Pascal Romieu

The interaction between neuroactive steroids and the σ1 receptor function: behavioral consequences and therapeutic opportunities☆

Steroids, synthesized in peripheral glands or centrally in the brain--the latter being named neurosteroids--exert an important role as modulators of the neuronal activity by interacting with different receptors or ion channels. In addition to the modulation of GABA(A), NMDA or cholinergic receptors, neuroactive steroids interact with an atypical intracellular receptor, the sigma(1) protein. This receptor has been cloned in several species, and highly selective synthetic ligands are available. At the cellular level, sigma1 agonists modulate intracellular calcium mobilization and extracellular calcium influx, NMDA-mediated responses, acetylcholine release, and alter monoaminergic systems. At the behavioral level, the sigma1 receptor is involved in learning and memory processes, the response to stress, depression, neuroprotection and pharmacodependence. Pregnenolone, dehydroepiandrosterone, and their sulfate esters behave as sigma1 agonists, while progesterone is a potent antagonist. This review will detail the physiopathological consequences of these interactions, focusing on recent results on memory and depression. The therapeutical interest of selective sigma1 receptor agonists in alleviating aging-related cognitive deficits will be discussed.

Histone Deacetylase Inhibitors Decrease Cocaine But Not Sucrose Self-Administration in Rats

Regulation of gene expression is known to contribute to the long-term adaptations taking place in response to drugs of abuse. Recent studies highlighted the regulation of gene transcription in neurons by chromatin remodeling, a process in which posttranslational modifications of histones play a major role. To test the involvement of epigenetic regulation on drug-reinforcing properties, we submitted rats to the cocaine operant self-administration paradigm. Using the fixed ratio 1 schedule, we found that the histone deacetylase (HDAC) inhibitors trichostatin A and phenylbutyrate dose-dependently reduced cocaine self-administration. Under the progressive ratio schedule, both trichostatin A and depudecin significantly reduced the breaking point, indicating that HDAC inhibition attenuated the motivation of rats for cocaine. Conversely, HDAC inhibition did not decrease self-administration for the natural reinforcer sucrose. This observation was correlated with measurements of HDAC activity in the frontal cortex, which was inhibited in response to cocaine, but not to sucrose self-administration. Control experiments showed that the decrease in the motivation for the drug was not attributable to a general motivational dysfunction because trichostatin A had no adverse effect on locomotion during the habituation session or on cocaine-induced hyperlocomotion. It was not attributable to anhedonia because the inhibitor had no effect on the sucrose preference test. In contrast, trichostatin A completely blocked the cocaine-induced behavioral sensitization. Together, the data show that epigenetic regulation of gene transcription in adult brain is able to influence a motivated behavior and suggest that HDAC inhibition may counteract the neural sensitization leading to drug dependence.

Involvement of the σ1 receptor in the cocaine-induced conditioned place preference

The sigma1 (σ1) receptor constitutes a particular target of cocaine believed to be involved in some of its behavioral effects. In the present study, its involvement in the rewarding effect of cocaine was examined using the conditioned place preference (CPP) procedure. CPP was induced in C57Bl/6 mice injected repeatedly with cocaine (20 mg/kg, i.p.). The selective σ1 receptor antagonists NE-100 and BD1047 (1-10 mg/kg, i.p.) significantly attenuated or blocked the cocaine-induced CPP. Animals treated centrally with a σ1 receptor antisense oligodeoxynucleotide failed to develop cocaine-induced CPP, unlike mismatch controls. The σ1 receptor thus appears to be critically involved in the development of the cocaine-induced CPP and, in consequence, may constitute a promising approach to blocking cocaine reward.

Involvement of the Sigma1 Receptor in Cocaine-induced Conditioned Place Preference: Possible Dependence on Dopamine Uptake Blockade

The involvement of the sigma1 receptor on the rewarding effects of cocaine was examined using the conditioned place preference (CPP) procedure in C57BL/6 mice. Acquisition or expression of cocaine (20 mg/kg i.p.)-induced CPP was significantly decreased by pre-treatment with the selective sigma1 receptor antagonists N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine (NE-100) or N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047), 1–10 mg/kg, i.p. The sigma1 receptor agonists igmesine or 2-(4-morpholinoethyl-1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084) failed to induce CPP when injected alone. Moreover, the CPP induced by N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine (BTCP), a selective dopamine reuptake inhibitor, was blocked by treatments with the sigma1 receptor antagonists as was similarly observed with cocaine. In addition, the repetitive treatment with cocaine during conditioning increased sigma1 receptor mRNA expression in the nucleus accumbens, but not in the caudate putamen, prefrontal cortex or cerebellum. These data show that the sigma1 receptor is not only necessary for acquisition of the cocaine-induced CPP, but that it is also implicated in its expression, confirming that activation of the sigma1 receptor is induced during cocaines early effects. The sigma1 receptor is activated consequently to dopamine reuptake blockade and is not sufficient to induce CPP by itself. The mechanism of the sigma1 receptor involvement in CPP and the selectivity toward the CPP-inducing drug remains however to be determined. These results show that strategies targeting the sigma1 receptor with selective antagonists may allow effective attenuation of cocaines rewarding properties and, in turn, offer new treatment strategies against drug addiction.

Involvement of the sigma1 receptor in the motivational effects of ethanol in mice

In the present study, we examined the involvement of the sigma(1) (sigma(1)) receptor in several behavioral manifestations of ethanol addiction. Administration of ethanol (0.5, 1, and 2 g/kg) in Swiss mice dose-dependently induced locomotor stimulation, conditioned place preference, and conditioned taste aversion, which are considered as behavioral index of drug-induced reward. Pretreatment with the selective sigma(1) receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047, 3-30 mg/kg) dose-dependently blocked ethanol (1 g/kg)-induced hyperlocomotion and taste aversion and ethanol (2 g/kg)-induced place preference. Pretreatment with the selective sigma(1) receptor agonist 2-(4-morpholino)ethyl 1-phenylcyclohexane-1-carboxylate (PRE-084, 1-10 mg/kg) before ethanol (0.5 g/kg) failed to affect the resulting locomotor stimulation, but dose-dependently enhanced the conditioned place preference. Each sigma(1) receptor ligand was devoid of behavioral effect by itself. These observations show that activation of the sigma(1) receptor is a necessary component of ethanol-induced motivational effects and suggest a new pharmacological target for alleviating ethanol addiction.

Strain differences in σ1 receptor-mediated behaviours are related to neurosteroid levels

The sigma1 (σ1) receptor exerts a potent neuromodulatory role in the brain with relevant consequences in memory processes, response to stress, depression and pharmacodependence. Its precise endogenous ligand is not yet identified but the σ1 receptor appears to be one target for the nongenomic rapid effects of neuroactive steroids in the brain. The aim of the present study was to establish whether differences in σ1 receptor‐mediated behaviours could be observed among mouse strains, in relation with differences in either σ1 receptor expression or steroid levels. The σ1‐receptor immunohistochemical distribution appeared similar between Swiss and C57BL/6 strains in all the brain structures examined. The levels of in vivo[3H](+)‐SKF‐10 047 binding to σ1 receptors were lower in Swiss than in C57BL/6. Adrenalectomy/castration significantly increased [3H](+)‐SKF‐10 047 binding only in Swiss. The behavioural efficacy of the selective σ1 agonists igmesine and PRE‐084 – reversion of the scopolamine‐induced amnesia in the passive avoidance test; diminution of the immobility duration in the forced swimming test – were significantly higher in C57BL/6 than in Swiss. Steroid levels were measured in the brain in basal conditions and after stress. C57BL/6 mice presented in both conditions, the lowest progesterone levels, this steroid acting as an endogenous σ1 antagonist. Collectively, the results suggested that strain differences in neuroactive steroid and particularly, progesterone, biosynthesis and sensitivity may contribute to the differential behavioural efficacy of σ1‐receptor ligands. Noteworthy, these observations are coherent with strain differences observed in the intensity of cocaine‐induced reward properties, known to critically involve the σ1 receptor.

The antidepressant-like effect induced by the sigma1 (σ1) receptor agonist igmesine involves modulation of intracellular calcium mobilization

AbstractRationale. Activation of the neuronal sigma1 (σ1) receptor potentiates calcium mobilization, leading to effective modulation of postsynaptic responses to neurotransmitters. At the behavioral level, σ1 agonists modulate learning, response to stress and depression. In particular, the selective σ1 agonist igmesine reduced immobility in the forced swimming test. Objectives and methods. We investigated the effect of modulators of Ca2+ influx and mobilization, administered intracerebroventricularly at doses ineffective alone, on the igmesine effect. The tricyclic antidepressant desipramine was also studied for comparison. Results. The calcium chelator EGTA blocked both igmesine and desipramine-induced decreases of immobility duration, indicating the importance of extracellular Ca2+ influx in the initial action of each compound. Both L- and N-type voltage-dependent calcium channel (VDCC) appeared involved in the σ1 agonist effect. Verapamil, an L-type VDCC antagonist or ω-conotoxin GVI, a N-type VDCC antagonist, blocked whereas (–)-Bay K8644, a L-type VDCC agonist, potentiated the igmesine effect. Mobilization of intracellular Ca2+ stores is involved selectively in the effect mediated by the σ1 receptor, since the membrane permeable intracellular Ca2+ chelator EGTA/AM affected only the igmesine effect. Inositol 1,4,5-trisphosphate (InsP3) receptor-sensitive Ca2+ pools appeared primarily involved, rather than Ca2+/caffeine-sensitive Ca2+ pools. Indeed, the InsP3 receptor positive modulator bradykinin potentiated, whereas the InsP3 receptor antagonist xestospongin C blocked the igmesine effect. The ryanodine receptor agonist caffeine failed to affect the efficacy of igmesine, whereas the antagonist ryanodine reduced it. Conclusions. The σ1 receptor-mediated behavioral effect is dependent not only on rapid Ca2+ influx, as observed for a classical antidepressant, but also on intracellular Ca2+ mobilization.

Enhanced antidepressant effect of sigma1 (σ1) receptor agonists in β25-35-amyloid peptide-treated mice

Abstract This study examined the antidepressant efficacy of the selective σ 1 receptor agonists igmesine or PRE-084 in mice injected intracerebroventricularly (i.c.v.) with β 25–35 -amyloid peptide and submitted to the forced swim test. β 25–35 peptide-injected animals developed memory deficits after 8 days contrarily to controls injected with scrambled β 25–35 peptide or vehicle solution. In the forced swim test, the i.c.v. treatment failed to affect the immobility duration, but the antidepressant effect of the σ 1 agonists was facilitated in β 25–35 animals. Igmesine reduced immobility duration at 30 versus 60 mg/kg in control groups. PRE-084 decreased immobility duration at 30 and 60 mg/kg only in β 25–35 animals. Desipramine reduced the immobility duration similarly among groups and fluoxetine appeared less potent in β 25–35 animals. The β 25–35 animals exhibited decreased progesterone levels in the hippocampus (−47%). The behavioural efficacy of σ 1 agonists is known to depend on neuro(active)steroids levels synthesised by glial cells and neurones, which are affected by the β-amyloid toxicity. This behavioural study suggests that σ 1 agonists, due to their enhanced efficacy, may allow to alleviate the depressive symptoms associated with Alzheimers disease.

The inhibition of histone deacetylases reduces the reinstatement of cocaine-seeking behavior in rats.

Drug addiction is a chronic brain disease characterized by a persistent risk of relapse, even after a long period of abstinence. A current hypothesis states that relapse results from lasting neuroadaptations that are induced in response to repeated drug administration. The adaptations require gene expression, some of which being under the control of stable epigenetic regulations. We have previously demonstrated that pretreatment with histone deacetylase (HDAC) inhibitors reduces the cocaine reinforcing properties as well as the motivation of rats for cocaine. We show here that the same HDAC inhibitors, trichostatin A and phenylbutyrate, significantly reduced the cocaine-seeking behavior induced by the combination of a cocaine injection together with the exposure to a light cue previously associated with cocaine taking. Reinstatement of drug-seeking behavior was carried out after a 3-week withdrawal period, which came after ten daily sessions of cocaine intravenous self-administration. Our results suggest that pharmacological treatment aimed at modulating epigenetic regulation, and particularly treatment that would inhibit HDAC activity, could reduce the risk of relapse, a major drawback in the treatment of drug addiction.

σ 1 Receptor Ligands and Related Neuroactive Steroids Interfere with the Cocaine-Induced State of Memory

The present series of experiments examined the involvement of the σ1 receptor and related neuroactive steroids in the memory state induced by a very low dose of cocaine. Using a modified passive avoidance procedure in mice, we examined whether cocaine induces state-dependent (StD) learning. Animals trained and tested with saline or the same dose of cocaine (0.1 or 0.3 mg/kg) showed correct retention, measured using two independent parameters: the retention latency and a ratio between the retention latency and the last training latency. Animals trained with cocaine (0.1 mg/kg) and tested with saline or cocaine (0.03, 0.3 mg/kg), or trained with saline and tested with cocaine, showed altered retention parameters, demonstrating that StD occurred. Therefore, cocaine administered before training produced a chemical state used as an endogenous cue to insure optimal retention. Since σ1 receptor activation is an important event during the acquisition of cocaine reward, we tested several σ1 ligands and related neurosteroids. The σ1 agonist igmesine or antagonist BD1047 failed to produce StD, but modified the cocaine state. Among neuroactive steroids, pregnanolone and allopregnanolone, positive modulators of the γ-aminobutyric acid type A (GABAA) receptor, produced StD. However, steroids also acting as σ1 agonists, dehydroepiandrosterone (3β-hydroxy-5α-androsten-17-one (DHEA)), pregnenolone, or antagonist, progesterone, failed to induce StD but modified the cocaine state. Furthermore, optimal retention was observed with mice trained with (igmesine or DHEA)+cocaine and tested with a higher dose of cocaine, or with mice trained with (BD1047 or progesterone)+cocaine and tested with vehicle. This study demonstrated that: (i) low doses of cocaine induce a chemical state/memory trace sustaining StD; (ii) modulation of the σ1 receptor activation, although insufficient to provoke StD, modulates the cocaine state; (iii) neuroactive steroids exert a unique role in state-dependent vs state-independent learning, via GABAA or σ1 receptor modulation, and are able to affect the cocaine-induced mnesic trace at low brain concentrations.