Dopamine D3 receptors (D3Rs) have been implicated in mediating behavioural sensitization to various drugs of abuse, but their role in ethanol (EtOH) sensitization has not been directly examined. Neil Richtand proposed a role for D3Rs in the modulation of sensitization by acting as an inhibitor of D1/D2 receptor-mediated behaviours, and several reports suggest D3Rs up-regulate in response to chronic drugs of abuse. In separate experiments, we examined EtOH sensitization in D3R knockout (KO) as well as in D1R and D2R KO mice. We also examined amphetamine sensitization in D3R KOs compared to wild type mice. We challenged C57Bl/6 and DBA/2 mice with a D3R agonist (PD128907) and antagonist (U99194A) to examine how acute and chronic D3R activation and inactivation may affect the induction and expression of EtOH sensitization. We investigated D1/D3R interactions in sensitized and control mice and examined whether EtOH sensitization leads to changes in D3R binding using [125I]-7-OH-PIPAT autoradiography. Results showed that D3R KOs, were resistant to EtOH but not to amphetamine sensitization. Chronic but not acute D3R blockade with U99194A inhibited the induction, whereas acute D3R activation with PD128907 attenuated the expression of EtOH sensitization. In our D1/D3R interaction study we observed that although PD128907 attenuated D1 agonist-induced hyperactivity with SKF81297, this effect was the same in sensitized and control animals, even though sensitized mice were more responsive to PD128907 than controls. This enhanced response, which suggests a functional up-regulation of D3Rs, was not accompanied by changes in D3R binding as indicated by autoradiography, and could mean that functional changes in the D3R associated with EtOH sensitization occur elsewhere than at the level of the membrane-bound receptor. Taken together, these results suggest a modulatory role for the D3R in EtOH but not amphetamine sensitization, where D3R activation attenuates the expression and D3R blockade prevents the induction of EtOH sensitization. These results are important because a better understanding of the role of the D3R in EtOH sensitization may help not only to identify some of the underlying neural mechanisms of sensitization, but also help in the identification of treatment strategies for patients that may be susceptible to alcohol abuse.

Dopamine D3 receptors (D3Rs) have been implicated in mediating behavioural sensitization to various drugs of abuse, but their role in ethanol (EtOH) sensitization has not been directly examined. Neil Richtand proposed a role for D3Rs in the modulation of sensitization by acting as an inhibitor of D1/D2 receptor-mediated behaviours, and several reports suggest D3Rs up-regulate in response to chronic drugs of abuse. In separate experiments, we examined EtOH sensitization in D3R knockout (KO) as well as in D1R and D2R KO mice. We also examined amphetamine sensitization in D3R KOs compared to wild type mice. We challenged C57Bl/6 and DBA/2 mice with a D3R agonist (PD128907) and antagonist (U99194A) to examine how acute and chronic D3R activation and inactivation may affect the induction and expression of EtOH sensitization. We investigated D1/D3R interactions in sensitized and control mice and examined whether EtOH sensitization leads to changes in D3R binding using [125I]-7-OH-PIPAT autoradiography. Results showed that D3R KOs, were resistant to EtOH but not to amphetamine sensitization. Chronic but not acute D3R blockade with U99194A inhibited the induction, whereas acute D3R activation with PD128907 attenuated the expression of EtOH sensitization. In our D1/D3R interaction study we observed that although PD128907 attenuated D1 agonist-induced hyperactivity with SKF81297, this effect was the same in sensitized and control animals, even though sensitized mice were more responsive to PD128907 than controls. This enhanced response, which suggests a functional up-regulation of D3Rs, was not accompanied by changes in D3R binding as indicated by autoradiography, and could mean that functional changes in the D3R associated with EtOH sensitization occur elsewhere than at the level of the membrane-bound receptor. Taken together, these results suggest a modulatory role for the D3R in EtOH but not amphetamine sensitization, where D3R activation attenuates the expression and D3R blockade prevents the induction of EtOH sensitization. These results are important because a better understanding of the role of the D3R in EtOH sensitization may help not only to identify some of the underlying neural mechanisms of sensitization, but also help in the identification of treatment strategies for patients that may be susceptible to alcohol abuse.

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No description available.

Fracture healing requires a series of events including inflammatory response and callus formation, callus remodeling and bone healing. Fracture healing is a complex process, there are several overlapping phases , including inflammation , cartilage formation and bone remodeling, there are many internal or external factors could impact on fracture healing, leading to delayed bone healing or non healing. The global androgen receptor knockout (GARKO) mice has been know to reduce bone mass in endochondral bone and osteoblast mineralization, but the impact for callus formation in fracture healing is still unclear. The goals of study is to investigate the role of androgen and androgen receptor in wild-type (WT) mice and GARKO mice after fracture healing during callus formation and bone mineralization and bone remodeling. Therefore, long-term animal experiments observed by micro-computed tomography to study the roles of androgen and androgen receptor on the process and mechanisms of fracture healing is necessary. We applied in vivo micro-computer tomography (Micro-CT) to build up the three-dimensional model images at different time points for wild-type mice and GARKO mice after fracture healing and observe the bone healing process of micro-structure of the development of callus during fracture healing. The callus tissue morphology observed by histological staining to study the proportion and position of collagen, fibrous tissue and bone. The results show that the healing of WT mice is better than GARKO mice. GARKO mice develop smaller callus size and less bone volume and show delayed healing. In general, orchiectomy (ORX) decreases callus size in WT mice but not in GARKO mice. However, the healing rate of elderly GARKO mice is not obvious in comparison with young GARKO mice. Together, our study demonstrated that the androgen and androgen receptor regulate fracture healing and play an important role in bone repair and healing. Our mouse model may be used for the therapeutic drug screening of bone fractures caused by osteoporosis.

No description available.

Neurons commonly have a primary cilium, which is a non-motile organelle extending from the centrosome into the extracellular space. In most brain regions, neuronal cilia are enriched in either somatostatin receptor type 3 (SstR3) or melanin concentrating hormone receptor type 1 (MCHR1), or both. The present immunohistochemical study provides novel evidence that primary cilia regulate neuronal excitability via G-protein coupled receptors (GPCRs), and that their identity is governed by brain region and by competition, both in adulthood and in postnatal development. The hippocampus, which is particularly vulnerable to seizures, has opposing gradients of SstR3(+) and MCHR1(+) ciliary GPCRs. We hypothesized that there is a competition between these two ciliary GPCRs, which might take place on any level from gene expression to presence in the cilium. We examined whether receptor colocalization occurs transiently in development before ciliary GPCR dominance is established in neurons in the CNS. In postnatal CA1 and CA3, the first GPCR to appear in cilia was the one that will dominate in adults: MCHR1 in CA1 and SstR3 in CA3. Some days later, the second GPCR was expressed along with the first; dual-receptor cilia were the exclusive type until single-receptor cilia emerged again around P14. Single-receptor cilia then increased in numbers through adulthood. By identifying ciliary receptors that modulate seizure activity in mice, the present study lays a foundation for therapeutic approaches to reduce neuronal excitotoxicity underlying cell death in epilepsy, CNS injury, and neurodegenerative diseases.

No description available.