The roles of αCaMKII and Ras-GRF2 in the establishment of drug addiction

Addiction is a chronic, relapsing disorder associated with health and social problems for the individual and great economic costs for society. Despite significant progress in the understanding of drug effects on the nervous system, major processes involved in the development of addiction are still insufficiently understood. At a cellular level, many drugs of abuse induce a long term potentiation-like state in the dopamine (DA) neurons of the ventral tegmental area (VTA), a process which enhances synaptic transmission and potentiates signals for longer within the cell. This is a major cellular mechanism underlying normal learning and memory formation, but is also important in the formation of drug-related memories and addiction. By adopting a correlative approach to further dissect which neuronal mechanisms contribute to addiction, the focus of this thesis is placed on two separate genes, each of which code for different proteins involved in synaptic plasticity. The thesis aims to assess whether these genes contribute to the development of drug preference and addiction, and the speed at which these behaviours are established. Alpha calcium/calmodulin dependent protein kinase II | (aCaMKII) and Ras-specific guanine nucleotide releasing factor 2 (Ras-GRF2) are calcium/calmodulin dependent kinases which play an important role in the plasticity of the glutamatergic and monoaminergic systems by influencing long-term potentiation (LTP). Transgenic mice were tested through an extensive battery of 3havioural (spontaneous behaviours, consumption and conditioned place Deference) and in vivo neurochemical (in vivo microdialysis and HPLC-ED) chniques, in order to assess whether aCaMKII and Ras-GRF2 have the tential to control the rate at which addiction related behaviours are acquired id/or established.<br/>The current thesis implicates aCaMKII itophosphorylation in the mediation of threat induced activity in responsethe same capacity as observed in wild-type mice. Alcohol administration also altered dopamine and serotonin levels in the mesocorticolimbic system of aCaMKII autophosphorylation deficient mice. Adaptations in this system were also found following the development of cocaine preference. Ras-GRF2 has an important role at the synapse and Ras-GRF2 deletion appears to result in the failure of the monoaminergic system to adapt in a typical way in response to alcohol exposure, which may make the animal less vulnerable to the rewarding properties of alcohol. One hypothesis is that the Ras-GRF2 deletion has the potential to serve as neuro-protective factor against alcoholism. Characterisation of the roles of aCaMKII and Ras-GRF2 suggests that the proteins encoded by these genes may contribute to aspects of drug addiction related behaviors by modulating monoaminergic drug responses in the brain.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2013

Author dc:creator

• Easton, Alanna

Advisors dc:contributor.advisor

• Muller, Christian Peter
• Fernandes, Catherine

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/dcf25ba5-9499-48b3-8eff-2b4525799456

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/dcf25ba5-9499-48b3-8eff-2b4525799456