Despite widespread misconceptions, cannabis is an addictive substance, and is a widely used drug of abuse. The CB1 cannabinoid receptor is garnered substantial attention from the research community over the past decade, due to its central role in synaptic homeostasis and remodeling. In addition, the contribution of CB1 to behavior, both in normal function and in response to cannabinoids, has been an area of interest due to the interesting array of behaviors in which CB1 is involved. Although many advances have been made, the CB1 receptor subpopulations which participate in distinct behaviors are only very generally known, in many cases with no more specific knowledge than whether the receptor subpopulation mediating a particular behavior exists on GABAergic or glutamatergic cells. In particular, CB1 is known to be involved in self-administration behaviors, in conditioned place preference, and in psychostimulant-induced locomotor sensitization - however it remains unknown which specific subpopulations of CB1 are participating in these behaviors. The purpose of this proposal is to undertake a highly specific genetic approach in order to understand more clearly the role of a well-defined CB1 receptor subpopulation on a behavior of interest: amphetamine- induced locomotor sensitization. We have created a mouse that expresses a copy of murine CB1 under a robust CBA promoter, and inserted it into the ROSA26 locus. Then, we have bred these mice into a CB1-null background, so that CB1 expression is present only on medium spiny neurons in our experimental animals (MSN-CB1). Since prior studies have explicitly implicated the medium spiny neuron CB1 receptor subpopulation as being necessary for amphetamine-induced locomotor activation, we will compare the performance of WT mice, CB1-KO mice, and MSN-CB1 mice in this behavior. The successful completion of this project will provide very specific information about a subpopulation of CB1 receptors for which there is currently no proven behavioral role. In addition, in the event that ou hypothesis is correct, this study will open the way for more detailed analyses of the role of MSN CB1 receptors not only in psychostimulant-induced locomotor sensitization, but also in behaviors which have more direct links to addiction, such as conditioned place preference and self-administration. In addition, the project would provide training for a young physician-scientis. We are hopeful that this project will yield information that will be of benefit to both the researc community and will lead to advances that benefit the general public.
This study focuses on an important group of projection inhibitory neurons, which are part of the brain's go/no-go filtering system. The role of CB1 endocannabinoid receptors on these neurons is unclear, but there is some indication that they affect the ability of neurons to produce long-term changes in behavior, in response to prior events. The goal of this study is to better understand the role of this specific population of endocannabinoid receptors in the neuroadaptive processes that accompany repeated psychostimulant drug exposure.
|Naydenov, Alipi V; Horne, Eric A; Cheah, Christine S et al. (2014) ABHD6 blockade exerts antiepileptic activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice. Neuron 83:361-371|
|Kow, Rebecca L; Jiang, Kelly; Naydenov, Alipi V et al. (2014) Modulation of pilocarpine-induced seizures by cannabinoid receptor 1. PLoS One 9:e95922|
|Naydenov, Alipi V; Sepers, Marja D; Swinney, Katie et al. (2014) Genetic rescue of CB1 receptors on medium spiny neurons prevents loss of excitatory striatal synapses but not motor impairment in HD mice. Neurobiol Dis 71:140-50|
|Chen, Dong-Hui; Naydenov, Alipi; Blankman, Jacqueline L et al. (2013) Two novel mutations in ABHD12: expansion of the mutation spectrum in PHARC and assessment of their functional effects. Hum Mutat 34:1672-8|