Investigating the Role of Corticostriatal Glutamate Signaling in Methamphetamine Reward and Reinforcement

Abstract

Highly addictive amphetamine‐type stimulants, including methamphetamine (MA), pose significant health and socioeconomic issues, with an estimated 27 million users worldwide. Understanding the neurobiological changes underlying various stages of MA abuse is key to developing safe and effective therapies. While the majority of addiction research has implicated the dopamine system, the long‐term neuroplasticity that maintains MA Use Disorder also involves drug‐induced changes in glutamate signaling in reward regions of the brain like the nucleus accumbens (NAC) and prefrontal cortex (PFC). In order to further characterize the role of glutamate in MA reward and reinforcement, glutamate receptor scaffolding protein Homer2 expression in the NAC and activity in the glutamatergic projection PFC‐NAC were manipulated prior to place‐ and operant‐conditioning procedures. Together the results from these studies argue that while research of the functional neuroanatomy of addiction tends to focus on traditional dichotomies between the NAC core and shell or PFC prelimbic and infralimbic sub‐regions, the role of these circuits in drug abuse is more complex than the narrow scope of our experiments were able to probe. Other inputs upstream from our regions of interest may be able to compensate for our manipulations via neurobiological redundancy. This would suggest that as research technologies advance, targeting functional networks will be crucial for elucidating the neurobiological underpinnings of addiction and discovering potential therapeutics.