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Environmental enrichment (EE) has been shown to produce powerful beneficial effects in animal models of addiction. In particular, the ability of EE to promote abstinence and prevent relapse may allow for the identification of brain mechanisms responsible for the recovery from addiction. Indeed, the effects of EE on specific brain mechanisms could be mimicked by old or new molecules, which may become novel medications, called enviromimetics. Here, we review the best known enviromimetics for the treatment of addiction and suggest that, whereas these compounds may be relatively ineffective by themselves, they may be useful complements for existing therapeutic approaches to manage addiction which includes behavioural, environmental and pharmacological interventions., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Addiction is a chronic disease characterized by persistent vulnerability to relapse during abstinence. In animal models of addiction, accumulating evidence suggests that exposure to environmental enrichment (EE) during periods of abstinence can have curative effects on addiction and reduce the risks of relapse. However, until present most studies have mainly focused on cocaine. In this study, we investigated whether EE could have beneficial effects on cue-induced seeking for several psychoactive drugs belonging to different pharmacological classes such as methamphetamine (METH), heroin (HER) and nicotine (NIC)., Methods: After self-administration training of METH, HER and NIC, rats were housed in enriched (EE) or standard environments (SE) for 21-28 days of forced abstinence and then drug-seeking behavior was assessed in the absence of the drug., Results: We found that, compared to SE housing, exposure to EE reduced drug seeking behavior for all drugs tested., Conclusions: These findings suggest that the anti-craving effects of EE are general for a wide variety of drugs and support the hypothesis that environmental stimulation may be a general intervention for attenuating relapse in humans., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Early exposure to enriched environments has been shown to decrease the locomotor effects induced by repeated injections of cocaine and modify basal and cocaine-induced total protein levels of the transcription factor ΔFosB in the whole striatum of mice. In this study, we aimed at characterizing whether the profile of ΔFosB accumulation induced by enriched environments and cocaine would be similar or different in terms of brain areas and cell type., Methods: We used mice expressing the eGFP protein in D1 receptor positive (D1R(+)) neurons to determine whether Δ FosB induced by enriched environment or cocaine injections (5×15 mg/kg) would occur in selective subpopulations of neurons in several subregions of the striatum and prefrontal cortex., Results: We found that: (1) exposure to enriched environment reduces cocaine-induced locomotor activation, confirming our previous findings; (2) exposure to enriched environment by itself increases the accumulation of Δ FosB mostly in D1R(-) cells in the shell part of the nucleus accumbens and dorsal striatum, whereas in the nucleus accumbens core, Δ FosB accumulates in both D1R(+) and D1R(-) neurons; (3) in standard environment mice, cocaine induces accumulation of Δ FosB selectively in D1R(+) cells in the nucleus accumbens, dorsal striatum, and infralimbic cortex; and (4) the effects of enriched environments and cocaine on accumulation of Δ FosB were reciprocally blocked by their combination., Conclusions: Altogether, these results suggest that the enriched environment-induced reduction in behavioral effects of cocaine might result from 2 distinct effects on ΔFosB in striatal medium-sized spiny neurons belonging to the direct and indirect pathways., (© The Author 2016. Published by Oxford University Press on behalf of CINP.)

Life experiences, especially during critical periods of maturation, such as adolescence, can dramatically affect vulnerability to diseases at adulthood. Early exposure to positive environmental conditions such as environmental enrichment (EE) has been shown to reduce the occurrence and the intensity of neurological and psychiatric disorders including drug addiction. However, whether or not exposure to EE during early stages of life would protect from addiction when, at adulthood, individuals may find themselves in non-enriched conditions has not been investigated. Here we show that switching mice from EE to non-enriched standard environments not only results in the loss of the preventive effects of EE but also increases the rewarding effects of cocaine. This enhanced vulnerability is associated with emotional distress and with increased levels in the mRNA levels of corticotropin releasing factor (CRF) in the bed nucleus of the stria terminalis (BNST), as well as with increases in CREB phosphorylation in the BNST and in the shell of the nucleus accumbens. The increased sensitivity to the rewarding effects of cocaine is completely blocked by the CRF antagonist antalarmin, confirming a major role of the CRF system in the negative consequences of this environmental switch. These results indicate that positive life conditions during early stages of life, if they are not maintained at adulthood, may have negative emotional consequences and increase the risks to develop drug addiction.

Early environmental enrichment (EE) produces several changes in gene expression in the brain and confers protection against the behavioral, neurochemical and molecular effects of repeated administration of drugs of abuse. Because the endogenous cannabinoid system (ECS) is known to play an important role in the rewarding effects of drugs, we investigated whether the positive effects of early exposure to EE are associated with changes in the expression of genes encoding for proteins that belong to the ECS in C57 mice. Using in situ hybridization, we compared the expression of the cannabinoid receptor CB1, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL) enzymes in brain regions involved in drug addiction in mice reared in either EE or standard environments (SE) from weaning until adulthood. We found that EE increases CB1 mRNA levels in the hypothalamus and in the basolateral amygdala but decreased them in the basomedial amygdala. Similarly, we found that FAAH mRNA levels are higher in the hypothalamus and the basolateral amygdala of EE mice compared to SE mice, with no change in the basomedial amygdala. In contrast, MGL mRNA levels were not affected by EE in any of the areas analyzed. The regional selectivity of EE-induced changes may indicate that early exposure to EE induces changes in the ECS that could result in reduced responses to stress, as confirmed in EE mice in a novelty-induced suppression of feeding test, and, ultimately, in resistance to addiction., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Abuse of amphetamine analogues, such as methamphetamine (METH), represents an important health problem because of their powerful addictive and neurotoxic effects. Abuse of METH induces dopamine neuron terminals loss and cell death in the striatum similar to what is found in other neurodegenerative processes. Exposing mice and rats to enriched environments (EE) has been shown to produce significant protective effects against drug-induced reward as well as against neurodegenerative processes. Here, we investigated whether exposure to EE could reduce the METH-induced reward and neurotoxicity. For this, we reared mice for 2 months during early stages of life in standard environments or EE and then, at adulthood, we tested the ability of METH to induce conditioned place preference and neurotoxicity. We found that, contrary to what we found with other drugs such as cocaine and heroin, EE was unable to reduce the rewarding effects of METH. In addition, contrary to what we found with other toxins such as MPTP, EE did not diminish the striatal neurotoxicity induced by METH (4 x 10 mg/kg) as measured by dopamine content, tyrosine hydroxylase protein levels and apoptosis. Our results demonstrate that the rewarding and neurotoxic effects of METH are not reduced by EE and highlight the great risks associated with the increased popularity of this drug amongst the young population.

Environmental enrichment (EE) has been shown to have powerful beneficial effects on a variety of physiological and pathological processes. Accumulating evidence indicates that EE can mimic positive life experiences and prevent the development of drug addiction. More recently, EE has also been shown to eliminate already developed addiction-related behaviors and to reduce the risks of relapse. These preventive and "curative" effects of EE are associated with dramatic plastic changes in several brain areas such as the hippocampus, the frontal cortex and the striatum. EE alters neurotransmitter systems, produces changes in gene expression and transcription factors, induces chromatin rearrangement, and stimulates hippocampal neurogenesis. Here we review the existent literature on behavioral, neurochemical, cellular and molecular effects of EE and we discuss different possible ways in which EE-induced neuroadaptations result in decreased vulnerability to addiction and relapse. We propose a unified theoretical framework in which EE is seen as a functional opposite of stress. On the one hand, the antistress effects of EE would reduce the reinforcing effects of drugs and their ability to induce long-lasting neuroplastic changes and, thus, they would prevent the development of drug addiction. On the other hand, permanent or transient restoration of the normal, pre-drug functioning of the stress system would facilitate resisting prepotent desire to take drug and it would decrease the risks of relapse. This theoretical framework highlights the importance of stress in each phase of drug addiction and strongly suggests that life conditions of abstinent addicts should be considered as part of their treatment., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Whereas earlier studies have focused on the preventive effects of enriched environments (EE) in drug addiction, in a recent study we suggested that EE can also have 'curative' effects. In fact, we found that cocaine addiction-related behaviors can be eliminated by housing cocaine-treated mice in EE during periods of forced abstinence. However, those results were obtained with two simple models of addiction, conditioned place preference (CPP), and behavioral sensitization. In this study, we used intravenous drug self-administration procedures in rats to further investigate the beneficial effects of EE on cocaine addiction in a reinstatement model of relapse. Singly housed rats learned to self-administer cocaine during 10 consecutive daily sessions (0.6 mg/injection, 6 h/day). They were then housed three per cage in either standard environments (SE) or EE and were kept abstinent in the animal facility until testing for extinction and reinstatement. We found that 30 days of EE significantly and consistently reduced cocaine seeking during a 6-h extinction session. In addition, EE significantly reduced cue- and stress-induced reinstatement. Surprisingly, given our earlier results in mice with CPP, EE did not reduce cocaine-induced reinstatement regardless of the level of exposure to cocaine and the duration of the period of abstinence and exposure to EE. Altogether, these results support the hypothesis that EE can reduce cocaine-induced craving and highlight the importance of positive life conditions in facilitating abstinence and preventing relapse to cocaine addiction.

Rationale: Environmental conditions during adolescence, a critical period of brain maturation, can have important consequences on subsequent vulnerability to drugs of abuse. We have recently found that the behavioral effects of cocaine as well as its ability to increase expression of zif-268 are reduced in mice reared in enriched environments (EE)., Objectives: The present experiments examined whether environmental enrichment has protective influences on the effects of heroin, a drug of addiction whose mechanism of action differs from that of cocaine., Materials and Methods: Mice were housed either in standard environments (SE) or in EE from weaning to adulthood before any drug exposure. EE were constituted by big housing cages and contained constantly a running wheel and a small house and four to five toys that were changed once a week with new toys of different shapes and colors. We assessed the influence of EE on the ability of heroin to (1) induce conditioned place preferences, (2) induce behavioral sensitization, (3) increase dopamine levels in the nucleus accumbens (NAc), and (4) increase expression of the immediate early gene zif-268 in the striatum., Results: Conditioned place preference but not behavioral sensitization was reduced in EE mice compared to SE mice. Heroin induced similar increases in dopamine levels and in the expression of zif-268 in the NAc of EE and SE mice., Conclusions: The rewarding effects of heroin are blunted by EE and appear to be, at least in part, independent from activation of the mesolimbic system.

It is known that negative environmental conditions increase vulnerability to drugs, whereas little is known on whether positive environmental conditions such as enriched environments (EE) have protective effects against addiction. We have previously found that EE consisting of bigger cages containing several toys that were changed once per week reduce cocaine-induced increases in locomotor activity. Here, we also show that the rewarding effects of cocaine are blunted in mice reared from weaning to adulthood in EE compared to mice reared in standard environments (SE). In addition, although both EE and SE mice develop behavioral sensitization to cocaine, EE mice show less activation in response to repeated administration of cocaine injections and reduced responses to cocaine challenges. In vivo microdialysis experiments demonstrate that the protective effects of EE do not depend on reduced cocaine-induced increases in the dopamine levels in the ventral or dorsal striatum. On the other hand, they were associated with reduced cocaine-induced expression of the immediate early gene zif-268 in the nucleus accumbens (shell and core) of EE mice. Finally, basal levels of Delta-Fos B, a transcription factor known to be increased by sustained activation of striatal neurons, are higher in the striatum of EE compared to SE mice and repeated administration of cocaine increases Delta-Fos B levels in SE mice but decreases them in EE mice. Altogether our results demonstrate that exposure to complex environments during early stages of life produce dramatic changes in the striatum that result in reduced reactivity to drugs of abuse.

Environmental conditions can dramatically influence the behavioral and neurochemical effects of drugs of abuse. For example, stress increases the reinforcing effects of drugs and plays an important role in determining the vulnerability to develop drug addiction. On the other hand, positive conditions, such as environmental enrichment, can reduce the reinforcing effects of psychostimulants and may provide protection against the development of drug addiction. However, whether environmental enrichment can be used to "treat" drug addiction has not been investigated. In this study, we first exposed mice to drugs and induced addiction-related behaviors and only afterward exposed them to enriched environments. We found that 30 days of environmental enrichment completely eliminates behavioral sensitization and conditioned place preference to cocaine. In addition, housing mice in enriched environments after the development of conditioned place preference prevents cocaine-induced reinstatement of conditioned place preference and reduces activation of the brain circuitry involved in cocaine-induced reinstatement. Altogether, these results demonstrate that environmental enrichment can eliminate already established addiction-related behaviors in mice and suggest that environmental stimulation may be a fundamental factor in facilitating abstinence and preventing relapse to cocaine addiction.

We have previously shown that environmental enrichment decreases the activating and rewarding effects of the psychostimulant cocaine and increases resistance to the neurotoxic effect of the Parkinson-inducing drug MPTP. These effects were accompanied by an increase in the striatal expression of the neurotrophin BDNF, an increase in the striatal levels of delta-Fos B and by a decrease in striatal levels of the dopamine transporter, the main molecular target for cocaine and MPTP. Here, we used cDNA arrays to investigate the effects of rearing mice in enriched environments from weaning to adulthood on the profile of expression of genes in the striatum focusing on genes involved in intracellular signalling and functioning. We found that mice reared in an enriched environment show several alterations in the levels of mRNA coding for proteins involved in cell proliferation, cell differentiation, signal transduction, transcription and translation, cell structure and metabolism. Several of these findings were further confirmed by real-time quantitative PCR and, in the case of protein kinase C lambda, also by western blot. These findings are the first description of alterations in striatal gene expression by an enriched environment. The striatal gene expression regulation by environment that we report here may play a role in the resistance to the effects of drugs of abuse and dopaminergic neurotoxins previously reported.