Abstract
BackgroundMajor depressive disorder (MDD) is a severe mental disorder related to the deficiency of monoamine neurotransmitters, particularly to abnormalities of 5-HT (5-hydroxytryptamine, serotonin) and its receptors. Our previous study suggested that acute treatment with a novel curcumin derivative J147 exhibited antidepressant-like effects by increasing brain derived neurotrophic factor (BDNF) level in the hippocampus of mice. The present study expanded upon our previous findings and investigated the antidepressant-like effects of sub-acute treatment of J147 for 3 days in male ICR mice and its possible relevancy to 5-HT1A and 5-HT1B receptors and downstream cAMP-BDNF signaling.MethodsJ147 at doses of 1, 3, and 9 mg/kg (via gavage) was administered for 3 days, and the anti-immobility time in the forced swimming and tail suspension tests (FST and TST) was recorded. The radioligand binding assay was used to determine the affinity of J147 to 5-HT1A and 5-HT1B receptor. Moreover, 5-HT1A or 5-HT1B agonist or its antagonist was used to determine which 5-HT receptor subtype is involved in the antidepressant-like effects of J147. The downstream signaling molecules such as cAMP, PKA, pCREB, and BDNF were also measured to determine the mechanism of action.ResultsThe results demonstrated that sub-acute treatment of J147 remarkably decreased the immobility time in both the FST and TST in a dose-dependent manner. J147 displayed high affinity in vitro to 5-HT1A receptor prepared from mice cortical tissue and was less potent at 5-HT1B receptor. These effects of J147 were blocked by pretreatment with a 5-HT1A antagonist NAD-299 and enhanced by a 5-HT1A agonist 8-OH-DPAT. However, 5-HT1B receptor antagonist NAS-181 did not appreciably alter the effects of J147 on depression-like behaviors. Moreover, pretreatment with NAD-299 blocked J147-induced increases in cAMP, PKA, pCREB, and BDNF expression in the hippocampus, while 8-OH-DPAT enhanced the effects of J147 on these proteins’ expression.ConclusionThe results suggest that J147 induces rapid antidepressant-like effects during a 3-day treatment period without inducing drug tolerance. These effects might be mediated by 5-HT1A-dependent cAMP/PKA/pCREB/BDNF signaling.
Highlights
Major depressive disorder (MDD) is a stress-related mental disorder related to the deficiency of monoamine neurotransmitters, to 5-HT (5-hydroxytryptamine, serotonin) and its receptors (Kennedy et al, 2002; Kessler et al, 2003; Patel et al, 2007)
The doses that induced the reduction of immobility time did not change locomotor activity (LMA) (Figure 1C), suggesting sub-acute treatment with J147 does not stimulate or inhibit the central nervous system
To evaluate whether sub-acute treatment with J147 affected 5-HT1A, 5-HT1B, and 5-HT7 receptors, we assessed the expression of these receptors in the hippocampus
Summary
Major depressive disorder (MDD) is a stress-related mental disorder related to the deficiency of monoamine neurotransmitters, to 5-HT (5-hydroxytryptamine, serotonin) and its receptors (Kennedy et al, 2002; Kessler et al, 2003; Patel et al, 2007). The link between depression and serotonin is supported by studies suggesting that most antidepressants may increase serotonin levels, such as the serotonin transporter inhibitors (SERTIs), the dual serotonin and norepinephrine reuptake inhibitors (SNRIs) and the selective serotonin reuptake inhibitors (SSRIs) (Chen et al, 2011). Both SNRIs and SSRIs induce delayed antidepressant response and undesired side effects, which substantially hamper their clinical application. The present study expanded upon our previous findings and investigated the antidepressant-like effects of sub-acute treatment of J147 for 3 days in male ICR mice and its possible relevancy to 5-HT1A and 5-HT1B receptors and downstream cAMP-BDNF signaling
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