The interaction between Environmental Enrichment and fluoxetine in inhibiting sucrose-seeking renewal in mice depend on social living condition.

RATIONALE: Several single or combined therapeutic approaches have been developed to treat addiction, however with partial efficacy in preventing relapse. Recently, the living environment has been suggested as a critical intervening factor determining the treatment outcomes. Despite accumulating evidence confirming a role of living conditions in the vulnerability to addictive behaviours, their impact on single or integrative therapeutic strategies preventing relapse is yet to be identified. OBJECTIVES: Here, we explore the possible interaction between brief Environmental Enrichment (EE) exposure and acute fluoxetine administration in inhibiting sucrose-seeking behaviours, and whether this effect could be affected by living environment. METHODS: Social and isolated adult male C57BL/6 mice were trained to sucrose self-administration associated to a specific conditioning context (CxA), followed by a 7-day extinction in a different context (CxB). Afterwards, mice were exposed for 22 h to EE and then injected with fluoxetine (10 mg/kg, i.p.) 1 h before a CxA-induced sucrose-seeking test. RESULTS: Brief EE exposure and acute fluoxetine administration alone inhibited context-induced sucrose-seeking in both housing conditions; however, they exhibited additive properties only in social condition. CONCLUSIONS: Our data show that social environment may influence the EE/fluoxetine interaction in inhibiting relapse to sucrose. These findings suggest that setting up proper living conditions to boost the efficacy of therapeutic approaches may represent a fundamental strategy to treat addiction disorders.

Brief Environmental Enrichment exposure enhances contextual-induced sucrose-seeking with and without memory reactivation in rats.

Chronic Environmental Enrichment (EE) has been shown to prevent the relapse to addictive behaviours, such as drug-taking and -seeking. Recently, acute EE was shown to reduce cue-induced sucrose-seeking, but its effects on contextual (Cx)-induced sucrose-seeking is still unknown. Here we report the effects of brief EE exposure on Cx-induced sucrose-seeking with and without prior Cx-memory reactivation. Adult male Sprague-Dawley rats were trained to sucrose self-administration associated to a specific conditioning Cx (CxA), followed by a 7-day extinction in a different Cx (CxB). Afterwards, rats were exposed for 22 h to EE, and 1 h later to either i) Cx-induced sucrose-seeking (1 h, renewal without Cx-memory reactivation), ii) or two different Cx-memory reactivations: short (2-min) and long (15-min) CxA-retrieval session (Cx-Ret). In Cx-Ret experiments, CxA-induced sucrose-seeking test (1 h) was done after a subsequent 3-day extinction phase. The assessment of molecular markers of memory reactivation/reconsolidation, Zif-268 and rpS6P, was performed 2 h after Cx-Ret. Brief EE exposure enhanced Cx-induced sucrose-seeking without and with short but not long Cx-retrieval. Moreover, EE impaired discriminative responding at test prior to long, whereas improved it with or without short Cx-retrieval. Different changes in Zif-268 and rpS6P expression induced by short vs. long Cx-Ret were correlated to behavioural data, suggesting the occurrence of different memory processes affected by EE. Our data show that brief EE exposure may differently affect subsequent appetitive relapse depending on the modality of re-exposure to conditioned context. This finding suggests caution and further studies to understand the proper conditions for the use of EE against appetitive and addiction disorders.

Nicotine increases the expression of neurotrophin receptor tyrosine kinase receptor A in basal forebrain cholinergic neurons.

In this study, we investigated whether the potential positive effects of nicotine in Alzheimer's disease (AD) may involve neurotrophic factors, such as nerve growth factor (NGF), closely associated with basal forebrain (BF) cholinergic function and survival. To this aim, we studied the effects of prolonged nicotine treatment on neurotrophin receptors expression and on NGF protein levels in the rat BF cholinergic circuitry. Both in vivo and in vitro experiments were conducted. We found that s.c. nicotine infusion (1.2 mg free base/kg/d delivered by mini-pumps for 7 days) induced in vivo an increase in tyrosine kinase receptor A (TrkA)-but not TrkB, TrkC or low affinity neurotrophin receptor p75 (p75)-expression in BF cholinergic neurons targeting the cerebral cortex. Nicotine did not produce statistically significant long-lasting effects on NGF levels in the cerebral cortex, or in the BF. In vitro experiments performed on primary BF neuronal cultures, showed that 72 h exposure to nicotine increased both TrkA expression, and NGF release in culture medium. Neutralization experiments with an anti-NGF antibody showed that NGF presence was not necessary for nicotine-induced increase of TrkA levels in cultured cholinergic neurons, suggesting that nicotine may act through NGF-independent mechanisms. This study shows that nicotine, independently of its action on NGF levels, may contribute to the restoration of the trophic support to BF cholinergic neurons by increasing TrkA levels.