Differential effects of intermittent and continuous exposure to novel environmental stimuli on the development of amphetamine-induced behavioral sensitization in mice: implications for addiction.

BACKGROUND: Previous studies have demonstrated a preventive effect of continuous environmental enrichment during early development on the vulnerability of rodents to drug addiction-related behaviors. Recently, it was demonstrated that a continuous environmental enrichment could eliminate already established addiction-related behaviors in mice. The present study compared the effects of intermittent or continuous exposure to novel stimuli during repeated amphetamine (Amp) treatment on the development of behavioral sensitization (an animal model of addiction-related neuroadaptations) in adult mice. METHODS: Three-month-old male Swiss mice were treated with 2.5mg/kg Amp every other day for 13 days in their home cages. Novel objects were presented in their home cages for 2h on non-drug treatment days (experiment 1) or for 24h/day during the 13 days of drug treatment (experiment 2). Seven days after the drug treatment had finished, the mice were challenged with 2.5mg/kg Amp, and their locomotor activity was quantified in a familiar open field for 10 min. RESULTS: Intermittent exposure to the novel objects did not modify the acute Amp locomotor stimulatory effect but potentiated the development of Amp-induced locomotor sensitization. This enhanced sensitization was due to increased locomotion in the central squares of the apparatus, which suggests anxiolysis or increased impulsiveness. Conversely, continuous exposure to the novel objects potentiated the acute Amp locomotor stimulatory effect and blunted the development of Amp-induced locomotor sensitization. CONCLUSIONS: We conclude that addiction-related behaviors can be differentially and critically modified depending on the schedule and period of the novelty exposure.

Withdrawal from repeated treatment with ethanol induces a protracted decrease in novelty-seeking behavior and enhancement of environmental habituation in mice.

Ethanol withdrawal syndrome is characterized by somatic and behavioral symptoms, including increased anxiety and anhedonia. In animal models, however, there are many studies on the anxiogenic effects occurring during the first 24h after ethanol withdrawal, while anhedonia has been overlooked. Recently, we have found that amphetamine withdrawal reduced novelty seeking and enhanced environmental habituation in mice, two motivation-related behaviors. We now investigate the effects of withdrawal from ethanol, a drug of abuse with a different pharmacological profile, on these two motivation-related behaviors. Swiss male mice (3months old) were treated with 1.8g/kg ethanol for 21 consecutive days in their home cages. Seven days after ethanol withdrawal, mice were tested in a free-choice novelty apparatus containing one familiar and one novel compartment. Novelty-seeking behavior was assessed by comparing time spent in the novel compartment versus the familiar compartment, whereas environmental habituation was concomitantly evaluated by the time-response curve of total locomotion (novel+familiar). Novelty seeking was decreased and environmental habituation was enhanced during ethanol withdrawal. These anhedonic responses were not associated with concurrent changes in the anxiety-like behavior of mice (as confirmed in the elevated plus-maze test). We propose that the concomitant evaluation of novelty-seeking behavior and environmental habituation can be useful to study the behavioral consequences not only of amphetamine withdrawal but also of ethanol withdrawal. Furthermore, the present data support recent clinical findings that suggest the occurrence of protracted anhedonia well beyond the limited period immediately following the abrupt cessation of ethanol intake.

Acute and chronic ethanol differentially modify the emotional significance of a novel environment: implications for addiction.

Using open-field behaviour as an experimental paradigm, we demonstrated a complex interaction between the rewarding/stimulating effects and the anxiogenic/stressful effects of both novelty and acute or chronic amphetamine in mice. As a consequence of this interaction, acute amphetamine-induced hyperlocomotion was inhibited, whereas the expression of its sensitization was facilitated in a novel environment. In the present study, we aimed to investigate the interactions between exposure to a novel environment and the acute and chronic effects of ethanol (Eth), a drug of abuse known to produce anxiolytic-like behaviour in mice. Previously habituated and non-habituated male Swiss mice (3 months old) were tested in an open field after receiving an acute injection of Eth or following repeated treatment with Eth. Acute Eth administration increased locomotion with a greater magnitude in mice exposed to the apparatus for the first time, and this was thought to be related to the attenuation of the stressful effects of novelty produced by the anxiolytic-like effect of acute Eth, leading to a subsequent prevalence of its stimulant effects. However, locomotor sensitization produced by repeated Eth administration was expressed only in the previously explored environment. This result might be related to the well-known tolerance of Eth-induced anxiolytic-like behaviour following repeated treatment, which would restore the anxiogenic effect of novelty. Our data suggest that a complex and plastic interaction between the emotional and motivational properties of novelty and drugs of abuse can critically modify the behavioural expression of addiction-related mechanisms.

Withdrawal from repeated treatment with amphetamine reduces novelty-seeking behavior and enhances environmental habituation in mice.

Anhedonia associated with a dysphoric state is an important feature of amphetamine withdrawal in humans. We aimed to investigate the effects of amphetamine withdrawal on two motivation-related behaviors in mice: novelty seeking and environmental habituation. Because anxiety can interfere with the behavioral outcome of other tasks, amphetamine-withdrawn mice were also evaluated in the elevated plus maze. Swiss male mice (three months old) were treated with 2.0mg/kg amphetamine for 13 days, every other day, in their home cages (a total of seven injections). Twenty-four hours after withdrawal from drug treatment, mice were tested in a free-choice novelty apparatus containing one familiar and one novel compartment or in the elevated plus maze. Novelty-seeking behavior was assessed by comparing the time spent in the novel compartment vs. the familiar compartment, whereas environmental habituation was concomitantly evaluated by the time-response curve of total locomotion (novel+familiar). Novelty seeking was decreased during amphetamine withdrawal, and this result was not associated with changes in the anxiety-like behavior of mice. Additionally, amphetamine withdrawal enhanced environmental habituation. The concomitant decrease in novelty seeking and the increase in environmental habituation seem to be related to amphetamine withdrawal-induced anhedonia. Thus, the model proposed here could be used as a tool for the study of mechanisms and potential treatment of the anhedonic behavioral consequences of psychostimulant withdrawal.

Environmental novelty and illumination modify ethanol-induced open-field behavioral effects in mice.

Both spontaneous and drug-induced animal behaviors can be modified by exposure to novel stimuli or different levels of environmental illumination. However, research into how these factors specifically impact ethanol (ETH)-induced behavioral effects is currently lacking. We aimed to investigate the effects of these two factors, considered separately or in conjunction, on ETH-induced acute hyperlocomotor effect and its sensitization in adult male Swiss mice. Mice were placed in a novel or familiar open-field under normal light (200 lx) or low light (9 lx) immediately after receiving an ip injection of either 1.8 g/kg ETH or saline (SAL). After 7 days, all animals received an ip challenge injection of 1.8 g/kg ETH, and were placed in the open-field under the same light conditions described above. Novelty increased central locomotion and decreased grooming, while low light increased grooming. Acute ETH administration increased both total and peripheral locomotion and these effects were potentiated by low light. Both low light and novelty were able to facilitate ETH-induced locomotor sensitization, which was detected by the central locomotion parameter. However, there was no synergism between the effects of these two modulating factors on ETH-induced behavioral sensitization. We conclude that both the acute behavioral effects of ETH and behavioral sensitization induced by previous administration of this drug can be critically modified by environmental factors. In addition, our study stresses the importance of using different behavioral parameters to evaluate the interaction between environmental factors and ETH effects.