Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
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Neuropsychopharmacology · Dec 2012
Upregulation of nerve growth factor in central amygdala increases sensitivity to opioid reward.
The rewarding properties of opioids are essential driving force for compulsive drug-seeking and drug-taking behaviors in the development of opioid-mediated drug addiction. Prior drug use enhances sensitivity to the rewarding effects of subsequently used drugs, increasing vulnerability to relapse. The molecular mechanisms underlying this reward sensitization are still unclear. ⋯ Histone deacetylase inhibitors that increased the acetylation level at the Ngf promoter and NGF expression in the CeA also induced reward sensitization in a CeA NGF signaling- and DOR-dependent manner. Furthermore, CeA-applied NGF substituted prior morphine to induce reward sensitization in naive rats and also substituted priming morphine to reinstate the CPP induced by prior morphine. Thus, epigenetic upregulation of NGF activity in the CeA may promote the behavior of opioid reward and increase the sensitivity to the rewarding effect of subsequent opioids, a potentially important mechanism in drug addiction.
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Neuropsychopharmacology · Dec 2012
Candesartan, an angiotensin II AT₁-receptor blocker and PPAR-γ agonist, reduces lesion volume and improves motor and memory function after traumatic brain injury in mice.
Traumatic brain injury (TBI) results in complex pathological reactions, the initial lesion worsened by secondary inflammation and edema. Angiotensin II (Ang II) is produced in the brain and Ang II receptor type 1 (AT₁R) overstimulation produces vasoconstriction and inflammation. Ang II receptor blockers (ARBs) are neuroprotective in models of stroke but little is known of their effect when administered in TBI models. ⋯ These results indicate that candesartan is neuroprotective, reducing neuronal injury, decreasing lesion volume and microglial activation, protecting CBF and improving functional behavior in a mouse model of TBI. Co-treatment with a peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist significantly reduced some of the beneficial effects of candesartan after CCI, suggesting that PPARγ activation may contribute to part or to all of the neuroprotective effect of candesartan. Overall, our data suggest that ARBs with dual AT₁R-blocking and PPARγ activation properties may have therapeutic value in treating TBI.