Neuroactive Neurosteroids as Endogenous Effectors for the Sigma1 (σ1) Receptor: Pharmacological Evidence and Therapeutic Opportunities

Behavioural phenotyping of knockout mice for the sigma-1 (σ1) chaperone protein revealed gender-related anxiety, depressive-like and memory alterations

“…Particularly, in the conditioned fear stress model, an index of the anxiogenic response induced by psychological stress, (+)-SKF-10,047, igmesine, dextromethorphan, pregnenolone sulphate and DHEA sulphate attenuated the locomotor suppression induced by previous electric footshock, through their σ 1 related action (Kamei et al, 1996, 1997; Noda et al, 2000; Urani et al, 2002). The effects of σ 1 ligands were also demonstrated in other behavioural tests assessing anxious response such as sexual dysfunction induced by stress, marble-burying behaviour and colonic motor disturbances induced by fear (for reviews, see Cobos et al, 2008; Maurice et al, 1999). In the marble-burying behaviour test, considered a potential model of obsessive–compulsive disorder on the basis of behavioural similarity, the σ 1 agonists (+)-SKF-10,047 and PRE 084 slightly inhibited the behavioural response and the effect of fluvoxamine was antagonized by BD1063 and BD1047, suggesting that the interaction of fluvoxamine with σ 1 receptors contributes to its anxiolytic effects (Egashira et al, 2007).…”

“…Our results must also be analysed in light of the previous data from the literature regarding the behavioural responses induced by σ 1 ligands, particularly antagonists, or after using antisense strategies targeting the σ 1 protein. Indeed, activation or inactivation of the σ 1 protein has been shown to play a major role in the modulation of memory responses (for extensive reviews, see Maurice, 2007; Maurice et al, 1999), if not being directly involved in the memory processes itself. However, with the notable exception of passive avoidance extinction facilitated by the σ 1 agonist PRE-084 (Maurice, 2007), σ 1 protein activation or inactivation has no direct impact.…”

“…This gender-related difference could be partly attributable to decreased circulating levels in E2 in σ 1 KO mice. Steroids, and particularly neurosteroids, are known to be modulators, and putatively endogenous ligands, of the σ 1 chaperone protein (Maurice et al, 1999, 2006; Robichaud and Debonnel, 2004; Su et al, 1988). Indeed, pregnenolone, dehydroepiandrosterone (DHEA) and their sulphate esters are identified σ 1 agonists and progesterone a very potent antagonist (Bergeron et al, 1996; Maurice et al, 1997; Monnet et al, 1995).…”

“…Activation of the σ 1 protein by using specific agonists has proven to be effective in learning and memory processes, response to stress and depression, addiction and pain and in neuroprotection against several kinds of insult, e.g. excitotoxicity, oxidative stress and amyloid toxicity (for reviews, see Cobos et al, 2008; Maurice et al, 1999, 2006; Maurice and Su, 2009; Monnet and Maurice, 2006). In particular, numerous σ 1 agonists, such as (+)-SKF-10,047, (+)-pentazocine, 1,3-di-o-tolylguanidine (DTG), PRE-084, igmesine, or SA4503, have been shown to reverse the pharmacological model of amnesia induced by selective blockade of nicotinic or muscarinic acetylcholine receptors, N-methyl- D -aspartate receptors or L-type voltage dependent calcium channels (Maurice et al, 1995), and pathological models of amnesia induced by lesions (Senda et al, 1996), amyloid peptide injections (Maurice et al, 1998) or in aged animals (Maurice, 2001).…”

Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma1 (σ1) ligand ANAVEX2-73, a novel aminotetrahydrofuran derivative

“…Moreover, this observation is coherent with the more limited effect of ANAVEX2-73 on dizocilpine- versus scopolamine-induced deficits. Indeed, the behavioural efficacy of σ 1 ligands has been shown to be highly dependent upon steroidal tonus and particularly progesterone (Bergeron et al, 1999; Maurice et al, 1999; Urani et al, 2001). The high acute stress-reinforcing passive avoidance training provokes a significant increase in the brain level of the steroid, acting as an efficient endogenous σ 1 antagonist.…”