Radixin in the nucleus accumbens contributes to the development of conditioned hyperactivity in an amphetamine-associated environment

Abstract

The nucleus accumbens (NAcc) is an important neuronal substrate mediating rewarding effects of drugs of abuse in the brain. It has been suggested that repeated exposure to psychostimulants induced dendritic spine plasticity in the NAcc, which is thought to be related with enduring drug-related behaviors including conditioning (associative form of memory) and behavioral sensitization (non-associative form of memory). Dendritic spines are postsynaptic structures located on dendritic shafts of neurons where they mediate electrical neurotransmission responding to excitatory axon terminals and can be classified into thin, stubby and mushroom based on their different size and shapes. Structural plasticity of dendritic spines has its basis on reorganization of actin cytoskeleton which is controlled by various actin binding proteins including ezrin-radixin-moesin (ERM) proteins. Previously, it has been shown that ERM proteins are expressed in the brain, most abundantly in neurogenic regions. However, there are few studies directly showing their presence and subcellular distribution on adult neurons in vivo. In my thesis, first I aimed to examine the subcellular distribution of radixin, one of ERM proteins, in the NAcc. In addition, ERM proteins have been implicated in cell-shape determination by crosslinking F-actin to plasma membrane. Thus, it was hypothesized that there might be a strong link between ERM proteins and dendritic spine plasticity in response to drugs of abuse. So, next, I aimed to investigate whether there are any effects of accumbal radixin in amphetamine-induced conditioning and sensitization. The lentiviral constructs expressing copGFP alone (GFP), radixin wild-type (Rdx-WT) or a pseudo-active radixin mutant T564D (Rdx-MUT) were injected into the NAcc of rats. It was found that Rdx-WT overexpression prevented the expression of conditioned locomotion in paired rats when compared to those infected with either GFP or Rdx-MUT in the same group. Moreover, Rdx-WT overexpression in the NAcc also prevented the expression of amphetamine-induced hyper-locomotion in a subsequent sensitization test in paired rats, while no behavioral changes were observed in paired rats overexpressing either GFP only or Rdx-MUT. Interestingly, the inhibition of the expression of sensitized locomotor responses shown in Unpaired GFP and MUT rats, a phenomenon termed as conditioned inhibition, was saved when Rdx-WT was overexpressed in the NAcc. Finally, it was found that the behavioral effect of Rdx-WT in paired rats was correlated with the number of total spine density in the NAcc. Among the sub-types of spines, thin spines are found to be the major contributor to this effect. These data, first time to my knowledge, demonstrated that radixin in the NAcc specifically contributes to amphetamine-induced associated memory (i.e., conditioning and context-specific sensitization) possibly through structural plasticity of dendritic spines in the NAcc.