The Sigma1 Protein as a Target for the Non-genomic Effects of Neuro(active)steroids: Molecular, Physiological, and Behavioral Aspects

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Growing evidence suggests a role for sigma 1 (s 1 ) receptors in cognitive function, anxiety, depression, regulation of stress responses, and, recently, the appetitive effects of cocaine as measured by conditioned place preference. This study was designed to extend understanding of the role of s 1 receptors in addiction-relevant conditioned effects of cocaine by testing the effects of a potent and selective s 1 receptor antagonist, BD1047, on conditioned reinstatement of cocaine-seeking. To determine whether modification of conditioned reinstatement by BD1047 is selective for drug-directed behavior or reflects general suppressant effects on motivated behavior, BD1047 was tested also on reinstatement induced by stimuli conditioned to a natural reward, sweetened condensed milk (SCM). Additionally, because s 1 receptors have been implicated also in processes linked to the acute reinforcing actions of cocaine, tests of the effects of BD1047 on cocaine self-administrationFincluding a comparison with the s 1 antagonist effects on SCM self-administrationFwere conducted as well. Cocaine self-administering male Wistar rats were trained to associate a discriminative stimulus (S D ) with the availability of cocaine or SCM, and then subjected to reinstatement tests following extinction of cocaine or SCM-reinforced behavior. BD1047 (1-30 mg/kg) reversed response reinstatement induced by the cocaine S D at 20 and 30 mg/kg but did not modify SCM S D -induced responding at all but the highest 30 mg dose, at which responding was reversed to extinction levels. BD1047 did not modify responding reinforced directly by SCM or cocaine. The findings support a role for s 1 receptors in regulating conditioned responses to cocaine-related contextual stimuli and identify this receptor as a potential treatment target for the prevention of craving and relapse.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential Effects of σ1 Receptor Blockade on Self-Administration and Conditioned Reinstatement Motivated by Cocaine vs Natural Reward

Martin‐Fardon

Maurice

Aujla

et al. 2007

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“…For example, progesterone has been shown to block several receptors that may modulate psychotic-like actions, such as sigma or 5-HT 3 receptors (Monnet and Maurice, 2006;Wetzel et al, 1998). Indeed, the blockade of these receptors has previously been shown to reduce spontaneous activity in rodents and to antagonize AMPHmediated hyperactivity (Costall et al, 1987;Wang et al, 1992).…”

Section: -A-reductase Inhibitors In Models Of Psychosis M Bortolato mentioning

confidence: 99%

Antipsychotic-Like Properties of 5-α-Reductase Inhibitors

Bortolato

Frau

Orrù

et al. 2008

Recent evidence indicates that neuroactive steroids may participate in the pathogenesis of schizophrenia spectrum disorders, yet the mechanisms of this involvement are elusive. As 5-a-reductase (5AR) is the rate-limiting enzyme of one of the two major metabolic pathways in brain steroidogenesis, we investigated the effects of its blockade in several rat models of psychotic-like behavior. The 5AR inhibitor finasteride (FIN, 60 or 100 mg/kg, intraperitoneal, i.p.) dose-and time-dependently antagonized prepulse inhibition (PPI) deficits induced by apomorphine (APO, 0.25 mg/kg, subcutaneous, s.c.) and d-amphetamine (AMPH, 5 mg/kg, s.c.), in a manner analogous to haloperidol (HAL, 0.1 mg/kg, i.p.) and clozapine (CLO, 5 mg/kg, i.p.). Similar results were observed with the other 5AR inhibitors dutasteride (DUT, 40 or 80 mg/kg, i.p.) and SKF 105111 (30 mg/kg, i.p.). FIN (60 or 100 mg/kg, i.p.) also reduced hyperlocomotion induced by AMPH (1 or 3 mg/kg, s.c.) and attenuated stereotyped behaviors induced by APO (0.25 mg/kg, s.c.). Nevertheless, FIN (100 mg/kg, i.p.) did not reverse the PPI disruption induced by the N-methyl-d-aspartate receptor antagonist dizocilpine (0.1 mg/kg, s.c.). FIN (60-300 mg/kg, i.p.) induced no catalepsy in either the bar test or the paw test. Our results suggest that 5AR inhibitors elicit antipsychotic-like effects in animals and may be proposed as a putative novel target in the management of psychotic disorders.

“…Increasing or activating s 1 proteins is expected to counteract ER stress response, whereas decreasing or inactivating them would enhance apoptosis (Hayashi and Su, 2007). Modifying s 1 protein activation using selective activators/agonists therefore mediates a unique pharmacological action on Ca 2 + homeostasis and signal transduction pathways, which has proven to allow an effective neuroprotection against several kinds of insults, including excitotoxicity, oxidative stress, and amyloid toxicity (for reviews, see Maurice et al, 2006;Monnet and Maurice, 2006). Indeed, preliminary experiments showed that, in vitro, the selective s 1 activators PRE-084 and MR-22 attenuate the Ab 25-35 -induced expression of the proapoptotic protein Bax and neuronal death in rat cortical cultures (Marrazzo et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Antiamnesic and Neuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1-41 Against Amyloid β25–35-Induced Toxicity in Mice

Villard

Espallergues

Keller

et al. 2008

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The antiamnesic and neuroprotective activities of the new aminotetrahydrofuran derivative tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride (ANAVEX1-41), a nonselective muscarinic receptor ligand and s 1 protein activator, were examined in mice injected intracerebroventricularly with amyloid b [25][26][27][28][29][30][31][32][33][34][35] ) peptide (9 nmol). Ab 25-35 impaired significantly spontaneous alternation performance, a spatial working memory, and passive avoidance response. When ANAVEX1-41 (1-1000 mg/kg i.p.) was administered 7 days after Ab 25-35 , ie, 20 min before the behavioral tests, it significantly reversed the Ab 25-35 -induced deficits, the most active doses being in the 3-100 mg/kg range. When the compound was preadministered 20 min before Ab 25-35 , ie, 7 days before the tests, it prevented the learning impairments at 30-100 mg/kg. Morphological analysis of corticolimbic structures showed that Ab 25-35 induced a significant cell loss in the CA1 pyramidal cell layer of the hippocampus that was prevented by ANAVEX1-41 (100 mg/kg). Increased number of glial fibrillary acidic protein immunopositive cells in the retrosplenial cortex or throughout the hippocampus revealed an Ab 25-35 -induced inflammation that was prevented by ANAVEX1-41. The drug also prevented the parameters of Ab 25-35 -induced oxidative stress measured in hippocampus extracts, ie, the increases in lipid peroxidation and protein nitration. ANAVEX1-41, however, failed to prevent Ab 25-35 -induced caspase-9 expression. The compound also blocked the Ab 25-35 -induced caspase-3 expression, a marker of apoptosis. Both the muscarinic antagonist scopolamine and the s 1 protein inactivator BD1047 prevented the beneficial effects of ANAVEX1-41 (30 or 100 mg/kg) against Ab 25-35 -induced learning impairments, suggesting that muscarinic and s 1 targets are involved in the drug effect. A synergic effect could indeed account for the very low active doses measured in vivo. These data outline the therapeutic potential of ANAVEX1-41 as a neuroprotective agent in Alzheimer's disease.