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

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Abstract

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 Because anxiety can interfere with the behavioral outcome of other tasks, amphetamine-withdrawn mice were also evaluated in the elevated plus maze.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 2.0 mg/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.

Highlights

►Amphetamine withdrawal decreased novelty-seeking behavior in mice. ►Amphetamine withdrawal enhanced environmental habituation in mice. ►Amphetamine withdrawal did not modify anxiety-like behavior in mice. ►The results are thought to be due to psychostimulant withdrawal-induced anhedonia.

Introduction

Drug withdrawal syndrome is a common problem among addicts. For example, approximately 87% of the amphetamine (Amp) users report withdrawal symptoms (Srisurapanont et al., 2001). For this reason, understanding the mechanisms that underlie drug withdrawal, as well as the behavioral alterations that occur during this state, is relevant, particularly because the intense craving related to this process may be a critical factor leading to relapse.

Amp withdrawal has been much less studied than cocaine, ethanol and opiate withdrawal, but an increasing interest on the part of clinicians and researchers in characterizing Amp withdrawal has been observed in recent decades (Kitanaka et al., 2008, McGregor et al., 2005). In humans, Amp increases arousal, reduces fatigue and appetite and induces hyperactivity, mood elevation as well as euphoria when taken acutely (Drevets et al., 2001, D'Souza and Markou, 2010). With repeated use, tolerance to those effects develops and increasing amounts of the drug must be taken to maintain the individual's mood (Brauer et al., 1996, Schenk and Partridge, 1997). Consequently, compulsive and uncontrolled drug intake occurs (Everitt and Robbins, 2005, Koob and Le Moal, 1997, Robinson and Berridge, 2008). Eventually, drug intake ceases, and the individual experiences the effects of psychostimulant withdrawal (Koob et al., 1997). The DSM-IV description of stimulant withdrawal requires cessation of cocaine or Amp followed by a dysphoric mood, typified by sadness or anhedonia, and at least two of the physiological changes, such as fatigue, sleep alteration, psychomotor agitation, drug craving, increased appetite, psychomotor retardation and vivid, unpleasant dreams (American Psychiatric Association, 2000). Amp withdrawal, particularly, has been reported to peak within a few days, with the most characteristic symptom being depression with occasional suicidal ideation (Lago and Kosten, 1994). In this regard, anhedonia is a core symptom of this depressive state (Barr et al., 2002, D'Souza and Markou, 2010) and is defined as a markedly diminished interest or pleasure in all or most activities, even those which are rewarding (Gardner, 2000, Kitanaka et al., 2008).

The small number of studies on Amp withdrawal along with the absence of clear-cut physical withdrawal symptoms makes it difficult to demonstrate conclusively the presence of Amp withdrawal as seen with other drugs. Clinical results on Amp withdrawal are conflicting, most likely due to differences between inpatient and outpatient samples (for example, outpatients may have used the drug and been exposed to drug-related stimuli) (Lago and Kosten, 1994). Therefore, there has been growing concern over the relevance of valid and reliable animal models that express the behavioral consequences of Amp withdrawal. It has proven very difficult to model all symptoms of withdrawal from not only Amp but all drugs of abuse in humans using one animal model (Kokkinidis et al., 1986, Murphy et al., 2001, Russig et al., 2003).

Animal models of Amp withdrawal focus on the dysphoric state associated with it, which is most commonly evaluated in rodents by a reduction in response to reward brain stimulation (Cassens et al., 1981, Kokkinidis et al., 1980, Leith and Barrett, 1976, Leith and Barrett, 1980, Lin et al., 1999, Markou and Koob, 1991, Wise and Munn, 1995) or natural rewards (Barr and Phillips, 1999, Barr and Phillips, 2002, Barr et al., 1999, Barr et al., 2002). Previous reports have also demonstrated decreases in several motivational components of sexual behavior after withdrawal from repeated treatment with Amp in rats (see D'Souza and Markou, 2010, Kitanaka et al., 2008 for recent reviews). Importantly, few reports are available regarding the behavioral aspects of Amp withdrawal in mice (Cryan et al., 2003, Kokkinidis et al., 1986), an animal species particularly useful for the study of gene expression.

More recently, novelty reward has been proposed as a putative measure of anhedonia in rats (Besheer and Bevins, 2003, Bevins and Besheer, 2005) because withdrawal from nicotine blocked the acquisition of conditioned place preference for novel objects (Besheer and Bevins, 2003). As for Amp, there are some indirect evidence of decreased novelty reward in Amp-withdrawn rats. Indeed, Amp withdrawal impaired novel object recognition (Bisagno et al., 2005, Schreiber et al., 1976) and decreased spontaneous locomotion in a novel experimental context (Russig et al., 2005). However, Amp withdrawal has also been reported to decrease spontaneous locomotion in previously habituated experimental contexts (Paulson et al., 1991), which could cause both decreased locomotion in novel environments and decreased novel object recognition. Within this context, it would be relevant to investigate the behavior of Amp-withdrawn rodents in more specific tasks related to novelty responses, such as within-session locomotor habituation and novelty-induced place preference, which have not been previously investigated in rats or mice. This study was aimed to evaluate the effects of withdrawal from Amp on these two tasks concomitantly in mice. Because enhanced anxiety has already been linked controversially to Amp withdrawal (see Lago and Kosten, 1994) and can interfere with the behavioral readout of other tasks, elevated plus-maze performance was also investigated during Amp withdrawal.

Section snippets

Subjects

Three-month-old Swiss EPM-M1 male mice (40–45 g) from our own colony were used. The animals were housed, 10–13 per cage, in polypropylene cages (32 cm × 42 cm × 18 cm) under conditions of controlled temperature (22–23 °C) and lighting (12/12 h light/dark, lights on at 06:45 h). Food and water were available ad libitum throughout the experiment.

The experimental protocol was approved by the committee for the use of animal subjects from our Institution (Universidade Federal de São Paulo, UNIFESP, CEP No.

Experiment 1. Effects of withdrawal from repeated treatment with Amp on novelty-seeking behavior and environmental habituation in mice

Mice were randomly allocated to two groups: Sal (N = 11) and Amp (N = 12). All animals were individually confined to one of the main compartments of the free-choice novelty apparatus (“familiar” compartment) for 20 min a day on three consecutive days. After 24 h, repeated treatment with saline or 2.0 mg/kg Amp commenced. Animals received an intraperitoneal (i.p.) injection of saline (Sal) or 2.0 mg/kg Amp (Amp) for 13 days, every other day, in their home cages (a total of seven injections of Sal or

Data analysis

ANOVAs with repeated measures (compartment vs. drug treatment and time vs. drug treatment) were used. Multiple comparisons were performed using the t-test for paired samples, Student's t-test or Duncan's post hoc test. A p-value less than 0.05 was considered as a statistically significant difference.

Experiment 1. Withdrawal from repeated treatment with Amp reduces novelty-seeking behavior and enhances environmental habituation in mice

Fig. 1 shows the time mice spent in the familiar and the novel compartments 24 h after withdrawal from repeated treatment with saline or Amp. ANOVA with repeated measures revealed significant effects due to the compartment (familiar vs. novel) [F(1,21) = 6.7, p < 0.05] as well as a significant interaction between compartment (familiar vs. novel) and drug treatment (Sal vs. Amp) [F(1,21) = 4.7, p < 0.05]. The t-test for paired samples showed that the Amp (but not the Sal) group presented a significant

Discussion

In the present study, we demonstrated that withdrawal from repeated treatment with Amp decreased novelty-seeking behavior and increased environmental habituation in mice, without concurrent changes in anxiety-like behavior.

Importantly, we have previously shown that the dose and protocol of repeated treatment with Amp used in the present paper are effective in inducing behavioral sensitization in mice (Araujo et al., 2006, Costa et al., 2001, Fukushiro and Frussa-Filho, 2011). The

Conclusions

In conclusion, by using novelty-seeking behavior and environmental habituation we could concomitantly evaluate the anhedonia that develops during Amp withdrawal. From a clinical point of view, as pointed out by Kitanaka et al. (2008), medication for treatment of the dysphoric state is important for Amp abusers to avoid impulsive self-injurious acts that are committed with unconscious on uncontrolled suicidal ideation. However, successful treatments for anhedonia induced by Amp withdrawal remain

Acknowledgements

This research was supported by fellowships from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP), from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), from Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), from Fundo de Apoio ao Docente e Aluno (FADA) and from Associação Fundo de Pesquisa em Psicobiologia (AFIP). This manuscript was edited for English language by American Journal Experts (AJE), but we are entirely responsible for

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    Financial support: CNPq, FAPESP, CAPES, FADA, AFIP.

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