Trace Amine-Associated Receptor 1 Contributes to Diverse Functional Actions of O-Phenyl-Iodotyramine in Mice but Not to the Effects of Monoamine-Based Antidepressants

Trace Amine-Associated Receptor 1 (TAAR1) is a potential target for the treatment of depression and other CNS disorders. However, the precise functional roles of TAAR1 to the actions of clinically used antidepressants remains unclear. Herein, we addressed these issues employing the TAAR1 agonist, o-phenyl-iodotyramine (o-PIT), together with TAAR1-knockout (KO) mice. Irrespective of genotype, systemic administration of o-PIT led to a similar increase in mouse brain concentrations. Consistent with the observation of a high density of TAAR1 in the medial preoptic area, o-PIT-induced hypothermia was significantly reduced in TAAR1-KO mice. Furthermore, the inhibition of a prepulse inhibition response by o-PIT, as well as its induction of striatal tyrosine hydroxylase phosphorylation and elevation of extracellular DA in prefrontal cortex, were all reduced in TAAR1-KO compared to wildtype mice. O-PIT was active in both forced-swim and marble-burying tests, and its effects were significantly blunted in TAAR1-KO mice. Conversely, the actions on behaviour and prefrontal cortex dialysis of a broad suite of clinically used antidepressants were unaffected in TAAR1-KO mice. In conclusion, o-PIT is a useful tool for exploring the hypothermic and other functional antidepressant roles of TAAR1. By contrast, clinically used antidepressants do not require TAAR1 for expression of their antidepressant properties.

Role of Melatonin in Reducing Amphetamine-Induced Degeneration in Substantia Nigra of Rats via Calpain and Calpastatin Interaction

Excessive intracellular calcium levels induce calpain activation, thereby triggering the cell death cascade. Several lines of evidence have demonstrated the neuroprotective role of the overexpression of calpain inhibitor, calpastatin. In this study, amphetamine-induced degeneration in the substantia nigra of rats was determined by evaluating the decrease in the levels of tyrosine hydroxylase phosphorylation. Amphetamine significantly decreased calpastatin levels but increased calpain levels. An induction in calpain activity was demonstrated by an increase in the formation of calpain spectrin breakdown products. The deleterious effects of amphetamine exposure were diminished in rats by pretreatment with melatonin. In addition, the effect of melatonin on calpastatin expression was investigated in human neuroblastoma SH-SY5Y cells. Melatonin was able to increase the calpastatin levels, and this effect could be blocked by luzindole, a melatonin receptor antagonist. These results demonstrate the neuroprotective ability of melatonin and its role in inducing calpastatin expression via a receptor-dependent pathway.

IRBIT regulates CaMKIIα activity and contributes to catecholamine homeostasis through tyrosine hydroxylase phosphorylation

Inositol 1,4,5-trisphosphate receptor (IP3R) binding protein released with IP3 (IRBIT) contributes to various physiological events (electrolyte transport and fluid secretion, mRNA polyadenylation, and the maintenance of genomic integrity) through its interaction with multiple targets. However, little is known about the physiological role of IRBIT in the brain. Here we identified calcium calmodulin-dependent kinase II alpha (CaMKIIα) as an IRBIT-interacting molecule in the central nervous system. IRBIT binds to and suppresses CaMKIIα kinase activity by inhibiting the binding of calmodulin to CaMKIIα. In addition, we show that mice lacking IRBIT present with elevated catecholamine levels, increased locomotor activity, and social abnormalities. The level of tyrosine hydroxylase (TH) phosphorylation by CaMKIIα, which affects TH activity, was significantly increased in the ventral tegmental area of IRBIT-deficient mice. We concluded that IRBIT suppresses CaMKIIα activity and contributes to catecholamine homeostasis through TH phosphorylation.