Poster Session I

2010 Neuropsychopharmacology  
The molecular mechanism of lithium (Li)'s moodstabilizing action is not yet unraveled. Since its clinical efficacy is characterized by a lag in onset of 1-3 weeks, it is reasonable that the therapeutic effect requires reprogramming of gene expression. Previous studies have shown alteration in gene expression following mood stabilizing drug treatment in a variety of genes, including genes involved in inositol metabolism. Inositol-monophosphatase 1 (IMPase1) is inhibited by
more » ... t Li concentrations in an uncompetitive manner, possibly resulting in decreased inositol, subsequent down regulation of the phosphatidylinositol (PI) cycle and dampening of assumed hyperactive neurotransmission through this pathway (the "inositol depletion" hypothesis). Li was also shown to down-regulate the expression of sodium myo-inositol co-transporter (SMIT)1, responsible for the uptake of myo-inositol from extracellular fluid. Both IMPA1 and SMIT1 homozygote knockout mice exhibit lithium-like behavior in the forced-swim test and the pilocarpineinduced seizures paradigm. We aimed to identify gene networks and pathways affected in homozygote IMPA1 and SMIT1 knockout mice and in Li-treated mice compared with wild-type (WT) untreated mice. Since our results of differentially expressed genes culminated in mitochondrial function, we used the oxidative phosphorylation inhibitor rotenone to evaluate behavioral reversal of Lithium effects. Methods: For the microarray study male, 2 months old, IMPA1 and SMIT1 homozygote knockout mice and their littermate wildtype (WT) mice were used. Mice received powdered food. Li-treated WT mice received powdered food supplemented with 0.2% Li for five days, followed by 0.4% Li for another 10 days. Microarray analysis was performed using the Affimetrix platform. Results were analyzed using the softwares IPA (Ingenuity Pathway Analysis), GSEA (Gene Set Enrichment Analysis) and DAVID (Database for Annotation, Visualization and Integrated Discovery). For the rotenone-treatment study two groups of male, 2 months old, ICR mice were administered subcutaneously for four weeks either 0.5% DMSO in 0.9% NaCl (vehicle) or 0.5 mg/Kg rotenone in vehicle. At the end of the second week each of the groups was subdivided into two groups receiving either lithium food or regular food as described for the microarray study. Results: We show that oxidative phosphorylation and mitochondrial function are the only significant pathways commonly affected in the frontal cortex of SMIT1 and IMPA1 knockout mice and Li-treated mice. Administration of rotenone, an inhibitor of mitochondrial oxidative phosphorylation, augments the hyperlocomotion response of mice to d-amphetamine, an effect attenuated by Li treatment. Discussion: Our results corroborate previous finding in bipolar patients and suggest that improvement of mitochondrial dysfunction, mediated by inositol depletion, might underlie the therapeutic effect of Li. Background: Attention deficit hyperactivity disorder (ADHD) is a developmental disorder wherein a subset of individuals with ADHD is at greater risk for substance use than the typical population. Substance use disorder (SUD) emerges earlier in the ADHD population. Impulsivity is an additional risk factor for addiction, and is another cardinal feature of ADHD. One measure of impulsive choice is delayed discounting and occurs in 26.8% of children with ADHD. We were interested in determining whether the same developmental manipulation could produce both a developmental shift in drug sensitivity and increase impulsivity. We have recently shown that sensitivity to cocaine-associated environments, a measure associated with drugseeking in rats, is relatively low during the juvenile period and increases during adolescence, paralleling what is observed in humans. A shift in cocaine sensitivity during the juvenile stage would be consistent with enhanced risk for later SUD. In addition, increased delayed discounting would further enhance risk for SUD. While the underlying biochemistry of ADHD is poorly understood, reduced cortical dopamine levels have been implicated in a number of studies. In addition, little is known about how dopamine levels may differentially alter behavior in juvenile males and females. Methods: Sprague-Dawley rat pups that were 10-11 days of age were pretreated with desimpramine to protect noradrenergic terminals, anesthetized with ice hypothermia, and given a bilateral, intraprefrontal microinjection of 6-OHDA or vehicle. Previous studies have shown that 6-OHDA does not produce a total depletion of dopamine when given during development. Subjects were then allowed to mature to weanling age of 22 days of age. Juvenile subjects were tested for place preferences to environments associated with 10 mg/kg cocaine, a dose that is a good threshold dose for age-related shifts in sensitivity. A second group of subjects was tested for impulsive choice with a delayed discounting task, with training beginning at 23 days of age. Results: We found a significant effect of 6-OHDA treatment in both place preferences for cocaine and impulsivity that interacted with sex. 6-OHDA-treated males had a greater preference for the cocaineassociated environment than vehicle-treated males, whereas 6-OHDA lesions reduced cocaine preferences in females (Condition X Sex interaction: 1,15 ¼ 6.12, po0.05). 6-OHDA treatment also increased impulsive choice in males 2.23-fold relative to controls, but was without effect in treated females (Condition X Sex interaction: 1,18 ¼ 5.04, po0.05). In a subset of subjects, preliminary investigations show a significant correlation (r ¼ 0.56) between delayed discounting and cocaine place preference.
doi:10.1038/npp.2010.216 fatcat:v3q2xjxc45b2hckv33pzz7mtee