| Summary: | 碩士 === 國立陽明大學 === 神經科學研究所 === 96 === α2 Adrenoceptors (α2-AR), mediating the effect of norepinephrine (NE), is known to couple to Gi and/or Go protein to (i) inhibit adenylyl cyclase, (ii) close Ca+2 channel, or (iii) open K+ channel, such that neuronal firing and the release of NE may be inhibited and thereby modulating many physiological functions in the central nervous system. In mouse, three subtypes of α2-AR: α2A, α2B, α2C are encoded by Adra2a, Adra2b, and Adra2c, respectively. To circumvent the limitation that no specific ligands (to differentiate α2B and α2C-AR), nor adequate antibodies for α2-AR are available, our lab has established Adra2c-knockout /lacZ knock-in (Adra2c-KO) mice to study the functions of α2C-AR. By in situ X-gal staining, we found α2C-AR is mostly expressed in the limbic system, such as frontal cortex, ventral striatum, hippocampus and amygdale etc., implicating this receptor may be involved in the regulation of emotional behaviors.
In this thesis we used forced swimming test (FST) to assess the possible effects of α2C-AR deficiency on the development of behavior despair under chronic restraint stress. In contrast to wild-type mice (C57BL/6), the normalized immobility of Adra2c-KO mice is significantly reduced under chronic stress than baseline control condition. The results suggest α2C-AR may participate in the development of depression under chronic stress. In addition, a modified resident-intruder (RI) test was used to elicit offensive aggressive behaviors. After post-weaning social isolation for 12 weeks, the resident mouse was introduced with a naïve intruder each day for 5 consecutive days. In contrast to WT, Adra2c-KO mice exhibited more biting attacks and enhanced aggressive level on day 2 to 4 than day 1, suggesting the participation of α2C-AR in the control of offensive aggression. Thus, α2C-AR modulates not only depression but also the expression of aggression. To explore the molecular mechanisms underlying the behavioral effects of α2C-AR deficiency, microarray analyses were performed on amygdala and ventral hippocampus obtained from Adra2c-KO and WT mice in control (group housing) and after RI test, respectively. Alterations of basal expression level of Avp and Gabra2 mRNA was confirmed by qRT-PCR. Immunohistochemistry (IHC) showed that after the RI test, AVP in the anterior hypothalamus (AH) and medial amygdala was significantly enhanced in Adra2c-KO mice, suggesting AVP might facilitate the enhanced offensive aggression noted in Adra2c-KO mice. The AVP expression in paraventricular nucleus of hypothalamus may be induced in part by NE neurons of locus coeruleus, which exhibit a significant up-regulation of dopamine receptor D2 in Adra2c-KO mice in contrast to that in WT. A dopaminergic input (i.e., VTA) to LC in the regulation of aggression is highly plausible. The above results indicate α2C-AR may play pivotal roles in modulating emotion, thus may serve as a target for developing pharmacological agents aiming to treat of psychiatric disorders marked by aggression.
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