A role for sigma receptors in stimulant self-administration and addiction

Abstract

Sigma-1 receptors (σ1Rs) are structurally unique intracellular proteins that function as chaperones. σ1Rs translocate from the mitochondria-associated membrane to other sub-cellular compartments, and can influence a host of targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Drugs binding to σRs can induce or block the actions of σRs. Studies indicate that stimulant self-administration induces reinforcing effects of σR agonists, due to dopamine transporter actions. Once established the reinforcing effects of σR agonists are independent of dopaminergic mechanisms traditionally thought to be critical in the reinforcing effects of stimulants. Self-administered doses of σR agonists do not increase dopamine concentrations in the nucleus accumbens shell, a transmitter and brain region considered important for reinforcing effects of abused drugs. However, the self-administration of σR agonists is blocked by σR antagonists. Several effects of stimulants have been blocked by σR antagonists, including reinforcing effects assessed by a place-conditioning procedure. However, the self-administration of stimulants is largely unaffected by σR antagonists, indicating fundamental differences in the mechanisms underlying these two procedures used to assess reinforcing effects. When σR antagonists are administered in combination with dopamine uptake inhibitors an effective and specific blockade of stimulant self-administration is obtained. Actions of stimulant drugs related to their abuse induce unique changes in σR activity and the changes induced potentially create redundant, and once established, independent reinforcement pathways. Concomitant targeting of both dopaminergic pathways and σR proteins produces a selective antagonism of stimulant self-administration, suggesting new avenues for combination chemotherapies to specifically combat stimulant abuse.

Cocaine engages a non-canonical, dopamine-independent, mechanism that controls neuronal excitability in the nucleus accumbens

“…Therefore, cocaine and other stimulants may engage additional mechanisms that would participate in specific addictionrelated phenotypes. In that regard, a stream of studies demonstrates that cocaine also engages mechanisms that are dependent on σ1, but independent of DA signaling, and which contribute to cocaine addiction [10]. For example, animals with cocaine experience, but not after experience with food reinforcement, self-administer σ1 agonists (e.g., PRE-084 and (+)-Pentazocine) [76] at doses that do not induce DA release in the NAcSh [77] (reviewed in [10]).…”

“…Consistent with this role, σ1 regulates both DA receptors signaling (DARs) via protein-protein interactions [7,8] and DA release in the striatum [9]. In contrast, there is evidence that cocaine and other stimulants may also engage σ1 independent of DA signaling and contribute to cocaine addiction [10], suggesting that redundant or complementary mechanisms exist to shape addiction-related phenotypes. However, no cellular mechanism has been identified so far.…”

2-Substituted 3 -Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations

“…More recently, it has been suggested that compounds with sigma receptor (sR) antagonist effects along with their affinity for the DAT will exhibit atypical DAT inhibitory effects similar to BZT . A number of previous studies indicated that sR antagonists can block several effects of cocaine, including locomotor stimulation, sensitization, and place conditioning (see review by Katz et al, 2011), and it is noteworthy that BZT analogs also have affinity for sRs Li et al, 2011).…”

Blockade of Cocaine or Receptor Agonist Self Administration by Subtype-Selective Receptor Antagonists

“…The present study exploited a recent finding that subjects with cocaine self administration experience will also self administer the sR ligands (1)-pentazocine, PRE-084, and DTG (Katz et al, 2016) to examine in vivo potential antagonist effects and selectivity of several novel ligands (Fig. 1).…”

“…Rats trained to self administer cocaine under fixed-ratio (FR) schedules continued to respond unabated when either (1)-pentazocine, PRE-084, or DTG was substituted for cocaine, although responding decreased with vehicle substitution. Further, pretreatment with several known nonselective sR antagonists blocked sR ligand self administration (Katz et al, 2016). This study used radioligand binding to assess subtype selectivity, and self administration in an attempt to distinguish subtype-selective agonist or antagonist effects of the novel sR ligands.…”