Original articleWithdrawal from chronic amphetamine induces Depressive-Like behavioral effects in rodents
Introduction
Diminished interest or pleasure in rewarding stimuli (anhedonia) is one of the core symptoms of both depression and psychostimulant withdrawal (American Psychiatric Association 1994), which suggests that there are common neurobiological correlates underlying the manifestations of these disorders Barr et al, Lynch and Leonard 1978, Markou and Kenny, Markou et al 1998. Therefore, the characterization of the behavioral changes associated with withdrawal from drugs of abuse can be used as an animal model of the symptom of anhedonia with construct, convergent, and predictive validities Geyer and Markou 1995, Kokkinidis et al 1986. The use of the intracranial self-stimulation (ICSS) paradigm has provided investigators with a reliable and quantitative behavioral readout that enables the assessment of reduced brain reward function following withdrawal from various drugs of abuse, including cocaine (Markou and Koob 1991), amphetamine Harrison et al 2001, Kokkinidis et al 1980, Paterson et al 2000, ethanol (Schulteis et al 1995), morphine (Schulteis et al 1994), and nicotine Epping-Jordan et al 1998, Harrison et al 2001.
The forced swim test, as originally described by Porsolt et al 1977, Porsolt et al 1978, is the most widely used pharmacologic model for assessing antidepressant activity in the rodent laboratory, largely because of its ease of use, reliability across laboratories, and ability to detect a broad spectrum of antidepressants (Cryan et al 2002a). The development of immobility when rats are placed in an inescapable cylinder of water is thought to reflect either a failure of persistence in escape-directed behavior (i.e., behavioral despair) or the development of passive behavior that disengages the animal from active forms of coping with stressful stimuli (Lucki 1997).
Lucki and colleagues modified the traditional forced swim test Detke et al 1995, Lucki 1997 and demonstrated that the test reveals specific behavioral components of active behaviors—namely swimming, which is sensitive to serotonergic compounds such as the selective serotonin (5-HT) reuptake inhibitors and 5-HT receptor agonists, and climbing, which is sensitive to tricyclic antidepressants and drugs with selective effects on catecholaminergic transmission Cryan and Lucki 2000, Cryan et al 2002a, Cryan et al 2002b, Detke et al 1995. These modifications include increasing the water depth to 30 cm from traditional depths of 15–18 cm and using a time sampling technique to rate the predominant behavior over a 5-sec interval.
The tail suspension test is theoretically similar to the forced swim test and also has the ability to detect a broad spectrum of antidepressants Mayorga and Lucki 2001, Steru et al 1985. Briefly, mice (rats are rarely used) are suspended by their tails for 6 min, and the amount of time they adopt an immobile position is determined. Antidepressants reduce the time the animals are observed to be immobile. Although both the forced swim test and tail suspension test are similar in the constructs that they purport to assess, it is becoming clear that they are probably different in terms of the biological substrates that underlie the observed behaviors (Bai et al 2001). Accordingly, the use of both tests often can give both complementary and converging data on potential antidepressant drugs Bai et al 2001, Conti et al 2002, Porsolt 2000. One interpretation of the behavioral immobility observed in the forced swim and tail suspension tests is that immobility behavior allows for adaptive retraction from the inescapable stress of forced swimming or tail suspension, which is interrupted with bouts of escape-motivated activity. Together these alternating behavioral responses comprise a coping strategy (Thierry et al 1984) in which immobility behaviors represent the psychological concept of “entrapment” described in clinical depression Dixon 1998, Gilbert and Allan 1998, Lucki et al 2001.
Although both the forced swim and the tail suspension tests initially were introduced to detect the effects of antidepressant compounds, interventions known to be involved in the susceptibility or induction of major depression in humans induce an increase in immobility. These manipulations include a genetic predisposition (Vaugeois et al 1996), genetic alterations to noradrenergic Sallinen et al 1999, Schramm et al 2001 or opioid receptors (Filliol et al 2000), exposure to early life stressors (Papaioannou et al 2002) or to prenatal stress (Alonso et al 2000), pharmacologic alterations of noradrenergic neurotransmission (Stone and Quartermain 1999), being in the postpartum state (Galea et al 2001), or deprivation of dietary tryptophan (Blokland et al 2002). In addition, withdrawal from both morphine and phencyclidine, which in humans has been associated with depressive-like behavior, recently have been shown to increase immobility in the forced swim test in rats and mice respectively Anraku et al 2001, Noda et al 2000. Furthermore, increases in immobility in the forced swim test also have been reported in some models of depression such as the Flinders rat model (Overstreet et al 1995), neonatal clomipramine administration Hansen et al 1997, Velazquez-Moctezuma and Diaz Ruiz 1992, and social isolation (Heritch et al 1990), further supporting the use of this parameter to detect depressive-like behavior and indicating the etiologic validity of these paradigms (Geyer and Markou 1995).
Because psychostimulant withdrawal precipitates depressive-like behaviors in humans (Barr et al, in press), we investigated whether withdrawal from chronic amphetamine also can induce immobility in the forced swim and the tail suspension tests. We used a regimen of continuous amphetamine or saline exposure administered through subcutaneous osmotic minipumps. The minipumps were removed after 6–7 days of exposure to amphetamine, and the animals’ behavior in the ICSS procedure, the forced swim test, and the tail suspension tests was assessed. We hypothesized that withdrawal from chronic amphetamine administration would result in behavioral alterations with relevance to depression that would be detectable in all three paradigms tested. In the case of ICSS, we predicted an elevation in brain reward thresholds reflecting diminished interest in the rewarding electrical stimuli, whereas in both the modified forced swim and tail suspension tests, we expected an increase in immobility reflecting decreased active coping with the situation. As described earlier, both diminished interest or pleasure in rewarding stimuli and decreased active coping are constructs characterizing depression in humans.
Section snippets
Animals
Male Wistar rats (Charles River, Hollister, CA), weighing 275–350 g for the ICSS study and 175–225g (Charles River, Portage, IN) for the forced swim test study, were housed in pairs with food and water available ad libitum, except during testing, in a temperature and humidity controlled vivarium (21°C). Rats were maintained on a 12-hour reverse light–dark cycle with lights on at 6 pm. DBA/2Ha mice (Harlan, Dublin, VA) were used in the tail suspension test study and were housed in the same
ICSS thresholds
Administration of amphetamine (10 mg/kg/day) followed by its termination resulted in prolonged alterations in ICSS thresholds for the amphetamine-treated rats compared with saline-treated animals as indicated by a significant time × amphetamine administration interaction [F(15,240) = 13.964, p < .001]. Upon exposure to amphetamine, rats had significantly lower thresholds compared with saline-treated rats (p < .05). Upon pump removal, amphetamine-treated animals exhibited elevated brain reward
Discussion
Withdrawal from chronic amphetamine resulted in marked behavioral changes in all three paradigms that may be interpreted as behaviors that are analogous to aspects of depression. These changes include a pronounced elevation in ICSS thresholds and an increase in immobility in both the forced swim test at certain doses of amphetamine and the tail suspension test at all doses tested. These data indicate that psychostimulant-withdrawal-induced depression is a robust phenomenon that is detectable
Acknowledgements
This work was supported by a Novartis Pharma AG Research grant and National Institute of Mental Health Grant No. MH 62527 to AM. The authors thank Dr. Irwin Lucki, University of Pennsylvania, for his valuable input on the swim test and tail suspension test studies; Karen Skjei for technical assistance; and Mike Arends for editorial assistance. Also, we thank Dr. Peter H. Kelly, Novartis Pharma AG, for his helpful comments on the manuscript. This is publication 15011-NP from the Scripps Research
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