geranylgeranylacetone and Morphine-Dependence

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Conditioning, Psychological; Cyclic AMP Response Element-Binding Protein; Diterpenes; Extinction, Psychological; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Hippocampus; Male; Mice, Inbred C57BL; Morphine; Morphine Dependence; Narcotics; Nucleus Accumbens; Phosphorylation; Psychotropic Drugs; Receptors, N-Methyl-D-Aspartate; Recurrence; Spatial Behavior; Thioredoxins

There are few efficacious interventions to combat morphine dependence. Thioredoxin-1 (Trx-1) and heat shock protein 70 (Hsp70) are emerging as important modulators of neuronal function. They have been shown to be involved in cellular protective mechanisms against a variety of toxic stressors. This study was designed to investigate the effects of geranylgeranylacetone (GGA), a pharmacological inducer of Trx-1 and Hsp70, on morphine-induced hyperlocomotion, rewarding effect, and withdrawal syndrome. Trx-1 and Hsp70 expression was increased in the frontal cortex, hippocampus, ventral tegmental area, and nucleus accumbens of mice after GGA treatment. GGA administration reduced morphine-induced motor activity and inhibited conditioned place preference. GGA markedly attenuated the morphine-naloxone-induced withdrawal signs, including jumping, rearing, and forepaw tremor. Furthermore, the activation of cAMP-responsive element-binding protein and the expression of ΔFosB and cyclin-dependent kinase 5 were decreased in the nucleus accumbens by GGA treatment after morphine withdrawal. In the nucleus accumbens, GGA enhanced morphine-induced expression of Trx-1 and Hsp70 after morphine withdrawal. These results suggest that strengthening the expression of Trx-1 and Hsp70 in the brain by using noncytotoxic pharmacological inducers may provide a novel therapeutic strategy for morphine dependence. GGA could be a safe and novel therapeutic agent for morphine dependence.

Topics: Analgesics, Opioid; Animals; Blotting, Western; Brain; Cell Movement; Diterpenes; HSP70 Heat-Shock Proteins; Mice; Mice, Inbred C57BL; Morphine; Morphine Dependence; Reward; Substance Withdrawal Syndrome; Thioredoxins