Alterations in pharmacological and behavioural responses in recombinant mouse line with an increased predisposition to catalepsy: role of the 5‐HT_1A receptor

Abstract

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 APPROACHTwo mouse lines, B6-M76C and B6-M76B, were created by transfer of the main locus of catalepsy containing the 5-HT 1A 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-HT 1A receptor were compared. KEY RESULTSB6-M76B mice were not cataleptic, whereas 14% of B6-M76C mice demonstrated catalepsy and decreased depressive-like behaviour. Acute administration of the 5-HT 1A 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-HT 1A 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-HT 1A receptor. CONCLUSIONS AND IMPLICATIONSOur findings indicate that transfer of the main locus of hereditary catalepsy containing the 5-HT 1A receptor from CBA mice to the C57BL/6 genetic background led to increased postsynaptic and decreased presynaptic functional responses of the 5-HT 1A receptor. This characteristic establishes the B6-M76C line as an attractive model for the pharmacological screening of 5-HT 1A receptor-related drugs specifically acting on either pre-or postsynaptic receptors. LINKED ARTICLESThis 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 Abbreviations 5-HIAA, 5-hydroxyindoleacetic acid; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino) tetralin; ASC, antidepressant-sensitive catalepsy; BDNF, brain-derived neurotrophic factor; EPM, elevated plus-maze test; FST, forced swim test; OF, open field test; Slc6a4, gene encoding 5-HT transporter; Tph2, tryptophan hydroxylase 2

Genetic Background Underlying 5-HT1A Receptor Functioning Affects the Response to Fluoxetine

“…Recently, we found that the changes in genetic background of B6-M76C mice altered the sensitivity of 5-HT 1A receptors to chronic activation with 5-HT 1A receptors agonist 8-OH-DPAT, which allowed us to suggest the altered sensitivity of presynaptic 5-HT 1A receptors in these animals [ 31 ]. The results of the current study allow us to suggest that fluoxetine led to the activation rather than desensitization of presynaptic 5-HT 1A receptors in B6-M76C mice after two weeks of exposure.…”

“…Mice created by a small genome fragment transfer represent promising models for studying the effects of genetic modification on molecular mechanisms of behavior and responses to drug treatment. Recently, we created recombinant B6.CBA-D13Mit76C (B6-M76C) and B6.CBA-D13Mit76B (B6-M76B) mouse lines on the C57Bl/6 genetic background [ 30 , 31 ]. The B6-M76C mice were differed by 5-HT 1A receptor sensitivity to chronic activation with 5-HT 1A receptor agonist 8-OH-DPAT, which allowed us to assume that B6-M76C mice have a genetically defined reduced sensitivity of presynaptic 5-HT 1A receptor [ 31 ] and that these changes in genetic background can modulate the response to 5-HT 1A -related antidepressants from the SSRIs family.…”

Updating neuropathology and neuropharmacology of monoaminergic systems

“…However, additional direct mechanisms may also facilitate these interactions, for example, through the transient receptor potential channel, TRPV1 and CB 2 receptors located in dopaminergic neurons as well as through postsynaptic interactions of CB 1 receptors with D 1 /D 2 receptors. It is possible that cannabinoids might have therapeutic potential through these actions that can facilitate a normalization of dopaminergic transmission in states such as Parkinson's disease.Ponimaskin and Kondaurova and their colleagues (Kulikova et al, 2016) propose an original work focusing on 5-HT 1A receptors. The role played by presynaptic and postsynaptic 5-HT 1A receptors in the action of antidyskinetic, antipsychotic, antidepressant or anxiolytic drugs is one of the main lines of research regarding 5-HT (serotonin)-based medicines (De Deurwaerdère and Di Giovanni, 2016).…”

“…Ponimaskin and Kondaurova and their colleagues (Kulikova et al, 2016) propose an original work focusing on 5-HT 1A receptors. The role played by presynaptic and postsynaptic 5-HT 1A receptors in the action of antidyskinetic, antipsychotic, antidepressant or anxiolytic drugs is one of the main lines of research regarding 5-HT (serotonin)-based medicines (De Deurwaerdère and Di Giovanni, 2016).…”

“…Genetic predisposition regarding pre‐ and postsynaptic 5‐HT 1A receptor responses could confer distinct pharmacological responses, and appropriate preclinical models are needed. The authors (Kulikova et al , ) created two mouse lines, B6‐M76C and B6‐M76B, by transfer of a chromosomic locus selected from CBA mice to C57BL/6 genetic background. This locus, which predisposes CBA mice to catalepsy, contains the 5‐HT 1A receptor gene.…”