector of apoptosis), in different brain structures of rats that were selected on a high aggression towards human (or its absence) was studied. A significant increase in the expression of the gene encoding caspase 3 was detected in the hypothalamus. This was accompanied by a significant decrease in the expression of proapoptotic
Bax
gene in the hippocampus and increase in mRNA level of antiapoptotic
Bcl-xl
gene in the raphe nuclei area of midbrain in highly aggressive rats. An increase in the ratio
Bcl-xl
:
Bax
was found in the midbrain and amygdala; a trend towards an increase in the ratio was also found in hippocampus of aggressive animals compared to tame animals. Thus, we demonstrated that genetically defined fear-induced aggression is associated with significant changes in the genetic control of apoptosis in the brain. It is assumed that an increase in the
Bcl-xl
gene expression (accompanied by a decrease in the
Bax
gene expression) can indicate an increase in the threshold of neuronal apoptosis in highly aggressive rats.
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