Amphetamine-Induced OCD-Related Repetitive Behaviors Are Potentiated in<i>Slc1a1-OE</i>Mice

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by obsessions and compulsions.Obsessions are intrusive thoughts or urges, and compulsions are repetitive behaviors that a person often performs to alleviate the anxiety related to these obsessions.The obsessions and compulsions associated with OCD can be debilitating, affecting the daily lives and overall quality of life for those with OCD (Pauls et al., 2014).OCD has a lifetime prevalence of 2-3% and although there are treatments for those diagnosed with OCD, unfortunately up to 50% of these patients continue to display symptoms (Dougherty et al., 2004).Better, more targeted treatment options are needed, and understanding the neurobiology of OCD is important in improving the treatment options for those affected by this disorder.Previous studies of OCD patients using neuroimaging techniques have identified increased activity of cortical and striatal regions (Pauls et al., 2014).Additionally, animal studies have also implicated the dysfunction of specific glutamate signaling circuits in OCD-relevant behaviors (Welch et al., 2007).With respect to genetic risk, the chromosome region 9p24, containing the gene SLC1A1, has been implicated in the development of OCD.Furthermore, the rs301430 polymorphism has been replicated in several OCD association studies, and this polymorphism increases SLC1A1 expression in humans, including in the brain tissue.SLC1A1 is a gene that encodes the protein EAAT3, which is a neuronal glutamate transporter.Thus, the increase in SLC1A1 expression observed with this polymorphism also leads to increased expression and activity of EAAT3 (Veenstra-VanderWeele et al., 2012).These studies suggest that there may be an increased risk of OCD and OCD-relevant behaviors in model systems with elevated SLC1A1/EAAT3 levels.Additionally, animal studies have displayed a relationship between Slc1a1/EAAT3 and abnormal repetitive behaviors such as a significant increase in amphetamine-induced repetitive behaviors in mice with increased expression of Slc1a1 (Escobar et al., 2021).In the recent eNeuro publication by Kopelman et al. ( 2024), the authors used a novel Slc1a1-overexpressing (OE) mouse model with elevated EAAT3 expression in forebrain regions to investigate the relationship between EAAT3 and amphetamine-induced repetitive behavior and striatal activation.The authors created this novel mouse model by crossing Slc1a1-tetO-STOP mice with Pgk1-flpo mice first, then crossing the offspring of these mice with CaMKII-tetracycline transactivator (tTA) mice which allowed for Slc1a1 to be selectively overexpressed in forebrain neurons in a doxycycline-dependent manner.The authors then confirmed that the expression of EAAT3 is selective and reversible in the forebrain of Slc1a1-OE mice.Baseline anxiety testing revealed no significant differences between tTA-control and Slc1a1-OE mice in open-field and light/dark behavioral paradigms.Additionally, the authors tested repetitive behaviors by observing OCD-related grooming behaviors in the mice but did not see any significant difference in either the baseline or drug-induced (D1-agonist SKF-38393) grooming behaviors exhibited.However, when mice were injected with low-dose amphetamine (3.0 mg/kg), compared with the tTA-control mice, the Slc1a1-OE mice showed significantly increased locomotor activity.The authors then injected the mice with high-dose amphetamine (8.0 mg/kg) and observed more stereotypy, characterized as stationary head bobbing, sniffing, shuffling, or licking behavior lasting at

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