Abstract
Drug addiction is a chronic, debilitating disease that affects millions of people around the world causing a substantial societal burden. Despite decades of research efforts, treatment possibilities remain limited and relapse represents the most treatment-resistant element. Neurosteroid sigma-1 receptors have been meticulously studied in psychostimulant reinforced Pavlovian learning, while the sigma-2 receptor subtype has remained unexplored. Recent development of selective sigma-2 receptor ligands have now made it possible to investigate if the sigma-2 receptor system is a potential target to treat drug addiction. We examined the effect of the sigma-2 receptor agonist Siramesine (Lu 28-179) on cocaine-associated locomotion, Pavlovian learning, and reward neurocircuitry using electrophysiology recordings and in vivo microdialysis. We found that Siramesine significantly attenuated conditioned place preference acquisition and expression, as well as it completely blocked cocaine-primed reinstatement. Siramesine, in a similar manner as the selective sigma-1 receptor antagonist BD 1063, decreased acute locomotor responses to cocaine. Immunohistochemistry suggests co-expression of progesterone receptor membrane component 1/sigma-2 receptors and vesicular glutamate transporter 1 in presynaptic boutons of the nucleus accumbens (NAc). Whole-cell voltage clamp recordings of neurons in the NAc indicated that Siramesine decreases the presynaptic release probability of glutamate. Further, we demonstrated, via in vivo microdialysis, that Siramesine significantly decreased cocaine-evoked dopamine release in the striatum of freely moving mice. Collectively, these findings demonstrate that sigma-2 receptors regulate neurocircuitry responsible for positive reinforcement and thereby play a role in cocaine-reinforced Pavlovian behaviors.
Highlights
Drug addiction is a chronic relapsing disorder with detrimental effects for the affected individuals and, despite decades of scientific effort, treatment possibilities remain scarce and relapse rates high (Volkow et al, 2016)
We evaluated if BD 1063 or Siramesine were able to attenuate cocaine-induced hyper-locomotion
To further investigate the role of σ2Rs in the reward neurocircuitry, we examined if Siramesine affects dopamine levels in the striatum using in vivo microdialysis
Summary
Drug addiction is a chronic relapsing disorder with detrimental effects for the affected individuals and, despite decades of scientific effort, treatment possibilities remain scarce and relapse rates high (Volkow et al, 2016). A recent study identified the σ2R as the progesterone receptor membrane component 1 (PGRMC1) (Xu et al, 2011), and a follow-up study showed that the PGRMC1 protein levels correlate with the binding activity of a σ2R-selective probe (SW120) in the rat brain (Zeng et al, 2016). These findings, are debatable due to newer studies showing that PGRMC1 knockdown/out or knock-in interventions do not change σ2R binding of [3H]-DTG (1,3-di-o-tolylguanidine; a shared σ1R and σ2R ligand) in affinity assays (Abate et al, 2015; Chu et al, 2015). The possible effects of Siramesine have not yet been explored in cocaine-reinforced behaviors
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