Characterizing the role of accumbens medium spiny neurons in vulnerability to heroin addiction

Abstract

Opioid addiction is a chronic, relapsing disorder that arises from dysregulation of the neural circuits responsible for reward processing, associative learning, and decision making, and is conceptualized as a three-stage, cyclical process encompassing drug consumption, withdrawal, and drug craving. Research into the neurobiological mechanisms that underlie addiction has demonstrated a central role for the cortico-basal ganglia circuit in the development and persistence of maladaptive addictive behaviors. The nucleus accumbens (NAc), which lies at the interface of the cortico-basal ganglia circuit, integrates cortical and subcortical inputs to guide behavioral output. The NAc is a heterogeneous structure containing two interspersed populations of medium spiny neurons (MSNs) with oppositional behavioral control: direct pathway MSNs (dMSNs) facilitate behavior and serve as a “go” signal; indirect pathway MSNs (iMSNs) suppress behavior and serve as a “stop” signal. Behavioral regulation is thought to rely on a balance between signaling of the direct and indirect pathways, and discrete behavioral aberrations, such as those associated with addiction, have been linked to disruptions of this balance. For example, driving NAc output (via dMSN activation or iMSN inhibition) facilitates drug taking and drug seeking, while dampening NAc output (via dMSN inhibition or iMSN activation) suppresses drug taking and drug seeking. Moreover, the excitability of iMSNs increases after cocaine exposure in cocaine-resistant mice, suggesting a role for MSNs in encoding individual vulnerability to addiction. It is important to note that most of our understanding of the role of these neuronal populations in regulating addictive behaviors is based on psychostimulant research, so their contribution to opioid addiction remains unknown. Furthermore, only a subset of individuals who use drugs medically or recreationally transition to addiction, so it is imperative to determine the neural correlates of vulnerability to addiction.