The sigma-1 receptor: a molecular hub for psychostimulant drugs in the nucleus accumbens

V. Le Corvec¹, A. Segev², I. Delint-Ramirez², F. Garcia-Oscos², A. Pavuluri³, S. Kourrich^1,2

¹Université du Québec à Montréal, Département des Sciences Biologiques - CERMO-FC, Montréal, Canada
²University of Texas Southwestern Medical Center in Dallas, Department of Psychiatry, Dallas, USA
³University of Maryland, College of Behavioral and Social Sciences, College Park, USA

The psychoactive properties of psychostimulant drugs (e.g., cocaine and methamphetamine) have long been considered a consequence of their ability to enhance dopamine (DA) signaling. Recently, we found that cocaine leads to an enduring depression of neuronal firing (i.e., neuronal hypoactivity) in nucleus accumbens shell (NAcSh) medium spiny neurons (MSNs), a brain region that is involved in reward and motivation. This neuroadaptation promotes behavioural sensitization to cocaine, a behavioural phenotype that contributes to the development of drug addiction. Strikingly, we found that cocaine-induced neuronal hypoactivity is independent of DA signaling, but dependent on the endoplasmic chaperon protein sigma-1 receptor (σ1R). Here we found that in vivo methamphetamine, a psychostimulant drug with pharmacological properties distinct from cocaine, also depresses NAcSh MSNs firing. Similar to cocaine, methamphetamine-induced neuronal hypoactivity is independent of DA signaling, but dependent on σ1R binding to Kv1.2 potassium channels, a mechanism that leads to enhanced Kv1.2 levels at the plasma membrane. Using site-directed mutagenesis of σ1R binding site for methamphetamine in HEK293T cells, we found that methamphetamine binding to σ1R is necessary for methamphetamine-induced enhanced surface Kv1.2. Our study provides direct evidence that besides actions mediated through conventionally studied mechanisms, psychostimulant drugs engage a common DA-independent, but σ1R binding-dependent mechanism that contributes to behavioural response to cocaine. Significantly, in contrast to mechanisms that are drug-specific, our data suggest that psychostimulants-induced NAcSh MSNs hypoactivity may be a core process of psychostimulant addiction, paving the way for the development of novel pharmacotherapeutic agents to treating addiction to a variety of stimulants.