Potential Molecular Mechanisms on the Role of the Sigma-1 Receptor in the Action of Cocaine and Methamphetamine

Abstract

The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum membrane protein that involves a wide range of physiological functions. The Sig-1R has been shown to bind psychostimulants including cocaine and methamphetamine (METH) and thus has been implicated in the actions of those psychostimulants. For example, it has been demonstrated that the Sig-1R antagonists mitigate certain behavioral and cellular effects of psychostimulants including hyperactivity and neurotoxicity. Thus, the Sig-1R has become a potential therapeutic target of medication development against drug abuse that differs from traditional monoamine-related strategies. In this review, we will focus on the molecular mechanisms of the Sig-1R and discuss in such a manner with a hope to further understand or unveil unexplored relations between the Sig-1R and the actions of cocaine and METH, particularly in the context of cellular biological relevance.

The sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission

“…Functional associations of DAT with other proteins regulates the activity of the transporter. Importantly, the σ 1 R interacts with and modulates the activity of various plasma membrane proteins 16 , 22 . Therefore, we considered the possibility that σ 1 R associates with DAT and thus regulates its function.…”

“…These ER structures provide direct communication between the ER and plasma membrane for Ca 2+ signaling and/or protein trafficking 21 . Although the mechanisms by which the σ 1 R translocates to the plasma membrane remain elusive, the σ 1 R has been shown to interact with and modulate the activity of various membrane proteins 16 , 22 , including recent evidence for interactions between the σ 1 R and DAT 23 .…”

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

“…Previous studies suggest that activation of the sigma-1 receptor (σ1), an endoplasmic reticulum (ER) chaperone [3] that regulates a variety of proteins through physical protein-protein interactions [4], contributes to addiction processes [5,6]. Consistent with this role, σ1 regulates both DA receptors signaling (DARs) via protein-protein interactions [7,8] and DA release in the striatum [9].…”

Is There a Potential of Misuse for Quetiapine?

“…Hence, there may be other factors [46][47] or pharmacological effects which may be behind the molecule misusing potential. These effects may include: norquetiapine-related norepinephrine reuptake blockade [13]; 5HT 7 antagonist properties [16]; and sigma receptors' activation [48][49]. Some pharmacokinetics' issues have been suggested to represent important issues as well in facilitating quetiapine misuse [50].…”