Sigma 1 Receptor Antagonists Inhibit Manic-Like Behaviors in Two Congenital Strains of Mice

Abstract

BackgroundSeveral currently available animal models reproduce select behavioral facets of human mania as well as the abnormal glutamatergic neurotransmission and dysregulation of glycogen synthase kinase 3β that accompanies this disease.MethodsIn this study, we addressed the therapeutic potential of ligands of sigma receptor type 1 (σ1R) in 2 putative models of mania: the “manic” Black Swiss outbred mice from Taconic farms (BStac) and mice with the 129 genetic background and histidine triad nucleotide-binding protein 1 (HINT1) deletion (HINT1-/- mice) that exhibit bipolar-like behaviors.ResultsThe activity of control mice, which do not exhibit manic-like behaviors in the forced swim test, was significantly enhanced by MK801, an inhibitor of glutamate N-methyl-D-aspartate receptor activity, an effect that was not or barely observed in manic-like mice. Typical mood stabilizers, such as glycogen synthase kinase 3β inhibitors, but not σ1R ligands, reduced the N-methyl-D-aspartate receptor-mediated behaviors in control mice. Notably, σ1R antagonists S1RA, PD144418, BD1047, and BD1063, but not σ1R agonists PRE084 and PPCC, attenuated the manic-like behaviors of BStac and HINT1-/- mice by increasing antiactivity behaviors. The antimanic effects of a single administration of σ1R antagonists persisted for at least 24 hours, and these drugs did not alter the behavior of the “bipolar” HINT1−/− mice during pro-depressive episodes.Conclusionsσ1R antagonists exhibit a selective normalizing effect on specific behavioral domains of mania without altering control (normal) or depressive-like behaviors.

Enlightened: addressing circadian and seasonal changes in photoperiod in animal models of bipolar disorder

“…of Wisconsin for exercise physiology experiments, mice display a mania-like phenotype Hyperactive day and night, ↓ immobility in FST, ↓ daytime sleep, sensitive to changes in photoperiod Mania [ 76 , 106 ,] Genetically modified strains DNA polymerase subunit gamma (POLG) transgenic mice (Tg+/−) POLG is the catalytic subunit of mitochondrial (mt) DNA polymerase, POLG mutation was limited to brain neurons Tg mice displayed a distortion in the daily circadian activity pattern, ↑ activity associated with estrous, antidepressant-induced mania Mania [ 107 ] Myshkin mice (Myk +/− ) In vivo mutagenesis-derived strain, point mutation in Na+,K+-ATPase α3 ↑ exploration of a novel object, ↑ open field activity and ↓ habituation, ↓ sleep, ↓ anxiety-like behaviors, ↑ sucrose pref. Mania [ 108 , 109 ,] Clock mutant mice Identified through in vivo mutagenesis as a deletion of exon 19 that affects circadian rhythms ↓ anxiety, ↑ locomotion, ↓ immobility in FST, ↑ sucrose pref., ↑ response to cocaine, ↓ sleep, mood cycling from daytime mania → night time euthymia Mania → euthymia [ 110 – 113 ] D-box binding protein mice (DBP−/−) DBP is a transcription factor that regulates the period length of the cellular circadian clock ↑ response to AMPH, ↑ activity after 4 weeks of chronic stress, ↑ activity after sleep deprivation Depression → mania [ 114 , 115 ,] Extracellular regulated kinase 1 (ERK1) KO mice ERK pathway is a major signaling cascade mediating the effects of BDNF ↑ activity, ↑ reward seeking, ↓ immobility in FST, ↑ response to AMPH Mania [ 116 ] Histidine triad nucleotide binding protein 1 (HINT1-/-) mice Identified as a risk gene for BD by GWAS, regulates activities of GPCRs and NMDA receptors in brain ↑ activity, ↓ anxiety, ↑ aggression, ↑ sucrose pref., ↓ immobility in FST, ↑response to apomorphine or AMPH, switch from mania → depression after acute stress Mania → depression [ 117 , 118 ,] SH3 and multiple ankyrin repeat domains 2 (Shank2) mice Shank2 mice were gen...…”