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  • hydroxydopamine OHDA is a selective catecholaminergic neurot


    6-hydroxydopamine (6-OHDA) is a selective catecholaminergic neurotoxin mainly used to generate lesions in the nigrostriatal pathway in rats (Ungerstedt, 1968). The most common use of 6-OHDA is via unilateral injection into the rat medial forebrain bundle (MFB). DA depletion, nigral DA cell loss, and neurobehavioral deficits have been successfully achieved using this model. Therefore, this study was carried out on rats with complete unilateral 6-OHDA lesion of the MFB to investigate (i) effects of activation and blockade of BLA 5-HT6 receptor on PD-associated anxiety-like behaviors, the firing activity of BLA putative glutamate neurons, extracellular GABA and glutamate levels in the BLA, and release of three monoamine levels in the limbic and limbic related Clozapine regions, and (ii) changes in the expressions of 5-HT6 receptor on glutamate and GABA neurons in the BLA after lesioning of the MFB.
    Materials and methods
    Discussion The present study investigates whether 5-HT6 receptor in the BLA is involved in the regulation of PD-associated anxiety. The main results of this study are as follows: (i) activation of BLA 5-HT6 receptor induced anxiolytic-like effects and increased extracellular GABA level in the BLA in the lesioned rats; (ii) blockade of BLA 5-HT6 receptor produced anxiolytic-like effects and increased extracellular GABA levels in the BLA in sham-operated and the lesioned rats; (iii) activation and blockade of BLA 5-HT6 receptor resulted in increases in DA levels and decreases in NA levels in the mPFC, amygdala and vHip in two groups of rats, without altering 5-HT levels in these areas; (iv) activation and blockade of BLA 5-HT6 receptor induced opposite effects on the firing activity of glutamate neurons between sham-operated and the lesioned rats; (v) the mean densities of 5-HT6 receptor and glutamate or GAD67 double-labeled neurons in the BLA were unchanged after unilateral lesioning of the MFB.
    Conflict of interest statement
    Acknowledgments This study was supported by the National Natural Science Foundations of China (No. 81601115). The authors wish to acknowledge Dr. Hui-Sheng Wang for technical support.
    Introduction Major depressive disorder (MDD) is the most common psychiatric disorder and a leading cause of disability worldwide (Ferrari et al., 2013). Cognitive dysfunction in patients with MDD has been demonstrated to be equally common and debilitating (Brambilla et al., 2010, Ferrari et al., 2013) and is linked to longer episode duration, worse functional recovery and reduced treatment response (Jaeger et al., 2006, Papakostas and Ionescu, 2014). However, there are few effective psychopharmacological options for selectively targeting cognitive dysfunction in MDD illnesses available in the clinic (Millan et al., 2012), and cognitive impairment is a reported side effect of the most currently available antidepressant treatments (McGrath et al., 2006, Papakostas, 2014). Thus, significant unmet needs exist in the development of a novel antidepressant to alleviate cognitive dysfunction. Our previous studies revealed that hypidone hydrochloride (YL-0919), a novel small-molecule antidepressant progressing in a phaseⅡclinical trial in China, acts as a 5-HT1A receptor partial agonist and SSRI and exerts significant antidepressant- and anxiolytic-like effects in various animal models (Chen et al., 2013, Qin et al., 2014, Zhang et al., 2017). Interestingly, our recent study found that YL-0919 also had high affinity with 5-HT6 receptors and showed significant memory-enhancing ability in several animal models, which warrants further pharmacological characterization of this compound. In fact, increasing evidence supports the role of the 5-HT system in learning and memory processes, and the 5-HT system provides a multitude of entry points for pharmacological intervention. Of the 14 known 5-HT receptor subtypes, the 5-HT6 receptor has emerged as a particularly promising target for treatment of cognitive disorders. The 5-HT6 receptor was discovered in 1993 as a G-protein coupled receptor that is positively coupled to adenylate cyclase (Ruat et al., 1993, Schoeffter and Waeber, 1994, Sebben et al., 1994). Several studies have shown that 5-HT6 receptor expression is largely restricted to the central nervous system (CNS), and the highest expression was detected in brain areas such as the striatum, olfactory tubercle, nucleus accumbens, and hippocampus (Gérard et al., 1996, Hamon et al., 1999, Ward and Dorsa, 1996, Yau et al., 1997). Quite recently, 5-HT6 receptors have begun to attract considerable interest as valuable targets in learning and memory processes (Mørk et al., 2017, Suárezsantiago et al., 2017, Woolley et al., 2004, Zhang et al., 2017). In fact, 5-HT6 receptor agonists have been proposed to statistically improve cognitive function (Ferrero et al., 2017, Grychowska et al., 2016).