A Role for CaMKII and ERK1/2 Pathways in Alcohol Self-Administration and Relapse-like Behavior

Alcoholism is a debilitating neuropsychiatric disorder that adversely affects many people worldwide. Understanding the neurobiological mechanisms that cause alcohol addiction is paramount to its treatment. New evidence suggests that addictive behaviors emerge as a result of plastic changes in the neural circuitry that mediates drug reinforcement and reward-learning. The goal of this dissertation was to identify changes in neuroplasticity-related proteins following alcohol consumption in areas of the brain that mediate alcohol reward. Initially, we analyzed the amygdala proteome following chronic alcohol consumption and found 26 proteins that showed differential protein expression. Several of these proteins are involved in synaptic plasticity including CaMKII[alpha], a protein kinase that modulates receptor activity and is required for the induction of long-term synaptic plasticity. We further characterized CaMKII expression in the amygdala, and found that it is specifically increased in the central and lateral amygdala following twenty-eight days of alcohol-drinking at the start of the dark cycle when there were no detectable blood alcohol levels. Consistent with CaMKII's role in AMPAR trafficking, we found a concomitant increase in AMPA/NMDA ratio in the central amygdala. We extended these findings by measuring CaMKII expression following operant self-administration and found that phosphorylated CaMKII was increased in the amygdala of alcohol-drinking mice. To determine if increased CaMKII activation played a role in alcohol's reinforcing properties, we infused CaMKII inhibitors into the amygdala prior to self-administration sessions. We found that CaMKII inhibition attenuates alcohol but not sucrose operant self-administration and concluded that CaMKII activity in the amygdala functionally regulates the reinforcing properties of alcohol. Lastly, we developed a mouse protocol for relapse-like behavior and tested the role of ERK1/2, a protein kinase that plays a role in plasticity, in relapse-like behavior. We found that inhibition of ERK1/2 phosphorylation potentiates cue-induced reinstatement of alcohol-seeking and induces sucrose-seeking. Collectively, these experiments demonstrate that inhibiting the activity of protein kinases that are involved in synaptic plasticity can affect alcohol-related behaviors in a reinforcer-specific manner and suggest that modulating these pathways has the potential for pharmacotherapeutic intervention in alcoholics

Modeling Group Perceptions Using Stochastic Simulation: Scaling Issues in the Multiplicative AHP

This paper proposes a new decision support approach for applying stochastic simulation to the multiplicative analytic hierarchy process (AHP) in order to deal with issues concerning the scale parameter. The paper suggests a new approach that captures the influence from the scale parameter by making use of probability distributions. Herein, the uncertainty both with regard to the scale and the inherent randomness from the parameter is captured by probabilistic input and output distributions. Provided that each alternative and criteria under consideration are independent it is assumed that the embedded uncertainty from the progression factors remains the same. The result is then an interval estimate for each alternative’s final scores. This can lead to overlapping intervals of scores which may be interpreted as possible rank reversals. Thus, the decision support approach makes it possible to calculate the probability of overlapping for any given set of pairwise comparisons.22 page(s

The effects of fluoxetine and environmental enrichment on recovery of function following focal dentate gyrus lesions

New neurons are formed in the dentate gyrus of the mammalian hippocampus throughout adulthood. Rates of adult neurogenesis can be manipulated by pharmacological and environmental factors. Specifically, two factors that lead to increased neurogenesis are the antidepressant fluoxetine which increases the proliferation of neural progenitor cells and environmental enrichment which increases neuronal survival. Although the putative function of adult neurogenesis is unknown, there is accumulating evidence that it plays a role in hippocampal-dependent learning and memory and as a self-repair response following brain insult. The aim of the present study was investigate whether increasing neurogenesis in rats could promote a recovery of spatial function following dentate gyrus damage. Intradentate infusions of colchcine selectively ablated the majority of dorsal dentate gyrus granule cells. Rats where then tested on the Morris water maze and matched to treatment groups. In the treatment paradigm aimed at increasing rates of neurogenesis, rats were given daily saline or fluoxetine injections and either lived in standard housing or a novel enriched environment for 5 weeks with BrdU injections occurring in the middle. Ki67-staining revealed a decrease in cell proliferation associated with the enriched environment. Doublecortin-staining revealed that fluoxetine increased cell survival in the standard housing. BrdU/NeuN-colabeling qualitatively revealed that neurogenesis did occur in the damaged dentate gyrus, but at a low rate. Overall, dentate gyrus lesions significantly decreased the proliferation and survival of new neurons following treatment. We concluded that the colchicine dose used profoundly disrupted the neurogenic niche and that the enriched environment was inhibiting proliferation because it was more stressful than the standard housing. In the post-treatment behavioral testing, lesion rats had significant spatial memory deficits but did improve and enriched rats improved more than standard housed rats. On the probe test, lesion rats outperformed sham rats and lesion rats in the enriched environment outperformed all other rats on target search but not target crossings which may be interpreted as an increased resistance to extinction