Sugar, a powerful substitute for ethanol in ethanol postdependent rats: Relevance for clinical consideration?

Sugar has been shown to be a powerful substitute for drugs in preclinical studies on addiction. However, the link between sugar intake and alcohol use disorder (AUD) is poorly understood. We assessed the influence of sucrose on ethanol drinking in both nondependent (ND) and dependent (D) Long-Evans rats during acute withdrawal using the postdependent state model. Ethanol (10%-40%) and sucrose (1%-4%) solutions were offered in an operant paradigm either independently or concurrently under ratio schedules of reinforcement. We showed that D rats displayed an enhanced motivation for both 10% ethanol solution (10E) and 4% sucrose solution (4S) as compared with ND rats, and a clear preference for 4S was observed in both groups. During acute withdrawal, D rats showed a strong motivation for 30% ethanol (30E), even when adulterated with quinine, but still preferred 4S despite the fact that a high level of negative reinforcement could be expected. However, when a premix solution (30E4S) was offered concurrently with 4S, the preference for 4S was lost in D animals, which consumed as much premix as 4S, whereas ND animals displayed preference for 4S. Altogether, those results suggest that reinforcing properties of sucrose surpass those of ethanol in D rats under acute withdrawal, which indicates that sugar is a powerful substitute for ethanol. Our results suggest that craving for sugar may be increased in AUD patients during withdrawal and raise the issue of dependence transfer from alcohol to sugar.

Time-dependent impact of glutamatergic modulators on the promnesiant effect of 5-HT6R blockade on mice recognition memory.

Selective antagonists at serotonin 5-HT6 receptors (5-HT6R) improve memory performance in rodents and are currently under clinical investigations. If blockade of 5-HT6R is known to increase glutamate release, only two studies have so far demonstrated an interaction between 5-HT6R and glutamate transmission, but both, using the non-competitive NMDA antagonist MK-801, insensitive to variations of glutamate concentrations. In a place recognition task, we investigated here in mice the role of glutamate transmission in the beneficial effects of 5-HT6R blockade (SB-271046). Through the use of increasing intervals (2, 4 and 6h) between acquisition and retrieval, we investigated the time-dependent impact of two different glutamatergic modulators. NMDAR-dependant glutamate transmission (NMDA Receptors) was either blocked by the competitive antagonist at NMDAR, CGS 19755, or potentiated by the glycine transporter type 1 (GlyT1) inhibitor, NFPS. Results showed that neither SB-271046, nor CGS 19755, nor NFPS, alter behavioural performances after short intervals, i.e. when control mice displayed significant memory performances (2h and 4h) (respectively 10, 3, and 0.625mg.kg-1). Conversely, with the 6h-interval, a situation in which spontaneous forgetting is observed in control mice, SB-271046 improved recognition memory performances. This beneficial effect was prevented when co-administered with either CGS 19755 or NFPS, which themselves had no effect. Interestingly, a dose-dependent effect was observed with NFPS, with promnesic effect observed at lower dose (0.156mg.kg-1) when administrated alone, whereas it did no modify promnesic effect of SB-271046. These results demonstrate that promnesiant effect induced by 5-HT6R blockade is sensitive to the competitive blockade of NMDAR and underline the need of a fine adjustment of the inhibition of GlyT1. Overall, our findings support the idea of a complex crosstalk between serotonergic and glutamatergic systems in the promnesic properties of 5-HT6R antagonists.

Etifoxine improves sensorimotor deficits and reduces glial activation, neuronal degeneration, and neuroinflammation in a rat model of traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) results in important neurological impairments which occur through a cascade of deleterious physiological events over time. There are currently no effective treatments to prevent these consequences. TBI is followed not only by an inflammatory response but also by a profound reorganization of the GABAergic system and a dysregulation of translocator protein 18 kDa (TSPO). Etifoxine is an anxiolytic compound that belongs to the benzoxazine family. It potentiates GABAergic neurotransmission, either through a positive allosteric effect or indirectly, involving the activation of TSPO that leads to an increase in neurosteroids synthesis. In several models of peripheral nerve injury, etifoxine has been demonstrated to display potent regenerative and anti-inflammatory properties and to promote functional recovery. Prior study also showed etifoxine efficacy in reducing brain edema in rats. In light of these positive results, we used a rat model of TBI to explore etifoxine treatment effects in a central nervous system injury, from functional outcomes to the underlying mechanisms. METHODS: Male Sprague-Dawley rats received contusion (n = 18) or sham (n = 19) injuries centered laterally to bregma over the left sensorimotor cortex. They were treated with etifoxine (50 mg/kg, i.p.) or its vehicle 30 min following injury and every day during 7 days. Rats underwent behavioral testing to assess sensorimotor function. In another experiment, injured rats (n = 10) or sham rats (n = 10) received etifoxine (EFX) (50 mg/kg, i.p.) or its vehicle 30 min post-surgery. Brains were then dissected for analysis of neuroinflammation markers, glial activation, and neuronal degeneration. RESULTS: Brain-injured rats exhibited significant sensorimotor function deficits compared to sham-injured rats in the bilateral tactile adhesive removal test, the beam walking test, and the limb-use asymmetry test. After 2 days of etifoxine treatment, behavioral impairments were significantly reduced. Etifoxine treatment reduced pro-inflammatory cytokines levels without affecting anti-inflammatory cytokines levels in injured rats, reduced macrophages and glial activation, and reduced neuronal degeneration. CONCLUSIONS: Our results showed that post-injury treatment with etifoxine improved functional recovery and reduced neuroinflammation in a rat model of TBI. These findings suggest that etifoxine may have a therapeutic potential in the treatment of TBI.

The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals.

Converging evidence indicates that epigenetic mechanisms are involved in drug addiction, and that enzymes involved in chromatin remodeling may represent interesting targets in addiction treatment. No study has addressed whether histone deacetylase (HDAC) inhibitors (HDACi) can reduce excessive ethanol intake or prevent relapse in alcohol-dependent animals. Here, we assessed the effects of two HDACi, sodium butyrate (NaB) and MS-275, in the operant ethanol self-administration paradigm in dependent and non-dependent rats. To characterize some of the epigenetic mechanisms associated with alcohol dependence and NaB treatment, we measured the levels of histone H3 acetylation in different brain areas of dependent and non-dependent rats, submitted or not to NaB treatment. Our results demonstrated that (1) NaB and MS-275 strongly decreased excessive alcohol intake of dependent rats in the operant ethanol self-administration paradigm but not of non-dependent rats; (2) NaB reduced excessive drinking and prevented the escalation of ethanol intake in the intermittent access to 20% ethanol paradigm; and (3) NaB completely blocked the increase of ethanol consumption induced by an alcohol deprivation, thus demonstrating a preventive effect of NaB on relapse. The mapping of cerebral histone H3 acetylation revealed a hyperacetylation in the amygdala and cortical areas in dependent rats. Interestingly, NaB did not exacerbate the hyperacetylation observed in these regions, but instead restored it, specifically in cortical areas. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.

Fluoxetine, desipramine, and the dual antidepressant milnacipran reduce alcohol self-administration and/or relapse in dependent rats.

A few clinical studies have shown that dual antidepressants (serotonergic (5-HT) and noradrenergic (NE) transporter inhibitors, SNRIs) may be effective in alcoholism treatment. We studied the effect of the dual antidepressant milnacipran on ethanol operant self-administration in acutely withdrawn ethanol-dependent and in -non-dependent Wistar rats, and used fluoxetine and desipramine to dissect both 5-HT and NE components, respectively, in the effect of milnacipran. Milnacipran was also tested for relapse after protracted abstinence and on ethanol-induced (1.0 g/kg) conditioned place preference in control rats and ethanol-induced locomotor sensitization in DBA/2J female mice. Milnacipran dose dependently (5-40 mg/kg) attenuated the increased ethanol self-administration observed during early withdrawal and was more potent in preventing reinstatement in dependent rats after protracted abstinence as compared with non-dependent rats. Desipramine and fluoxetine (10 mg/kg) blocked ethanol self-administration during early withdrawal, and recovery was delayed in dependent animals, indicating a potent effect. Ethanol self-administration was also reduced 1 day after treatment with desipramine and fluoxetine but not with milnacipran. Finally, milnacipran prevented ethanol-induced place preference in ethanol-naive rats and reduced the magnitude of ethanol-induced sensitization associated with a delayed induction in mice. Desipramine (20 mg/kg) countered sensitization development and reduced its expression at 1 week after treatment; fluoxetine (10 mg/kg) reduced sensitization expression. Thus, 5-HT and NE transmissions during sensitization expression may mediate the effect of milnacipran on sensitization induction. These results support that SNRIs may have a potential use in alcoholism treatment.